Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
Neo-adjuvant SABR for IVC Tumor Thrombus in Newly Diagnosed RCC
To evaluate the safety and feasibility of pre-operative SABR of RCC IVC tumor thrombus.
To evaluate the effect of pre-operative SABR in RCC IVC tumor thrombus on relapse free
survival at one year.
1. Radiographic evidence of renal cancer with IVC tumor thrombus
2. Tumor thrombus must be ≥ level II (As per Mayo classification, it would be ≥ level I
[Refer to NEVES, R. and ZINCKE, H. (1987), Surgical Treatment of Renal Cancer with
Vena Cava Extension. British Journal of Urology, 59: 390-395.
doi:10.1111/j.1464-410X.1987.tb04832.x])
3. Patient eligible for SABR to the IVC tumor thrombus as decided by the treating
radiation oncologist
4. Patient eligible for IVC tumor thrombectomy as decided by the treating urologist
5. Any number of metastatic disease is allowed in the Pilot phase of the trial
• For Phase II, metastatic patients will be allowed only if all sites of metastasis
has been treated either surgically or radio-surgically (If limited sites of metastasis
are present, all of which can be resected during the nephrectomy, then the patient can
be eligible)
6. Age ≥ 18 years.
7. Performance status ECOG 0-2
8. Any serum Albumin is allowed, but ≥ 3.4 g/dL is strongly encouraged
• Serum albumin <3.4 is a significant predictor of peri-operative mortality(12)
9. Any serum AST is allowed but serum AST ≤ 34 IU/L is strongly encouraged
• Significant predictor of mortality in univariate but not multivariate analysis(12)
10. Women of childbearing potential and men must agree to use adequate contraception
(hormonal such as birth control pills, patch or ring; Depo-Provera, Implanon or
barrier method, such as condom or diaphragm used with a spermicide of birth control;
abstinence) prior to study entry, for the duration of study treatment, and for 90 days
following completion of radiation therapy. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.
10.1 A female of childbearing potential is any woman (regardless of sexual
orientation, marital status, having undergone a tubal ligation, or remaining celibate
by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
11. Ability to understand and the willingness to sign a written informed consent.
12. Subjects must be able to undergo either MRI or CT.
Exclusion Criteria:
1. Subjects who have had radiotherapy to a target within 3 cm of the IVC tumor thrombus.
2. Subjects may have received any other investigational agents or chemotherapy as long as
they are eligible for SABR and surgery
3. Subjects with brain metastases should be excluded from this clinical trial unless all
the metastasis are treated surgically or radio-surgically
4. Subjects with a history of pulmonary embolism is excluded
5. Subjects with a history of pulmonary hypertension is excluded
6. Subjects must not be pregnant due to the potential for congenital abnormalities.
7. Contraindication for contrast-enhanced MRI as defined by the standard operating
procedures of the Department of Radiology at UT Southwestern. Briefly, these include
medically unstable; cardiac pacemaker; intracranial clips, metal implants; metal in
the eyes; pregnant or nursing; claustrophobia; and impairment of the renal function
with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2. Patients with one
or more of these contraindications but eligible to undergo contrast-enhanced CT can
participate in this study and will not receive an MRI
89Zr-DFO-Atezolizumab ImmunoPET/CT in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma
This is an exploratory clinical trial to assess the potential of 89Zr-DFO-Atezolizumab
Positron Emission Tomography/Computed Tomography (PET/CT) scans in patients with locally
advanced or metastatic renal cell carcinoma (RCC). This open label, nontherapeutic trial will
test the correlation of 89Zr-DFO-Atezolizumab immunoPET/CT with programmed death-ligand 1
(PD-L1) expression and the response to immune checkpoint inhibitor therapy in patients with
RCC. There will be two cohorts, one made up of patients with localized RCC who will undergo
89Zr-DFO-Atezolizumab PET/CT prior to nephrectomy and a second cohort of patients with
metastatic RCC who will undergo 89Zr-DFO-Atezolizumab PET/CT prior to treatment with an
immune checkpoint inhibitor.
• Patients with suspected renal cell carcinoma with planned surgery or patients with
metastatic RCC and a tissue diagnosis. (In standard clinical practice, biopsy is not
routinely performed in patients who will be having surgery).
• Ability to understand and the willingness to sign a written informed consent.
• Patient must be able to lie still for a 30 to 60 minute PET/CT scan.
• One of the following:
1. Patients with locally advanced RCC planned for surgery determined to be a high
risk of recurrence, defined by presence of at least clinical T2 or thioredoxin 1
(TxN1), OR patients with metastatic RCC for whom treatment with metastasectomy is
planned by the treating physician.
2. Patients with metastatic RCC for whom immuno-oncology (IO) therapy is planned.
• Women of child-bearing potential must agree to undergo and have documented a negative
pregnancy test on the day of 89Zr-DFO-Atezolizumab administration. A female of
child-bearing potential is any woman (regardless of sexual orientation, having
undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
Exclusion Criteria:
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to
atezolizumab or any other chimeric or humanized antibodies.
• Uncontrolled severe and irreversible intercurrent illness or psychiatric
illness/social situations that would limit compliance with study requirements.
• Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
• Significant autoimmune disease requiring treatment with either prednisone (or steroid
equivalent) at a dose > 10 mg/day or other immunosuppressive agents. (Replacement
steroid therapy is acceptable).
• Any patient for whom ICI therapy would be contraindicated for other reasons. Patients
with adverse reactions to ICI therapy may undergo second 89Zr-DFO-Atezolizumab
injection and PET/CT at the discretion of the treating physician considering that the
dose of antibody represents 1% of a single therapeutic dose and therefore unlikely to
cause adverse events.
• Subjects unable to provide informed consent.
• Subjects who are claustrophobic or have other contraindications to PET/CT.
• Subjects must not weigh more than the maximum weight limit for the table for the
PET/CT scanner where the study is being performed. (>200 kg or 440 lbs).
Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)
Substudy 03A is part of a larger research study that is testing experimental treatments for
renal cell carcinoma (RCC). The larger study is the umbrella study (U03).
The goal of substudy 03A is to evaluate the safety and efficacy of experimental combinations
of investigational agents in participants with advanced first line (1L) clear cell renal cell
carcinoma (ccRCC).
This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety
lead-in phase will be used to demonstrate a tolerable safety profile for the combination of
investigational agents. There will be no hypothesis testing in this study.
• Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
• Has received no prior systemic therapy for advanced RCC; prior neoadjuvant/adjuvant
therapy for RCC is acceptable if completed ≥12 months before randomization/allocation
• Is able to swallow oral medication
• Has adequate organ function
• Participants receiving bone resorptive therapy must have therapy initiated at least 2
weeks before randomization/allocation
• Has resolution of toxic effects of the most recent prior therapy to ≤Grade 1
• If participants receive major surgery or radiation therapy, they must have recovered
from complications from the intervention
• Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change in
hypertensive medications within 1 week before randomization/allocation
• Male participants are abstinent from heterosexual intercourse or agree to use
contraception during treatment with and for at least 7 days after the last dose of
lenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped,
if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab,
favezelimab/pembrolizumab or a combination of the aforementioned drugs, no
contraception is needed
• Female participant is not pregnant or breastfeeding and is not a woman of childbearing
potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using
contraception during the intervention period and for at least 120 days after the last
dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab for 30
days after the last dose of lenvatinib or belzutifan, whichever occurs last
Exclusion Criteria:
• Has urine protein ≥1 g/24 hours and has any of the following: (a) hypoxia defined as a
pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen,
or (c) requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 12 months from the first dose
of study intervention administration
• Has had major surgery within 3 weeks before first dose of study interventions
• Has a history of lung disease
• Has a history of inflammatory bowel disease
• Has preexisting gastrointestinal (GI) or non-GI fistula
• Has malabsorption due to prior GI surgery or disease
• Has received prior radiotherapy within 2 weeks of start of study intervention
• Has received a live or live attenuated vaccine within 30 days before the first dose of
study drug; killed vaccines are allowed
• Has received more than 4 previous systemic anticancer treatment regimens
• Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive
therapy within 7 days prior to the first dose of study intervention
• Has known additional malignancy that is progressing or has required active treatment
within the past 3 years
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2
years; replacement therapy is not considered a form of systemic treatment and is
allowed
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B
• Has had an allogenic tissue/solid organ transplant
A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)
The goal of this study is to evaluate the efficacy and safety of pembrolizumab plus
belzutifan plus lenvatinib or pembrolizumab/quavonlimab plus lenvatinib versus pembrolizumab
plus lenvatinib as first-line treatment in participants with advanced clear cell renal cell
carcinoma (ccRCC).
The primary hypotheses are (1) pembrolizumab plus belzutifan plus lenvatinib is superior to
pembrolizumab plus lenvatinib with respect to progression-free survival (PFS) and overall
survival (OS), in advanced ccRCC participants and (2) pembrolizumab/quavonlimab plus
lenvatinib is superior to pembrolizumab plus lenvatinib with respect to PFS and OS, in
advanced ccRCC participants.
• Has histologically confirmed diagnosis of RCC with clear cell component
• Has received no prior systemic therapy for advanced ccRCC
• Male participants are abstinent from heterosexual intercourse or agree to use
contraception during and for at least 7 days after last dose of study intervention
with belzutifan and lenvatinib
• Female participants are not pregnant or breastfeeding and are either not a woman of
child-bearing potential (WOCBP) or use a contraceptive method that is highly effective
or are abstinent from heterosexual intercourse during the intervention period and for
at least 120 days after pembrolizumab or pembrolizumab/quavonlimab or for at least 30
days after last dose of lenvatinib or belzutifan, whichever occurs last
• Has adequately controlled blood pressure with or without antihypertensive medications
• Has adequate organ function
• Participants receiving bone resorptive therapy must have therapy initiated at least 2
weeks prior to randomization/allocation
Exclusion Criteria:
• Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years
• Has had major surgery, other than nephrectomy within 4 weeks prior to randomization
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has received prior radiotherapy within 2 weeks prior to first dose of study
intervention
• Has hypoxia or requires intermittent supplemental oxygen or requires chronic
supplemental oxygen
• Has clinically significant cardiac disease within 12 months from first dose of study
intervention
• Has a history of interstitial lung disease
• Has symptomatic pleural effusion; a participant who is clinically stable following
treatment of this condition is eligible
• Has preexisting gastrointestinal or non-gastrointestinal fistula
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of study treatment
• Has a known psychiatric or substance abuse disorder that would interfere with
requirements of the study
• Has received a live or live-attenuated vaccine within 30 days before the first dose of
study drug; killed vaccines are allowed
• Has an active autoimmune disease that has required systemic treatment in the past 2
years
• Has a history of noninfectious pneumonitis that required steroids or has current
pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B
• Has radiographic evidence of intratumoral cavitation, encasement or invasion of a
major blood vessel
• Has clinically significant history of bleeding within 3 months prior to randomization
• Has had an allogenic tissue/solid organ transplant
Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B)
Substudy 03B is part of a larger research study that is testing experimental treatments for
renal cell carcinoma (RCC). The larger study is the umbrella study (U03).
The goal of substudy 03B is to evaluate the safety and efficacy of experimental combinations
of investigational agents in participants with advanced second line plus (2L+) clear cell
renal cell carcinoma (ccRCC).
This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety
lead-in phase will be used to demonstrate a tolerable safety profile for the combination of
investigational agents. There will be no hypothesis testing in this study.
• Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
• Has experienced disease progression on or after having received systemic treatment for
locally advanced or metastatic RCC with a PD-(L)1 checkpoint inhibitor (in sequence or
in combination with a vascular endothelial growth factor •tyrosine kinase inhibitor
[VEGF-TKI]) where PD-(L)1 checkpoint inhibitor treatment progression is defined by
meeting ALL of the following criteria: (a) has received ≥2 doses of an anti-PD-(L)1
monoclonal antibody (mAb) (b) has shown radiographic disease progression during or
after an anti-PD-(L)1 mAb as defined by RECIST 1.1 by investigator (c) disease
progression has been documented within 12 weeks from the last dose of an anti-PD-(L)1
mAb
• Has experienced disease progression on or after having received systemic treatment for
locally advanced or metastatic RCC with a VEGF-TKI (in sequence or in combination with
a PD-[L]1 checkpoint inhibitor) where VEGF-TKI treatment progression is defined by
meeting the following criterion: has shown radiographic disease progression during or
after a treatment with a VEGF-TKI as defined by RECIST 1.1 by investigator
• Is able to swallow oral medication
• Has adequate organ function
• Participants receiving bone resorptive therapy must have therapy initiated at least 2
weeks before randomization/allocation
• Has resolution of toxic effects of the most recent prior therapy to ≤Grade 1
• If participants receive major surgery or radiation therapy, they must have recovered
from complications from the intervention
• Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change in
hypertensive medications within 1 week before randomization/allocation
• Male participants are abstinent from heterosexual intercourse or agree to use
contraception during treatment with and for at least 7 days after the last dose of
lenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped,
if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab,
favezelimab/pembrolizumab, MK-4830 or a combination of the aforementioned drugs, no
contraception is needed
• Female participant is not pregnant or breastfeeding and is not a woman of childbearing
potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using
contraception during the intervention period and for at least 120 days after the last
dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab, MK-4830
or 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last
Exclusion Criteria:
• Has urine protein ≥1 g/24 hours and has any of the following: (a) hypoxia defined as a
pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen,
or (c) requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 12 months from the first dose
of study intervention administration
• Has had major surgery within 3 weeks before first dose of study interventions
• Has a history of lung disease
• Has a history of inflammatory bowel disease
• Has preexisting gastrointestinal (GI) or non-GI fistula
• Has malabsorption due to prior GI surgery or disease
• Has previously received treatment with a combination of pembrolizumab plus lenvatinib
• Has received prior treatment with belzutifan
• Has received prior radiotherapy within 2 weeks of start of study intervention
• Has received a live or live attenuated vaccine within 30 days before the first dose of
study intervention; killed vaccines are allowed
• Has received more than 4 previous systemic anticancer treatment regimens
• Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive
therapy within 7 days prior to the first dose of study intervention
• Has known additional malignancy that is progressing or has required active treatment
within the past 3 years
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2
years; replacement therapy is not considered a form of systemic treatment and is
allowed
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B
• Has had an allogenic tissue/solid organ transplant
Non-Contrast Perfusion Using Arterial Spin Labeled MR Imaging for Assessment of Therapy Response in Metastatic Renal Cell Carcinoma
Magnetic Resonance Imaging (MRI) including Arterial Spin Labeling (ASL) will be performed
before, during, and after the treatment, in a total of up to 6 MRI sessions until 7 months
after the first session, or when progression is clinically indicated. Thereafter, patients
will be followed through standard clinical examinations for the next 3 years or until demise,
whichever occurs first.
Clinically, metastatic renal cell carcinoma (RCC) patients are imaged every 2-3 months after
the initiation of anti-angiogenic therapy, since morphological (i.e. size) changes are not
anticipated earlier. However, our preliminary experience has shown functional changes
including perfusion as early as 2-weeks after the initiation of the treatment. T0, T1, and T2
sessions will be performed for this proposal, while T3, T4, and T5 will be performed along
with the clinical imaging sessions. All MR imaging sessions will be scheduled within ±1 or ±2
weeks of the target time period.
The research MR imaging may take approximately an additional 15 minutes per each imaging
session, when done in conjunction with the clinical imaging. The T0, T1, and T2 research MR
imaging sessions will be performed additionally for the purpose of this study, with each
taking approximately one hour.
• Patients with locally advanced or metastatic renal cell carcinoma.
• Patients scheduled to undergo anti-angiogenic treatment or immunotherapy
• Eastern Cooperative Oncology Group (ECOG) Status 0, 1 and 2.
• Women of child-bearing potential must agree to undergo a urine pregnancy screening per
standard Radiology departmental protocol, in place to prevent imaging of pregnant
patients. A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria: 1) Has not undergone a hysterectomy or bilateral
oophorectomy; or 2) Has not been naturally postmenopausal for at least 12 consecutive
months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
• Subjects may not be receiving any other anti-angiogenic agents, at the time of
enrollment.
• Subjects must not be pregnant since pregnancy is a contraindication to administration
of gadolinium-based contrast agents.
• Any contraindication to MRI per Radiology Department's routine protocol, e.g.
MRI-incompatible objects, including but not limited to medical devices (e.g.
pacemakers, automated implantable cardioverter defibrillators, etc.) and other foreign
bodies.
• Known severe allergic reaction to Gadolinium-based contrast agents.
• Patients with sickle cell disease and patients with other hemolytic anemias (low red
blood count in body).
• Patients with uncontrollable claustrophobia, severe lower back pain, and
uncontrollable tremors, to the point that it would render them unable to tolerate an
MRI study.
Procedure: MRI with ASL
Renal Cell Carcinoma, Kidney
magnetic resonance imaging, arterial spin labeling
Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC
This research study will assess whether cabozantinib, nivolumab and ipilimumab in combination
are safe and effective in slowing down the growth of kidney cancer(renal cell carcinoma or
RCC) that has advanced or spread to other areas the body.
• histologically or cytologically confirmed unresectable advanced or metastatic nccRCC,
including but not limited to:
• Papillary RCC, any type
• Unclassified RCC
• Translocation RCC
• Chromophobe RCC
• Collecting duct RCC
• Medullary RCC
• Renal cell carcinoma with 80% or more sarcomatoid features on primary nephrectomy
specimen or a biopsy
• Other nccRCC histologies
• Measurable disease as per RECIST 1.1. See Section 11 for the evaluation of measurable
disease.
• Age ≥ 18 years
• ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A)
• Participants must undergo fresh tumor biopsy after registration but prior to the start
of treatment unless medically unsafe or not feasible. If a fresh tumor biopsy is not
medically safe or not feasible, confirmation of the availability of archival tumor
tissue is required. For archival tissue, a recommended minimum of 20 unstained slides
should be obtained.
• Normal organ and marrow function as defined below:
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• hemoglobin ≥9g/dL (transfusions allowed)
• total bilirubin ≤2.0 x institutional upper limit of normal with the following
exception: patients with known Gilbert disease should have a serum bilirubin ≤ 3
x ULN
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal with the following
exception: patients with known liver metastases should have AST and ALT ≤ 5 x ULN
• creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault equation.
• Normal coagulation INR ≤ 1.5
• Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
5 months after the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 7 months after completion of cabozantinib,
nivolumab or ipilimumab administration.
• Ability to understand and willingness to sign a written informed consent document
Exclusion Criteria:
•Patients could be untreated or have received prior lines of therapies. Patients who
receive prior therapy may receive only one VEGF based therapy. A combination therapy (e.g.
lenvatinib+everolimus) is considered 1 line of therapy.
• Previous therapy with CD137 agonists and immune checkpoint inhibitors, including but
not limited to inhibitors of the PD-1/PD-L1 and/or CTLA-4 axes. Previous treatment
with IFNα or IL-2 is allowed if received > 4 weeks from enrollment.
• Treatment with small molecule tyrosine kinase inhibitors within 2 weeks of enrollment,
or any other anticancer agent within 4 weeks of enrollment.
• Prior therapy with cabozantinib
• Patients receiving any other therapeutic investigational agents.
• Treatment with hydroxychloroquine within two weeks of treatment start.
• Radiotherapy for nccRCC within 14 days of first study treatment with the exception of
a single fraction of radiation administered for palliation of symptoms.
• Untreated brain metastases. Patients might be included if they underwent radiation
therapy or surgery at least 4 weeks prior enrollment. Stability of the central nervous
system disease should be confirmed by brain MRI or CT-scan or as determined by
treating investigator. Patients should not be receiving prednisone dose >10 mg/d at
C1D1.
• Other malignancy diagnosed within 2 years of first study treatment unless negligible
risk of metastases or death (included but not limited to carcinoma in situ of the
cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal
carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma, or other
malignancy not deemed to impact patients 5-year life expectancy).
• Significant cardiovascular disorders including:
• Significant cardiovascular disease including dyspnea of New York Heart
Association (NYHA) class II or greater, myocardial infarction within the previous
3 months of first study treatment, unstable arrhythmias, unstable angina.
Patients with known coronary artery disease or congestive heart failure not
meeting the above criteria, or left ventricular ejection fraction < 50%, must be
on a stable and optimized in the opinion of the treating physician, in
consultation with a cardiologist when appropriate.
• Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or
diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy is allowed.
• Personal history of hypertensive crisis or hypertensive encephalopathy within the
previous 3 months of registration.
• Personal history of stroke or transient ischemic attack within 3 months of
registration.
• Significant vascular disease, such as but not limited to aortic aneurysm
requiring surgical repair or recent peripheral arterial thrombosis, within 6
months of registration.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG). Furthermore, subjects with a history of additional risk
factors for torsades de pointes (eg, long QT syndrome) are also excluded.
• Known history of severe allergic reactions attributed to compounds of similar chemical
or biologic composition human antibodies, or known hypersensitivity to any component
of cabozantinib, nivolumab or ipilimumab products.
• Systemic immunosuppressive medications including but not limited to: Corticosteroids
at a dose > 10mg equivalent prednisone daily, cyclosporin, azathioprine, methotrexate,
thalidomide, anti-tumor necrosis factor (TNF) agents, hydroxychloroquine, within 2
weeks of first study dose.
• Patients who have received acute, low-dose systemic immunosuppressant medications
may be enrolled.
• Patients with adrenal insufficiency on physiologic replacement doses of steroids
may be enrolled.
• The use of inhaled, topical, intraocular, or intraarticular corticosteroids or
mineralocorticoids are allowed
• Prior allogenic stem cell or solid organ transplant.
• Personal history of autoimmune disease including: myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,
Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple
sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis. Patients with
a history of autoimmune-related hypothyroidism on thyroid replacement hormone, or
those with autoimmune dermatologic conditions not requiring the use of prednisone > 10
mg or equivalent are eligible.
• History of idiopathic pulmonary fibrosis, organized pneumonia, or evidence of active
pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in
the radiation field is permitted.
• History of following infectious diseases:
• Active or chronic hepatitis B (defined as having a positive hepatitis B surface
antigen [HBsAg] test at screening).
• Active hepatitis C infection. Patients with positive hepatitis C antibody test
are eligible if PCR is negative for hepatitis C viral DNA.
• Infection requiring therapeutic oral or IV anti-microbials within 2 weeks of
first study treatment. Patients receiving routine antimicrobial prophylaxis for
dental procedures are eligible.
• Known positive test for HIV.
• Administration of a live, attenuated vaccine within 3 weeks for first study treatment.
• Bleeding diathesis, or significant coagulopathy in the absence of therapeutic
anticoagulation.
• Use of strong inhibitors and inducers of CYP3A4
• Significant bleeding, including but not limited to hematemesis, hematuria, hemoptysis
of > 0.5 teaspoon (2.5 mL), within 3 months before registration.
• Invasion of major pulmonary blood vessels. A discussion with PI may be needed if
invading lesions are suspected.
• Concomitant use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded.
Aspirin (≤ 325 mg per day) is allowed. Prophylactic anticoagulation with oral or
parenteral anticoagulants for the patency of venous access devices or other
indications is allowed.
Therapeutic use of low-molecular weight heparin (such as enoxaparin) and subcutaneous or
oral Factor Xa inhibitors are allowed. Use of warfarin is prohibited.
• Significant GI conditions at risk of perforation or bleeding, including but not
limited to:
• Active GI obstruction or requirement of routine parenteral nutrition or tube
feedings.
• Personal history of abdominal or tracheoesophageal fistula or GI perforation
within 6 months of registration.
• Evidence of abdominal free air not explained by paracentesis or recent surgical
procedure.
• Serious, non-healing or dehiscing wound or active ulcer.
• Major surgical procedure to include major dental, oral or maxillofacial procedures
within 14 days of first study treatment.
• Proteinuria as demonstrated by > 1.5 gram of protein in a 24-hour urine collection.
All patients with ≥ 2+ protein on urinalysis must undergo 24-hour urine collection for
protein.
• Unable to swallow pills.
• Malabsorption syndrome.
• Inability to receive IV medications
• Pregnant or lactating women.
Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus
This study will be evaluating safety and efficacy of the combination of lenvatinib and
pembolizumab neoaadjuvant therapy prior to surgical resection of locally advanced renal cell
carcinoma with IVC tumor thrombus.
• Male/female participants who are at least 18 years of age
• Have histologically confirmed cT3-4,N0-1,M0-1 (clinical stage III-IV) diagnosis of
renal cell carcinoma (any subtype) with level II-IV inferior vena cava tumor thrombus
• The primary tumor and thrombus may be assessed to be resectable or unresectable at the
time of enrollment
• Male participants: A male participant must agree to use a protocol-approved
contraception during the 120 day neoadjuvant treatment period and for at least 90 days
after the last dose of study treatment and refrain from donating sperm during this
period.
• Female participants: A female participant is eligible to participate if she is not
pregnant, not breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to follow the protocol-approved contraceptive guidance during
the treatment period and for at least 30 days after the last dose of study
treatment.
• The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions.
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
archived tissue.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention.
• Have adequate organ function as defined in the following table. Specimens must be
collected within 10 days prior to the start of study intervention.
• Absolute neutrophil count (ANC): ≥1500/µL
• Platelets: ≥100 000/µL
• Hemoglobin: ≥9.0 g/dL or ≥ 5.6 mmol/La
• Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in
place of creatinine or CrCl): ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine
levels >1.5 × institutional ULN
• Total bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total
bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT): ≤2.5 × ULN (≤5 × ULN for participants with liver
metastases)
• International normalized ratio (INR) OR prothrombin time (PT) OR Activated partial
thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants
• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST
(SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);
GFR=glomerular filtration rate; ULN=upper limit of normal.
• Criteria must be met without erythropoietin dependency and without packed red blood
cell (pRBC) transfusion within last 2 weeks.
• Creatinine clearance (CrCl) should be calculated per institutional standard.
• Note: This includes eligibility-defining laboratory value requirements for treatment;
laboratory value requirements should be adapted according to local regulations and
guidelines for the administration of specific chemotherapies.
Exclusion Criteria:
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX 40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents prior
to allocation.
• Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. COVID-19
vaccines are permitted provided they are not live attenuated vaccines.
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment
within the past year. Participants with basal cell carcinoma of the skin, squamous
cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical
cancer, bladder in situ) that have undergone potentially curative therapy are not
excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study intervention.
• Has more than three different sites of metastatic renal cell carcinoma.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and lenvatinib and/or any of
its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
• Has had an allogenic tissue/solid organ transplant.
• Has prolongation of QTcF interval to >480 ms.
• Has a left ventricular ejection fraction (LVEF) below the institutional (or local
laboratory) normal range, as determined by multigated acquisition (MUGA) or
echocardiogram (ECHO)
• Has clinically significant cardiovascular disease within 12 months from first dose of
study intervention, including New York Heart Association Class III or IV congestive
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or
cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled
arrhythmia would be permitted
• Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+>1+ (≥100
mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection
for quantitative assessment of proteinuria.
• Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite
of an optimized regimen of antihypertensive medication.
[18F]PT2385 PET/CT in Patients With Renal Cell Carcinoma
This is an exploratory study to assess [18F]PT2385 Positron Emission Tomography/Computed
Tomography (PET/CT) in patients with renal cell carcinoma (RCC). This is an open-label,
nontherapeutic trial. The main objective is to correlate hypoxia-inducible factor-2alpha
(HIF2α) levels as determined by an investigational [18F]PT2385 PET/CT scan with the levels on
subsequently obtained tissue by HIF2α immunohistochemistry (IHC). There will be three
cohorts. The first pre-surgical cohort will have [18F]PT2385 PET/CT prior to nephrectomy. The
uptake and retention on Positron Emission Tomography (PET), quantified as standardized uptake
value (SUV) max and mean, abbreviated SUV henceforth will be correlated with HIF2α levels by
IHC on the primary tumor. The second cohort will comprise patients with metastatic clear cell
renal carcinoma (ccRCC). SUV will be correlated with HIF2α levels measured by IHC on a biopsy
sample from a metastasis. Both low- and high-avidity sites will be biopsied and tracer uptake
correlated with HIF2α IHC. A third cohort will include patients with Von Hippel-Lindau (VHL)
syndrome and any of the following disease manifestations - RCC, central nervous system (CNS)
hemangioblastoma, and/or pancreatic neuroendocrine tumor(s). Investigational imaging will
evaluate HIF2α expression within a tumor type and across different tumor types. A biopsy is
encouraged but not mandatory for this cohort.
• Ability to understand and the willingness to sign a written informed consent that
includes study interventions (PET/CT and, if cohort 2, mandatory biopsy).
• Ability to lie still for a 30- to 60-minute PET/CT scan.
• One of the following:
1. Cohort 1. Patients with suspected RCC planned for surgery.
2. Cohort 2. Patients with metastatic ccRCC or VHL syndrome and RCC. Biopsy is
required (planned resection for treatment reasons of a metastatic site is
acceptable in lieu of the biopsy).
3. Cohort 3. Patients with VHL syndrome with RCC, CNS hemangioblastoma, and/or
pancreatic neuroendocrine tumor(s) planning to start belzutifan.
• Women of child-bearing potential must agree to undergo and have documented a negative
pregnancy test on the day of [18F]PT2385 administration. A female of child-bearing
potential is any woman (regardless of sexual orientation, having undergone a tubal
ligation, or celibate by choice) who meets the following criteria:
1. Has not undergone a hysterectomy or bilateral oophorectomy; or
2. Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
Exclusion Criteria:
• Uncontrolled severe and irreversible intercurrent illness or psychiatric
illness/social situations that would limit compliance with study requirements.
• Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
• Claustrophobia or other contraindications to PET/CT.
• Subjects must not weigh more than the maximum weight limit for the table for the
PET/CT scanner where the study is being performed (>200 kilograms or 440 pounds).
• For cohort 2 patients, lack of suitable sites for mandatory biopsy. For example,
patients with metastatic disease restricted to the lungs that would require
percutaneous biopsies with associated risk of bleeding and pneumothorax will be
excluded.
A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011)
This study will compare the efficacy and safety of belzutifan + lenvatinib versus
cabozantinib in participants with advanced renal cell carcinoma (RCC) with clear cell
component after prior therapy.
The primary hypothesis is that belzutifan + lenvatinib is superior to cabozantinib in terms
of progression-free survival or overall survival.
• Unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC).
• Disease progression on or after an anti-programmed cell death-1/ligand 1 (PD-1/L1)
therapy as either first or second-line treatment for locally advanced/metastatic RCC
or as adjuvant treatment or neoadjuvant/adjuvant with progression on or within 6
months of last dose.
• Measurable disease per RECIST 1.1 criteria as assessed by local study investigator.
• Karnofsky performance status (KPS) score of at least 70% assessed within 10 days
before randomization.
• Received no more than 2 prior systemic regimens including: one anti-PD-1/L1 containing
adjuvant or neoadjuvant/adjuvant regimens with progression on or within 6 months from
the last dose of that regimen OR one or 2 regimens for locoregional/advanced disease
• Received only 1 prior antiPD-1/L1 therapy for adjuvant, neoadjuvant/adjuvant or
locally advanced/metastatic RCC.
• A male participant is eligible to participate if he is abstinent from heterosexual
intercourse or agrees to use contraception during the intervention period and for at
least 7 days after the last dose of belzutifan or lenvatinib in the
belzutifan+lenvatinib arm, whichever occurs last, and 23 days after the last dose of
cabozantinib.
• A female participant is eligible to participate if they are not pregnant, not
breastfeeding, and at least 1 of the following conditions applies: Not a woman of
childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive
guidance during the intervention period and for at least 30 days after the last dose
of study intervention in the belzutifan+ lenvatinib arm, or 120 days after the last
dose of study intervention in the cabozantinib arm.
• Adequately controlled blood pressure.
• Adequate organ function.
Exclusion Criteria:
• A pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or
requires chronic supplemental oxygen.
• Known additional malignancy that is progressing or has required active treatment
within the past 3 years except for basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in
situ) that have undergone potentially curative therapy.
• Known central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Clinically significant cardiac disease within 6 months of first dose of study
intervention.
• Prolongation of QTc interval to >480 ms.
• Symptomatic pleural effusion (e.g.,cough, dyspnea, pleuritic chest pain) that is not
clinically stable.
• Pre-existing ≥Grade 3 gastrointestinal or nongastrointestinal fistula.
• Moderate to severe hepatic impairment.
• History of significant bleeding within 3 months before randomization.
• History of solid organ transplantation.
• Known psychiatric or substance abuse disorder that would interfere with cooperation
with the requirements of the study.
• Unable to swallow orally administered medication or has a gastrointestinal disorder
affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
• Known hypersensitivity or allergy to the active pharmaceutical ingredients or any
component of the study intervention formulations.
• Received colony-stimulating factors [eg, granulocyte colony-stimulating factor
(G-CSF), granulocyte macrophage colony-stimulating factor (GMCSF) or recombinant
erythropoietin (EPO)] within 28 days before randomization.
• Prior treatment with belzutifan or another hypoxia-inducible factor (HIF)-2α
inhibitor.
• Prior treatment with lenvatinib.
• Prior treatment with cabozantinib.
• Currently participating in a study of an investigational agent or using an
investigational device.
• Active infection requiring systemic therapy.
• History of human immunodeficiency virus (HIV) infection.
• History of hepatitis B or known active hepatitis C infection.
A Study of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in Participants With Clear Cell Renal Cell Carcinoma Post Nephrectomy (MK-6482-022)
The purpose of this study is to assess the efficacy and safety of oral belzutifan (MK-6482)
plus intravenous (IV) pembrolizumab (MK-3475) compared to placebo plus pembrolizumab, in the
adjuvant treatment of Clear Cell Renal Cell Carcinoma (ccRCC) post nephrectomy.
The primary study hypothesis is that belzutifan plus pembrolizumab is superior to placebo
plus pembrolizumab with respect to disease-free survival (DFS).
The main inclusion and exclusion criteria include but are not limited to the following:
Inclusion Criteria:
• Has a histologically or cytologically confirmed diagnosis of RCC with clear cell
component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without
sarcomatoid features
• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as
defined by the following pathological tumor-node metastasis and tumor grading:
1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade,
N0, M0
2. High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0
3. M1 NED RCC participants who present not only with the primary kidney tumor but
also solid, isolated, soft tissue metastases that can be completely resected at
one of the following: the time of nephrectomy (synchronous) or, ≤2 years from
nephrectomy (metachronous)
• Has undergone complete resection of the primary tumor (partial or radical nephrectomy)
and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED
participants
• Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to
randomization
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10
days before randomization.
• Male participants must agree to continue contraception at least 7 days after the last
dose of belzutifan/placebo
• Female participants of childbearing potential must be willing to use an adequate
method of contraception, for the course of the study through 120 days after the last
dose of pembrolizumab or at least 30 days after last dose of belzutifan/placebo,
whichever occurs last
• Has adequate organ function
Exclusion Criteria:
• Has had a major surgery, other than nephrectomy plus resection of preexisting
metastases for M1 NED participants, within 4 weeks prior to randomization
• Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen,
or requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 6 months from first dose of
study intervention
• Has other clinically significant disorders such as: serious active nonhealing
wound/ulcer/bone fracture; requirement for hemodialysis or peritoneal dialysis
• Has preexisting brain or bone metastatic lesions
• Has received prior systemic therapy for RCC
• Has received prior radiotherapy for RCC
• Has received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention; administration of killed vaccines are allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has a known additional malignancy (other than RCC treated with nephrectomy and/or
metastasectomy) that is progressing or has required active treatment within the past 3
years
• Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs); replacement therapy is allowed
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease
• Has an active infection, requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection, a known history
of Hepatitis B or known active Hepatitis C virus infection
• Has had an allogenic tissue/solid organ transplant
Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, the RadiCaL Study
This phase II trial studies whether adding radium-223 dichloride to the usual treatment,
cabozantinib, improves outcomes in patients with renal cell cancer that has spread to the
bone. Radioactive drugs such as radium-223 dichloride may directly target radiation to cancer
cells and minimize harm to normal cells. Cabozantinib may stop the growth of cancer cells by
blocking some of the enzymes needed for cell growth. Giving radium-223 dichloride and
cabozantinib may help lessen the pain and symptoms from renal cell cancer that has spread to
the bone, compared to cabozantinib alone.
• Documented histologic or cytologic diagnosis of renal cell cancer (RCC). All subtypes
of RCC are eligible including but not limited to clear cell, papillary, chromophobe,
translocation, collecting duct carcinoma, medullary carcinoma, and unclassified
categories. Enrollment of non-clear cell patients will be limited to 20% of the total
sample size (~ 42 patients). Once this goal is met, accrual of non-clear cell patients
will be discontinued (a notice will be sent out 2 weeks in advance). Sarcomatoid and
rhabdoid differentiation are allowed
• Presence of at least 1 metastatic bone lesion not treated with prior radiation is
required.
• The presence of bone metastases can be detected by computed tomography (CT),
magnetic resonance imaging (MRI), Tc-99m bone scan or positron emission
tomography (PET) (fludeoxyglucose F-18 [FDG] or sodium fluoride [NaF]) imaging.
Patients with non-measurable bone-only disease are allowed. Patients may have
received prior radiation therapy for bone metastases or other external radiation
>= 7 days prior to registration, as long as they still have at least 1 metastatic
bone lesion not treated with radiation. Patients with visceral metastases are
allowed, as long as they have at least one untreated bone metastases
• No prior treatment with cabozantinib
• No treatment with any type of small molecular kinase inhibitor (including
investigational kinase inhibitors) within 2 weeks or 5 half-lives (whichever is
shorter) of registration or receipt of any anti-cancer therapy (including
investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of
registration
• No prior hemibody external radiotherapy
• No prior therapy with radium-223 dichloride or systemic radiotherapy (such as
samarium, strontium)
• No major surgery within 6 weeks of randomization. Procedures such as thoracentesis,
paracentesis, percutaneous biopsy, Moh's or other topical skin surgery, Lasik eye
surgery are not considered major surgery. Patients who have had a nephrectomy may be
registered >= 3 weeks after surgery, providing there are no wound-healing
complications. Subjects with clinically relevant ongoing complications from prior
surgery are not eligible
• Recovery to baseline or =< grade 1 CTCAE version 5.0 from toxicity related to any
prior treatment, unless adverse events are clinically nonsignificant and/or stable on
supportive therapy
• The use of osteoclast targeted therapy including either bisphosphonates or denosumab
is mandated on this study except in patients with contraindications as determined by
the treating investigator, including:
• Hypocalcemia
• Hypophosphatemia
• Renal impairment including those with a glomerular filtration rate (GFR) < 35
mL/min using the Cockcroft-Gault equation or acute renal impairment
• Hypersensitivity to drug formulation
• Dental condition or need for dental intervention that per the investigator
would increase the risk of osteonecrosis of jaw (ONJ).
• Use of osteoclast targeted therapy or reason against use needs to be
recorded in the electronic case report form (eCRF). Additionally, reason for
discontinuation of osteoclast targeted therapy need to be appropriately
documented in the eCRF
• Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
are unknown.
• Therefore, for women of childbearing potential only, a negative urine pregnancy
test done =< 28 days prior to registration is required. A female of childbearing
potential is a sexually mature female who: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least
12 consecutive months (i.e., has had menses at any time in the preceding 12
consecutive months)
• Karnofsky performance status >= 60%
• No brain metastases or cranial epidural disease unless adequately treated with
radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to
registration as documented by MRI or CT imaging or deemed stable by clinical
investigator. Treated brain metastases are defined as having no ongoing requirement
for steroids and no evidence of progression or hemorrhage after treatment for at least
4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by
clinical investigator
• No imminent or established spinal cord compression based on clinical symptoms and/or
imaging. In patients with untreated imminent or established spinal cord compression,
treatment with standard of care as clinically indicated should be completed at least 2
weeks before registration
• No imminent or impending pathologic fracture based on clinical symptoms and/or
imaging. In patients with untreated imminent or impending pathologic fracture,
treatment with standard of care as clinically indicated should be completed at least 2
weeks before registration
• No significant, uncontrolled intercurrent or recent illness, including but not limited
to the following conditions:
• Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina
pectoris, serious cardiac arrhythmia; uncontrolled hypertension defined as
sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite
optimal antihypertensive treatment; stroke (including transient ischemic attack),
myocardial infarction, or other ischemic event, within 6 months before
randomization; thromboembolic event (e.g., deep venous thrombosis, pulmonary
embolism) within 1 month before randomization
• Gastrointestinal disorders: Disorders associated with a high risk of perforation
or fistula formation: active inflammatory bowel disease, active diverticulitis,
active cholecystitis, active symptomatic cholangitis or active appendicitis,
active acute pancreatitis or active acute obstruction of the pancreatic or
biliary duct, or active gastric outlet obstruction; abdominal fistula,
gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess
within 3 months before randomization. Note: Complete healing of an
intra-abdominal abscess must be confirmed before randomization
• No clinically significant hematuria, hematemesis, or hemoptysis, or other history
of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before
randomization
• No lesions invading major pulmonary blood vessels
• No other clinically significant disorders:
• Human immunodeficiency virus (HIV)-infected patients on effective
anti-retroviral therapy (with no medications prohibited by this protocol
[e.g. drug-drug interactions]) with undetectable viral load within 6 months
are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the
HBV viral load must be undetectable on suppressive therapy (with no
medications prohibited by this protocol [e.g. drug-drug interactions]), if
indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For patients with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load
(with no medications prohibited by this protocol [e.g. drug-drug
interactions])
• No serious non-healing wound or ulcer
• No malabsorption syndrome
• No uncompensated/symptomatic hypothyroidism
• No moderate to severe hepatic impairment (Child-Pugh B or C)
• No requirements for hemodialysis or peritoneal dialysis
• No history of solid organ transplantation
• No chronic concomitant treatment with strong CYP3A4 inducers or inhibitors. Because
the list of these agents is constantly changing, it is important to regularly consult
a frequently updated medical reference. Patients may not have received a strong CYP3A4
inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7
days prior to registration
• No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants include:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor.
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 9 g/dl (transfusions allowed)
• Calculated (calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault
equation
• Total bilirubin =< 1.5 x upper limit of normal (ULN), for patients with Gilberts
disease =< 3.0 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN
• Urine protein to creatinine (UPC) ratio =< 2 mg/mg OR 24-hr urine protein < 2 g
Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy With or Without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial (PROBE)
This phase III trial compares the effect of adding surgery to a standard of care
immunotherapy-based drug combination versus a standard of care immunotherapy-based drug
combination alone in treating patients with kidney cancer that has spread to other places in
the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab,
ipilimumab, pembrolizumab, and avelumab, may help the body's immune system attack the cancer,
and may interfere with the ability of tumor cells to grow and spread. Axitinib may stop the
growth of tumor cells by blocking some of the enzymes needed for cell growth. Surgery to
remove the kidney, called a nephrectomy, is also considered standard of care; however,
doctors who treat kidney cancer do not agree on its benefits. It is not yet known if the
addition of surgery to an immunotherapy-based drug combination works better than an
immunotherapy-based drug combination alone in treating patients with kidney cancer.
• STEP 1 REGISTRATION: Participants must have a histologically proven diagnosis of clear
cell or non-clear cell renal cell carcinoma. Participants with collecting duct
carcinoma histology are not eligible. Participants with multifocal or bilateral tumors
are eligible
• STEP 1 REGISTRATION: Participants must have primary tumor in place
• STEP 1 REGISTRATION: Participants must have the following scans performed, showing
clinical evidence of measurable or non-measurable metastatic disease:
• Computed tomography (CT) scan of the chest (can be performed without contrast if
CT contrast cannot be given)
• CT of abdomen and pelvis with contrast OR magnetic resonance imaging (MRI) of the
abdomen and pelvis with or without contrast
Scans must be performed within the following timeframes:
• Treatment naive participants must have scans documenting metastatic disease completed
within 90 days prior to study registration
• Previously treated participants must have scans documenting metastatic disease
completed within 90 days prior to first dose of systemic treatment
• STEP 1 REGISTRATION: Participants with symptomatic metastases may have received
palliative radiotherapy or receive palliative radiotherapy after registration
• STEP 1 REGISTRATION: Participants must have no clear contraindications to
nephrectomy
• STEP 1 REGISTRATION: Participants must be offered the opportunity to participate
in specimen bank. With participant consent, specimens must be collected and
submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System
• STEP 1 REGISTRATION: Participants must be informed of the investigational nature
of this study and must sign and give informed consent in accordance with
institutional and federal guidelines
• STEP 1 REGISTRATION: As part of the Oncology Patient Enrollment Network (OPEN)
registration process the treating institution's identity is provided in order to
ensure that the current (within 365 days) date of institutional review board
approval for this study has been entered in the system
• STEP 2 REGISTRATION: Participants must have at least one of the following scans
performed 12 weeks (+/- 2 weeks) after starting pre-randomization treatment
• CT scan of the chest (can be performed without contrast if CT contrast cannot be
given)
• CT of abdomen and pelvis with contrast OR MRI of the abdomen and pelvis with or
without contrast Scans must be performed within 28 days prior to randomization.
Response should be assessed by comparing with a CT or MRI of the chest, abdomen and
pelvis obtained prior to starting pre-randomization treatment. Participants with
complete response in all metastatic sites are not eligible to randomize to Step 2
• STEP 2 REGISTRATION: Participants must have one of the following objective statuses
after 12 weeks of pre-randomization treatment
• Stable disease
• Partial response
• The treating investigator believes the patient is deriving clinical benefit from
systemic therapy AND have Zubrod performance status 0-1
• STEP 2 REGISTRATION: Participants must plan to continue the immune-based therapy
received during pre-randomization treatment
• STEP 2 REGISTRATION: Participants must be randomized on or between the 11th and
14th week of protocol-directed pre-randomization treatment therapy
• STEP 2 REGISTRATION: Participants must have received at least one of the minimum
amounts of immunotherapy:
• 2 infusions of nivolumab + 1 infusion of ipilimumab
• 2 infusions of pembrolizumab
• 2 infusions of avelumab
• STEP 2 REGISTRATION: Participants must have a planned surgery date within 42 days
of randomization
• STEP 2 REGISTRATION: Participants must be a surgical candidate as determined by
study urologist. The urology consult should be done within 42 days prior to
randomization
• STEP 2 REGISTRATION: Participants must have a complete physical examination and
medical history within 28 days prior to randomization
• STEP 2 REGISTRATION: Participants must have a Zubrod performance status of 0-1
within 28 days prior to randomization
• STEP 2 REGISTRATION: Total bilirubin =< institutional upper limit of normal (ULN)
(within 28 days prior to randomization)
• STEP 2 REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase
(ALT) =< 3 x institutional upper limit of normal (ULN) (within 28 days prior to
randomization)
• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x the institutional upper limit of
normal (IULN) OR measured OR calculated creatinine clearance >= 50 mL/min using
the Cockcroft-Gault Formula) (must have been drawn and processed within 28 days
prior to randomization)
Exclusion Criteria:
• STEP 1 REGISTRATION: Participants must not have known active brain metastases.
Participants with previously treated brain metastases are eligible if participant has
no neurologic signs or symptoms suggestive of brain metastasis. Brain imaging studies
are not required. If brain imaging studies are performed, they must be negative for
disease
• STEP 1 REGISTRATION: Participants must not have received the following prior treatment
of metastatic renal cell carcinoma:
• Treatment naive participants must not have received any prior lines of systemic
therapy for metastatic renal cell carcinoma beyond the line intended as part of
protocol therapy
• Previously treated participants must not have received any systemic therapy for
metastatic renal cell carcinoma beyond the one regimen received off protocol as
specified in Step 1 pre-randomization treatment
• STEP 1 REGISTRATION: Participants must not have received more than the following
amounts protocol-directed pre-randomization treatment:
• Treatment naive participants must not have received any pre-randomization
treatment.
• Previously treated participants must not be planning to receive any additional
treatment prior to Step 2 randomization, and must not have received more than the
following amounts of pre-randomization treatment:
• 4 infusions of nivolumab
• 4 infusions of ipilimumab
• 4 infusions of pembrolizumab
• 7 infusions of avelumab
• STEP 1 REGISTRATION: Participants must not have received immunotherapy for any cancer
within the following timeframes:
• Treatment naive participants must not have received any immunotherapy within a
year of registration
• Previously treated participants must not have received any other immunotherapy
within a year of the start of off protocol specified pre-randomization treatment
• STEP 1 REGISTRATION: Participants must not have a solitary kidney and not have a
transplanted kidney
• STEP 1 REGISTRATION: No other prior malignancy is allowed except for the following:
adequately treated basal cell or squamous cell skin cancer, any in situ or T1 cancer,
adequately treated stage I or II cancer from which the participant is currently in
complete remission, or any other cancer from which the participant has been disease
free for at least two years
• STEP 1 REGISTRATION: Participants must not have been previously diagnosed with a
medical condition that makes them ineligible for immune based combination therapy or
nephrectomy
• STEP 2 REGISTRATION: Participants must not show progression in the primary tumor.
Participants who are considered to have pseudo progression are allowed
• STEP 2 REGISTRATION: Participants must not have known active brain metastases.
Participants with previously treated brain metastases are eligible if participant has
no neurologic signs or symptoms suggestive of brain metastasis. Brain imaging studies
are not required. If brain imaging studies are performed, they must be negative for
disease
• STEP 2 REGISTRATION: No other prior malignancy is allowed except for the following:
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
adequately treated stage I or II cancer from which the participant is currently in
complete remission, or any other cancer from which the participant has been disease
free for two years
Procedure: Cytoreductive Nephrectomy, Drug: Active Comparator
Metastatic Renal Cell Carcinoma, Metastatic Clear Cell Renal Cell Carcinoma, Stage IV Renal Cell Cancer AJCC v8, Kidney
A Study of Combination Chemotherapy for Patients With Newly Diagnosed DAWT and Relapsed FHWT
This phase II trial studies how well combination chemotherapy works in treating patients with
newly diagnosed stage II-IV diffuse anaplastic Wilms tumors (DAWT) or favorable histology
Wilms tumors (FHWT) that have come back (relapsed). Drugs used in chemotherapy regimens such
as UH-3 (vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan)
and ICE/Cyclo/Topo (ifosfamide, carboplatin, etoposide, cyclophosphamide, and topotecan) work
in different ways to stop the growth of tumor cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. This trial may help doctors find out
what effects, good and/or bad, regimen UH-3 has on patients with newly diagnosed DAWT and
standard risk relapsed FHWT (those treated with only 2 drugs for the initial WT) and regimen
ICE/Cyclo/Topo has on patients with high and very high risk relapsed FHWT (those treated with
3 or more drugs for the initial WT).
• Patients with newly diagnosed stages 2 •4 diffuse anaplastic Wilms tumor must be
enrolled on AREN03B2 and have received an initial risk assignment showing DAWT (if
anaplasia first identified at diagnostic, pre-treatment nephrectomy or biopsy) or a
delayed nephrectomy classification showing DAWT (if anaplasia first noted at delayed
nephrectomy) prior to enrollment on AREN1921. Prior enrollment on AREN03B2 is not an
eligibility requirement for patients with relapsed favorable histology Wilms tumor.
• Patients must be =< 30 years old at study enrollment
• Patients with the following diagnoses are eligible for this study:
• Newly diagnosed stages 2 •4 diffuse anaplastic Wilms tumor as confirmed by
central review
• Favorable histology Wilms tumor at first relapse. Relapsed FHWT patients must
have previously achieved remission for their initial FHWT diagnosis to be
eligible for this study. The relapse risk groups are defined as follows,
regardless of radiation therapy:
• Standard-Risk relapse: Patients who received two chemotherapy agents for
frontline therapy; primarily actinomycin D and vincristine
• High-Risk relapse: Patients who received three chemotherapy agents for
frontline therapy; primarily vincristine, actinomycin D and doxorubicin or
vincristine, actinomycin D and irinotecan
• Very High-Risk relapse: Patients who received four or more chemotherapy
agents as part of initial therapy; primarily regimen M or its variations
• Patients with newly diagnosed DAWT must have had histologic verification of the
malignancy. For relapsed FHWT patients, biopsy to prove recurrence is encouraged, but
not required
• Note: For relapsed FHWT patients, an institutional pathology report confirming
favorable histology Wilms tumor (from relapse, if available, or from original
diagnosis) must be available for upload prior to initiation of protocol therapy
• Patients with newly diagnosed Stages 2 •4 diffuse anaplastic Wilms tumor must be
enrolled on AREN1921 within 2 weeks of the tumor-directed surgery or biopsy procedure
that first confirms a diagnosis of DAWT, whether at initial diagnostic procedure or
delayed nephrectomy (such surgery/biopsy is day 0). For patients who received prior
therapy for presumed favorable histology Wilms tumor, later confirmed to have diffuse
anaplastic Wilms tumor at subsequent review of the initial biopsy
• Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least
1 lymph node sampled prior to study enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
• Patients must have a life expectancy of >= 8 weeks
• Diffuse Anaplastic Wilms Tumor: Patients with diffuse anaplastic histology must have
had no prior systemic therapy, except in the following situations:
• Patients with diffuse anaplastic Wilms tumor who received no more than 12 weeks
of pre nephrectomy chemotherapy for what was originally presumed to be favorable
histology Wilms tumor, subsequently confirmed to be diffuse anaplastic Wilms
tumor at delayed nephrectomy
• Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeks of
chemotherapy following upfront biopsy, initiated within 14 days of biopsy, for
presumed favorable histology Wilms tumor based on institutional review, but
subsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2
initial risk assignment results (if available per current version of AREN03B2)
• Treatment consisting of vincristine/doxorubicin/cyclophosphamide initiated on an
emergent basis and within allowed timing as described
• Note: Patients who received prior therapy for presumed favorable histology Wilms
tumor, later identified to have diffuse anaplastic Wilms tumor as per above, must
begin study treatment starting at cycle 3 (week 7) of regimen UH 3. Patients who
received emergency radiation to preserve organ function are eligible as noted.
Patients who received radiation as part of standard of care for presumed newly
diagnosed favorable histology Wilms tumor, along with chemotherapy as noted
above, prior to identification of diffuse anaplasia, are also eligible
• Relapsed Favorable Histology Wilms Tumor: Patients must not have received prior
chemotherapy for their relapsed favorable histology Wilms tumor diagnosis. In
addition, patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
onto this study
• Radiation therapy (RT): >= 2 weeks (wks) must have elapsed for local palliative
RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >=
50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone
marrow (BM) radiation. Patients with relapsed favorable histology Wilms tumor who
received emergency radiation to preserve organ function are eligible and do not
need to washout with the above criteria
• Patients may not be receiving any other investigational agents (within 4 weeks prior
to study enrollment)
• Peripheral absolute neutrophil count (ANC) >= 750/uL (performed within 7 days prior to
enrollment)
• Platelet count >= 75,000/uL (transfusion independent) (performed within 7 days prior
to enrollment)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performed
within 7 days prior to enrollment)
• Patients with high-risk or very high-risk relapsed FHWT who will be treated with
regimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance or
radioisotope glomerular filtration rate (GFR) and meet the following requirement:
• Creatinine clearance or radioisotope GFR >= 60 mL/min/1.73 m^2 (performed within
7 days prior to enrollment)
• Patients diagnosed with stage 2-4 DAWT or standard risk relapsed FHWT, who will be
treated with regimen UH 3, may either obtain a creatinine clearance, radioisotope GFR
(meeting the above criteria of GFR >= 60 mL/min/1.73 m^2), or an adequate serum
creatinine as per the following table:
• Age: Maximum Serum Creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 0.6 (male and female)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: 1.7 (male), 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age or direct bilirubin =<
ULN for patients whose total bilirubin > 1.5 x ULN (performed within 7 days prior to
enrollment)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age or =< 5 x ULN for patients with liver metastases
(performed within 7 days prior to enrollment)
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
radionuclide angiogram (obtained within 21 days prior to enrollment and start of
protocol therapy)
Exclusion Criteria:
• Patients with a history of bilateral Wilms tumor (synchronous or metachronous)
• Patients with any uncontrolled, intercurrent illness including, but not limited to,
ongoing or active infection, or symptomatic congestive heart failure (defined as grade
2 or higher heart failure per Common Terminology Criteria for Adverse Events [CTCAE]
version 5.0)
• Relapsed FHWT patients who did not receive frontline chemotherapy (e.g., very low risk
FHWT initially observed without chemotherapy) or received only one chemotherapy agent
for frontline therapy
• For patients with high-risk or very high-risk relapsed FHWT:
• Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16
mmol/L and serum phosphate =< 2 mg/dL (or < 0.8 mmol/L) without supplementation
• For stages 2-4 DAWT and standard-risk relapsed FHWT patients:
• Chronic inflammatory bowel disease and/or bowel obstruction
• Concomitant use of St. John's wort, which cannot be stopped prior to the start of
trial treatment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation
Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer
This phase II/III trial compares the effect of adding durvalumab to chemotherapy versus
chemotherapy alone before surgery in treating patients with upper urinary tract cancer.
Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune
system attack the cancer, and may interfere with the ability of tumor cells to grow and
spread. Chemotherapy drugs, such as methotrexate, vinblastine, doxorubicin, cisplatin, and
gemcitabine work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Durvalumab in
combination with chemotherapy before surgery may enhance the shrinking of the tumor compared
to chemotherapy alone.
• STEP 1 REGISTRATION AND RANDOMIZATION
• Patients must be >= 18 years of age
• Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC) who
have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible
• Patient must have a diagnosis of high grade upper tract urothelial carcinoma proven by
biopsy within 12 weeks (84 days) prior to registration/randomization with one of the
following:
• Upper urinary tract mass on cross-sectional imaging or
• Tumor directly visualized during upper urinary tract endoscopy before referral to
medical oncology
• NOTE: Biopsy is standard of care (SOC) and required for enrollment to study.
This is vital for best practice
• Leukocytes >= 3,000/mcL (obtained =< 14 days prior to registration/randomization)
• Platelets >= 100,000/mcL (obtained =< 14 days prior to registration/randomization)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.5 x ULN
for patients with Gilbert's disease) (obtained =< 14 days prior to
registration/randomization)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (obtained =< 14 days prior to registration/randomization)
• Hemoglobin (Hgb) >= 9 g/dL (obtained =< 14 days prior to registration/randomization)
• NOTE: Packed red blood transfusion is allowed to achieve this parameter as per
treating investigator
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months prior to
registration/randomization are eligible for this trial
• NOTE: These patients must be stable on their anti-retroviral regimen with
evidence of at least two undetectable viral loads within the past 6 months on the
same regimen; the most recent undetectable viral load must be within the past 12
weeks. They must have a CD4 count of greater than 250 cells/mcL over the past 6
months on this same anti-retroviral regimen and must not have had a CD4 count <
200 cells/mcL over the past 2 years, unless it was deemed related to the cancer
and/or chemotherapy induced bone marrow suppression. They must not be currently
receiving prophylactic therapy for an opportunistic infection and must not have
had an opportunistic infection within the past 6 months
• NOTE: For patients who have received chemotherapy in the past 6 months, a CD4
count < 250 cells/mcL during chemotherapy is permitted as long as viral loads
were undetectable during this same chemotherapy. They must have an undetectable
viral load and a CD4 count >= 250 cells/mcL within 7 days of
registration/randomization
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
• NOTE: Testing for HIV, hepatitis B or hepatitis C is not required unless
clinically indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated
and have undetectable viral load. For patients with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load
• Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
• Patient must have a body weight of > 30 kg
• Patient must have life expectancy of >= 12 weeks
• Patient must have creatinine clearance > 15 ml/min as by Crockroft-Gault formula or
24-hour creatinine clearance within 28 days prior to registration/randomization
• NOTE: Patients will be assigned to cisplatin-ineligible and cisplatin-eligible
cohorts based on their creatinine clearance, Eastern Cooperative Oncology Group
(ECOG) performance status, and grade (if any) of peripheral neuropathy and/or
hearing loss in keeping with SOC cisplatin contraindications. Patients that are
cisplatin-eligible will be randomized to either Arm A or Arm B
• Patients that meet any of the following criteria will be registered and
assigned to the cisplatin-ineligible Arm C if they meet other eligibility
criteria:
• Creatinine clearance > 15 ml/min and =< 50 ml/min or hearing loss grade
>= 3, or neuropathy >= 2, or ECOG PS 2
• Patient must have an absolute neutrophil count (ANC) >= 1,000/mcL
obtained =< 14 days prior to registration
• Patient must have ECOG performance status 0-2
• Patients that meet the following criteria will be randomized to the
cisplatin-eligible Arm A or Arm B:
• Patient must have creatinine clearance of > 50ml/min, PS ECOG 0-1,
absence of hearing loss grade >= 3, and/or neuropathy >= 2
• Patient must have an absolute neutrophil count (ANC) >= 1,500/mcL
obtained =< 14 days prior to randomization
• Patient must have left ventricular ejection fraction (LVEF) >= 50% by
(either multigated acquisition scan [MUGA] or 2-D echocardiogram)
obtained within obtained within 28 days prior to randomization
Exclusion Criteria:
• Patients must not have any component of small cell/neuroendocrine carcinoma. Other
variant histologic types are permitted provided the predominant (>= 50%) subtype is
urothelial carcinoma
• Patients must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used. All patients of childbearing potential must have a blood test or
urine study within 14 days prior to registration to rule out pregnancy. A patient of
childbearing potential is defined as any patient, regardless of sexual orientation or
whether they have undergone tubal ligation, who meets the following criteria: 1) has
achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
therapy does not rule out childbearing potential) for at least 24 consecutive months
(i.e., has had menses at any time in the preceding 24 consecutive months)
• Patients of childbearing potential and sexually active patients must not expect to
conceive or father children, either by using accepted and effective method(s) of
contraception or by abstaining from sexual intercourse from the time of registration,
while on study treatment and for at least 6 months after the last dose of protocol
treatment
• Patients must have no evidence of metastatic disease or clinically enlarged regional
lymph nodes (>= 1.5 cm short axis) on imaging required within 28 days prior to
registration (Non-regional findings >=1.5 cm short axis that in the opinion of the
investigator are not concerning for involvement based on radiographic characteristics,
chronicity, avidity on positron emission tomography (PET) or other imaging or other
criteria can be eligible based on investigator discretion).
• NOTE: Patients with elevated alkaline phosphatase, calcium or suspicious bone
pain/tenderness can also undergo baseline bone scans to evaluate for bone
metastasis at the discretion of local provider.
• Patient must meet below criteria for prior/current malignancy history:
• Non-urothelial cancer malignancy history:
• Patient must not have another active (or within two years) second malignancy
other than resected non-melanoma skin cancers, resected in situ breast,
cervical or other in situ carcinoma, and either clinically insignificant per
the investigator (e.g. =< Gleason 3+4) on active surveillance (or watchful
waiting) or previously treated prostate cancer with no rising prostate
specific antigen (PSA) and no plan to treat
• NOTE: Patients with a prior or concurrent malignancy whose natural
history or treatment does not have the potential to interfere with the
safety or efficacy assessment of the investigational regimen are
eligible for this trial. Patients in whom concomitant or prior
bladder/urethra predominant (>= 50%) urothelial carcinoma have been
surgically resected and demonstrated to be only non-invasive cancer (<
cT1N0) are eligible regardless of time elapsed
• Urothelial cancer malignancy history:
• Patient may have a history of resectable urothelial cancer as long as
patients meet one of the following:
• T0, Ta or Tis at any time
• T1-4a N0 and no evidence of disease (NED) for more than 2 years from
the latest therapy [e.g., radical surgery, transurethral resection of
bladder tumor (TURBT), radiation, chemotherapy (neoadjuvant or
adjuvant, or with radiation)]. Prior immune checkpoint inhibitor is not
allowed.
• Patient with history of >= pT4b, N+, and/or M1 is not eligible.
• NOTE: Patients in whom concomitant or prior bladder/urethra predominant
(>= 50%) urothelial carcinoma have been surgically resected and
demonstrated to be only Ta or carcinoma in situ (CIS) (< cT1 N0) are
eligible regardless of time elapsed
• Patient must not have any uncontrolled illness including, but not limited to, ongoing
or active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis [TB] testing
in line with local practice), symptomatic congestive heart failure (CHF), myocardial
infarction (MI) in last three months, or unstable angina pectoris, significant
uncontrolled cardiac arrhythmia, clinically relevant liver cirrhosis, interstitial
lung disease, or psychiatric illness/social situations that would limit compliance
with study requirements
• Patient must not have received prior radiation therapy to >= 25% of the bone marrow
for other diseases
• Patient must not have received prior systemic anthracycline therapy
• NOTE: Patients who have received prior intravesical chemotherapy at any time for
non-muscle invasive urothelial carcinoma of the bladder are eligible
• Patient must not have either history of or active autoimmune disease requiring
immunosuppressive therapy within 2 years prior to registration/randomization or any
history of inflammatory bowel disease (inflammatory bowel disease [IBD], colitis, or
Crohn's disease), neuromuscular autoimmune condition, immune-related pneumonitis or
interstitial lung disease. Patients with well-controlled hyper/hypothyroidism, celiac
controlled by diet alone, diabetes mellitus type I, vitiligo, alopecia, psoriasis,
eczema, lichen planus, or similar skin/mucosa condition are eligible
• Patient must not be on or have used immunosuppressive medication within 14 days prior
to the first dose of durvalumab. The following are exceptions to this criterion:
• Intranasal, inhaled, intra-auricular, topical steroids, or local steroid
injections (e.g. intra-articular injection
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent at the time of enrollment
• Steroids as premedications for hypersensitivity reactions (e.g. computed
tomography [CT] scan premedication)
• Patient must not have received live attenuated vaccine within 30 days prior to the
first dose of durvalumab, while on protocol treatment and within 30 days after the
last dose of durvalumab
• Patient must not have had a major surgical procedure within 28 days prior to
registration/randomization
• NOTE: Cystoscopy/ureteroscopy, stent placement or nephrostomy tube is not
considered major surgery
• Patient must not have history of allogenic organ transplantation
Gemcitabine Versus Water Irrigation in Upper Tract Urothelial Carcinoma
There is a high rate of intravesical (bladder) recurrence following extirpative surgery for
upper tract urothelial carcinoma. There is no single established standard of care for
prevention of intravesical recurrence; however, one protocol in common use involves the use
of intravesical gemcitabine instilled into the bladder during surgery and prior to entry into
the bladder. There are barriers to the use of gemcitabine, especially at lower volume
centers. Some evidence suggests that intravesical irrigation with sterile water has
equivalent efficacy to intravesical chemotherapy in prevention of recurrent bladder cancer
following transurethral resection of bladder tumors (TURBT). This study is intended to
compare recurrence rates using intravesical gemcitabine (as a pseudo-standard of care) and
continuous bladder irrigation with sterile water.
• Biopsy proven UTUC with plan for excisional surgery (distal ureterectomy or
nephroureterectomy) with curative intent
• Age 18 •90 years
• Life expectancy > 1 year
• Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Female participants who become pregnant or who suspect that they are pregnant should
notify the treating investigator immediately.
• Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
• Concurrent or prior diagnosis of bladder cancer with a disease-free interval of less
than three years.
• Synchronous bilateral upper tract urothelial carcinoma (prior history of contralateral
UTUC is permissible with a disease-free interval of more than three years).
• Plan for radical cystectomy.
• 3.2.4 Suspicion for small bladder capacity (< 100 mL) based on treating urologist's
clinical judgment.
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to gemcitabine or other agents used in study.
Procedure: sterile water irrigation, Drug: Gemcitabine
Urinary Bladder, Urothelial Cancer of Renal Pelvis, Urothelial Carcinoma Ureter
Cancer and Blood Pressure Management, CARISMA Study
This phase II trial studies how well intensive blood pressure management works in decreasing
systolic blood pressure in patients with kidney or thyroid cancer that has spread to other
places in the body (metastatic) who are starting anti-angiogenic tyrosine kinase inhibitor
cancer therapy. This study is being done to find out if a systolic blood pressure to a target
of less than 120 mmHg (intensive systolic blood pressure management) can be achieved, well
tolerated, and beneficial as compared to the usual approach to a target of less than 140 mmHg
while taking an anti-angiogenic tyrosine kinase inhibitor. This study may help doctors
understand the best way to control blood pressure in kidney or thyroid cancer patients taking
anti-angiogenic tyrosine kinase inhibitor.
• English speaking
• Patient must have histologically or cytologically-proven advanced metastatic renal
cell cancer (mRCC) or medullary thyroid cancer initially treated with anti-angiogenic
tyrosine kinase inhibitors (AA-TKIs) including: sunitinib, sorafenib, pazopanib,
cabozantinib, lenvatinib, vandetanib, or axitinib)
• NOTE: If patient has a severe sulfa allergy (e.g. Stevens Johnson reaction), then
alternative non-sulfa medications can be considered in consultation with the
C-BAC. Patient with a noted severe allergic reactions to medications listed in
the algorithms is not necessarily excluded from this trial, as alternative
medications could be considered in consultation with the C-BAC. Moreover, the
patient treated with pre-existing medications that may interact with proposed BP
medications is not necessarily excluded, as alternative medications exist. The
clinical significance of any potential drug interactions can also be addressed
with the C-BAC.
• Prior exposure to another AA-TKI is permissible. Concurrent or prior treatment with
immunotherapy is also permissible
• Patient must have either clinical cardiovascular (CV) disease or evidence of increased
CV risk as defined by one or more of the following:
• Clinical CV disease (history of myocardial infarction [MI] acute coronary
syndrome, coronary revascularization, carotid endarterectomy or stenting greater
than 3 months prior to registration, peripheral artery disease, cerebrovascular
accident greater than 3 months prior to registration, abdominal aortic aneurysm
or heart failure [HF])
• An American College of Cardiology/American Heart Association (ACC/AHA) CV risk
score of at least 10%
• Chronic kidney disease (defined as an estimated glomerular filtration rate [eGFR]
between 30 and 60 ml/min per 1.73 m^2). Dialysis patients and patients with an
eGFR < 30 ml/min/1.73m^2 will be excluded. eGFR will be calculated according to
the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation
• Patient must have systolic blood pressure (SBP) >= 130 mmHg on two or more occasions
according to any in-clinic visit in the 12 weeks prior to or during their initial 4
weeks of treatment with an AA-TKI. Patient who have a prior diagnosis of hypertension
or on pre-existing anti-hypertensive medications are eligible for enrollment. However,
patient must not be on more than 3 baseline blood pressure medications at time of
entry
• NOTE: If a patient has a single elevated SBP >= 130mmHg but not on repeat
assessment, an additional SBP assessment should be performed to confirm
ineligibility
• Patient must agree to comply with performing home blood pressure monitoring using an
Omron7250 oscillometric monitor at home, or equivalent models
• Women of childbearing potential and sexually active males must be strongly advised to
use accepted and effective methods of contraception or to abstain from sexual
intercourse for the duration of their participation in the study
• Patient must have internet access through a computer, tablet, or smart phone to use
EASEE-PRO and home BP monitoring. A valid phone number to receive text messages and
email address are also necessary
• Leukocytes >= 3,000/mcL (obtained within 14 days prior to registration)
• Absolute neutrophil count >= 1,500/mcL (obtained within 14 days prior to registration)
• Platelets >= 100,000/mcL (obtained within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal (ULN) (obtained within 14 days prior to
registration)
• Patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
• Patient with a history of hepatitis C virus (HCV) infection must have been treated and
cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
• Patient with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
• Patient with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS specific treatment is not required and is unlikely to be required during
the first cycle of therapy
• Patient with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Exclusion Criteria:
• Patient must not have end-stage renal failure on dialysis, history of repeated
hyperkalemia with a potassium > 5.5 mEq/l, or have a kidney transplant, or an eGFR <
30 ml/min/1.73 m^2
• Patient must not have coronary artery bypass grafting, MI acute coronary syndrome
severe/unstable angina, stroke, transient ischemic attack, clinically significant
bleeding requiring hospitalization or pulmonary embolism within 3 months prior to
registration
• Patient must not have brain surgery or radiotherapy within 2 weeks prior to
registration
• Patient must not have uncontrolled blood pressure defined by SBP > 160 mmHg on three
or more antihypertensives prior to TKI initiation
• Patient with an arm circumference too large (> 50 cm) or small (< 17 cm) to allow
accurate BP measurement with available devices will not be eligible
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with some
anti-hypertensives, including angiotensin receptor blockers. All females of
childbearing potential must have a blood test or urine study within 14 days prior to
registration to rule out pregnancy. A female of childbearing potential is defined as
any woman, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: has achieved menarche at some point, has
not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months (i.e., has had menses at any time in the
preceding 24 consecutive months)
Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
This phase III trial compares the usual treatment (treatment with ipilimumab and nivolumab
followed by nivolumab alone) to treatment with ipilimumab and nivolumab, followed by
nivolumab with cabozantinib in patients with untreated renal cell carcinoma that has spread
to other parts of the body. The addition of cabozantinib to the usual treatment may make it
work better. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may
help the body's immune system attack the cancer, and may interfere with the ability of tumor
cells to grow and spread. Cabozantinib may stop the growth of tumor cells by blocking some of
the enzymes needed for cell growth. It is not yet known how well the combination of
cabozantinib and nivolumab after initial treatment with ipilimumab and nivolumab works in
treating patients with renal cell cancer that has spread to other parts of the body.
• STEP I REGISTRATION CRITERIA
• Histologically documented renal cell carcinoma with clear cell component, including
patients who have sarcomatoid or rhabdoid features
• Any metastatic disease, including visceral, lymph node, other soft tissue and bone,
measurable per RECIST 1.1.
• Measurable disease as defined in the protocol.
• Must be intermediate or poor risk patient per International Metastatic Renal Cell
Carcinoma Database (IMDC) criteria (1 or more of the following): Karnofsky performance
status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic
treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN],
corrected calcium concentration greater than upper limit of normal [ULN], absolute
neutrophil count greater than ULN, platelet count > ULN).
• Central nervous system (CNS) disease permitted, if stable and not otherwise causing
symptoms or needing active treatment.
• Karnofsky performance status >= 70%.
• No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not
limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab,
tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting
T-cell co-stimulation or checkpoint pathways. The only exception is for prior
treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or
post-operative trials, as long as > 1 year since completion of systemic therapy.
• No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days]
and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as
above are allowed).
• No systemic cancer therapy less than 28 days prior to registration; no radiation
therapy less than 14 days prior to registration. There must be a complete recovery and
no ongoing complications from radiotherapy.
• Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing
potential only, a negative serum or urine pregnancy test done =< 14 days prior to
registration is required.
• Age >= 18 years
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Hemoglobin >= 8 g/dL.
• Calculated (Calc.) creatinine clearance >= 30 mL/min.
• Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with known
or likely Gilbert's syndrome, for whom total bilirubin up to 3 mg/dL is allowed with
direct bilirubin =< 20% total bilirubin)
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of
normal (ULN) or < 5 x ULN if hepatic metastases present.
• STEP 2 REGISTRATION ELIGIBILITY CRITERIA
• Successful completion of at least 1 cycle of ipilimumab/nivolumab.
• Resolution of any treatment-related adverse events to grade 1 or less per dose
modification section (this criteria does not include any adverse events [AEs] not
attributable to treatment which are present due to disease), with
prednisone-equivalent dosing at 10 mg daily or less. Exceptions for this criteria
include patients receiving replacement hormone treatments (such as levothyroxine for
treatment-related hypothyroidism or glucocorticoid replacement for adrenal
insufficiency). Please contact study chair if further discussion is needed.
• No more than 80 days from last dose of ipilimumab/nivolumab.
Exclusion Criteria:
• Active autoimmune disease requiring ongoing therapy.
• Ongoing acute toxicity > grade 2 from previous treatment.
• History of severe allergic, anaphylactic or other hypersensitivity reactions to
chimeric or humanized antibodies.
• Active hepatitis B/C, or active tuberculosis (PPD response without active TB is
allowed)
• Human immunodeficiency virus (HIV) -infected patients with detectable viral load
within 6 months prior to registration. Patients on effective anti-retroviral therapy
with undetectable viral load within 6 months prior to registration are eligible.
• Concurrent use of immunosuppressive medication including prednisone above 10 mg daily.
• Uncontrolled adrenal insufficiency.
• Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP > 90
mmHg).
• Major surgery less than 28 days prior to registration.
• Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to
registration.
• Any arterial thrombotic events within 180 days prior to registration.
• Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks prior to
registration.
• Cavitating pulmonary lesions or known endotracheal or endobronchial disease
manifestations.
• Lesions encasing or invading any major blood vessels (this does not include tumor
thrombus extending into/through renal vein/inferior vena cava [IVC]). Patients with
tumor thrombus extending into/through renal vein are considered eligible.
• Moderate of severe hepatic impairment (Child-Pugh B or C).
• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in the 180
days prior to registration. (Any asymptomatic, treated pulmonary embolism or
asymptomatic, treated deep venous thrombosis > 30 days prior to registration allowed).
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
• Unstable cardiac arrhythmia within 6 months prior to registration.
• Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs of
pulmonary hemorrhage =< 90 days prior to registration.
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess,
bowel obstruction, or gastric outlet obstruction within 180 days prior to
registration.
• Active peptic ulcer disease, inflammatory bowel disease, or malabsorption syndrome
within 28 days prior to registration.
• Untreated hypothyroidism (treated hypothyroidism on thyroid replacement therapy is
allowed. Abnormal thyroid-stimulating hormone (TSH) is acceptable with normal T3/free
T4 if treated on thyroid replacement therapy)
• Evidence of pancreatitis, history of organ transplant, or history of congenital QT
syndrome.
• Active treatment with coumarin agents (e.g., warfarin), direct thrombin inhibitors
(e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g.,
clopidogrel) within 5 days of registration. Allowed anticoagulants include:
prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses of
LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban,
apixaban. Allowed also in patients with known brain metastases who are on a stable
dose of the anticoagulant for at least 1 week prior to registration without clinically
significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] or
non-ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart
Association class 3-4 heart failure symptoms
Clear Cell Renal Cell Carcinoma, Metastatic Malignant Neoplasm in the Bone, Sarcomatoid Renal Cell Carcinoma, Metastatic Malignant Neoplasm in the Soft Tissues, Stage IV Renal Cell Cancer AJCC v8, Metastatic Malignant Neoplasm in the Viscera, Metastatic Malignant Neoplasm in the Lymph Nodes, Stage III Renal Cell Cancer AJCC v8
Safety and Efficacy Study of IMSA101 in Refractory Malignancies
Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients
receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor
(ICI) (Phase I and II)
1. Signed informed consent and mental capability to understand the informed consent
2. Male or female patients > 18 years of age
3. Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancies refractory to or otherwise ineligible for treatment with standard-of-care
agents/regimens, including but not limited to:
• Malignant melanoma
• Hormone receptor negative breast cancer
• Gastro-esophageal cancer
• Non-small cell lung cancer
• Head and neck cancer
• Hepatoma
• Renal cell carcinoma
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5. Evaluable or measurable disease as follows:
• A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and
biopsied; one non-injected that will be biopsied for abscopal effect; and one
measurable lesion that will be followed for response only.
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous
injection only, including those lesions that are visible, palpable, or detectable
by standard radiographic or ultrasound methods. Neither surgical procedures nor
endoscopically-guided injections including those to endobronchial, endoluminal,
or endosinusial spaces shall be allowed. While no anatomic locations are required
or disallowed, lesions selected for intratumoral injection must, in the opinion
of the investigator:
• Not be immediately adjacent to blood vasculature or other physiologic landmarks
in such a way that will accrue undue safety risk to the patient
• Have longest diameter ≥ 10 mm and ≤ 50 mm
• Be fully efficacy evaluable per RECIST v1.1 criteria
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA)
7. ECG without evidence of clinically meaningful conduction abnormalities or active
ischemia as determined by the investigator
8. Acceptable organ and marrow function as defined below:
• Absolute neutrophil count > 1,500 cells/μL
• Platelets > 50,000 cells/μL
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If
liver metastases are present, AST/ALT < 5 times ULN
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min
using the Cockcroft-Gault formula
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN
9. Women of child-bearing potential (defined as a female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at
the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy
test prior to first dose of study drug
10. Male and female patients with reproductive potential must agree to use two forms of
highly effective contraception throughout the study
11. Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive
cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events
considered by the investigator to be drug-related.
Exclusion Criteria:
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug.
2. Failure to recover to Grade 1 or less from clinically significant AEs due to prior
anti-cancer therapy.
3. Known untreated brain metastases or treated brain metastases that have not been stable
(scan showing no worsening of central nervous system (CNS) lesion[s] and no
requirement of corticosteroids) ≥ 4 weeks prior to study enrollment
4. Baseline prolongation of QT/QTc interval (QTc interval > 470)
5. Uncontrolled intercurrent illness (including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations) that in opinion of the
investigator would limit compliance with study requirements
6. Women who are pregnant or breastfeeding
7. Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI
therapy.
Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
This phase I/II trial studies how well tiragolumab and atezolizumab works when given to
children and adults with SMARCB1 or SMARCA4 deficient tumors that that has either come back
(relapsed) or does not respond to therapy (refractory). SMARCB1 or SMARCA4 deficiency means
that tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancers
that are typically hard to treat. Immunotherapy with monoclonal antibodies, such as
tiragolumab and atezolizumab, may help the body's immune system attack the cancer, and may
interfere with the ability of tumor cells to grow and spread.
• Patients must be >= 12 months of age at the time of study enrollment. For part A,
patients must be <18 years old at enrollment. For part B, there is no upper age limit
• The Part B (phase 2) cohorts will initially open concurrently with the part A but
will only enroll patients at least 18 years of age. Patients <18 years of age
will be included in the part B cohorts only after the tiragolumab monotherapy
dose has been assessed to be safe in the part A portion
• Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through
institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic
tumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory
Improvement Act (CLIA) certified lab with the following disease histologies:
• Renal medullary carcinoma
• Malignant rhabdoid tumor (extra-CNS)
• Atypical teratoid rhabdoid tumor (CNS)
• Poorly differentiated chordoma
• Epithelioid sarcoma
• Other SMARCB1 or SMARCA4 deficient tumors
• Note: Documentation of the institutional IHC or molecular testing must be
uploaded via the RAVE system
• Part A: Patients must have either measurable or evaluable disease Part B: Patients
must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response
criteria for CNS tumors
• Patients must have relapsed, refractory disease or newly diagnosed disease for which
there is no known curative therapy or therapy proven to prolong survival with an
acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for
patients > 16 years of age and Lansky for patients =< 16 years of age. Note:
Neurologic deficits in patients with CNS tumors must have been stable for at least 7
days prior to study enrollment. Patients who are unable to walk because of paralysis,
but who are up in a wheelchair, will be considered ambulatory for the purpose of
assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
numerical eligibility criteria are met, e.g., blood count criteria, the patient is
considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group
(COG) Members site for commercial and investigational agent classifications. For
agents not listed, the duration of this interval must be discussed with the study
chair and the study-assigned Research Coordinator prior to enrollment
• >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if
prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer
Agents on the COG website:
https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyel
osuppressiveAnti-CancerAgents.pdf
• Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent. See the DVL homepage on the COG Members site for commercial
and investigational agent classifications. For agents not listed, the duration of
this interval must be discussed with the study chair and the study-assigned
Research Coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For
agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Autologous stem cell infusion including boost infusion: >= 30 days
• Cellular therapy: >= 30 days after the completion of any type of cellular therapy
(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• External radiation therapy (XRT)/external beam irradiation including protons: >=
14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation
to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131
metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered
radiopharmaceutical therapy
• Patients must not have had prior TIGIT targeting therapy
• Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1,
anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory
or co-inhibitory T cell receptor (i.e. OX-40, CD137)
• Patients must not have received live/attenuated vaccine within 30 days of first
dose of treatment
• Patients must not be receiving concomitant systemic steroid medications and > 14
days must have elapsed since last dose of systemic corticosteroid with the
following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10
mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are acceptable
• Treatment with systemic immunosuppressive medication (including, but not limited
to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor-alpha [TNF-alpha] agents) must have concluded >= 14 days prior to
study enrollment
• For patients with solid tumors without known bone marrow involvement
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7
days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment) (must be performed
within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided
they meet the blood counts above (may receive transfusions provided they are not known
to be refractory to red cell or platelet transfusions). These patients will not be
evaluable for hematologic toxicity
• A creatinine based on age/gender as follows (must be performed within 7 days prior to
enrollment):
• Age; Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years; Male: 0.6; Female: 0.6
• 2 to < 6 years; Male: 0.8; Female: 0.8
• 6 to < 10 years; Male: 1; Female: 1
• 10 to < 13 years; Male: 1.2; Female: 1.2
• 13 to < 16 years; Male: 1.5; Female: 1.4
• >= 16 years; Male: 1.7; Female: 1.4 OR- a 24 hour urine creatinine clearance
>= 70 mL/min/1.73 m^2 (must be performed within 7 days prior to enrollment)
OR- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be
performed using direct measurement with a nuclear blood sampling method OR
direct small molecule clearance method (iothalamate or other molecule per
institutional standard) (must be performed within 7 days prior to
enrollment)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal
(ULN) for age (must be performed within 7 days prior to enrollment)
• Patients with known Gilbert disease: Total bilirubin < 3 x ULN
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(must be performed within 7 days prior to enrollment). For the purpose of this study,
the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5)
resulting from prior therapy must be =< grade 2, with the exception of decreased
tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to
enrollment)
• Serum amylase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Serum lipase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Grade 1 or lower calcium level
• Note: can have history of hypercalcemia as long as controlled and asymptomatic
Exclusion Criteria:
• Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because there
is yet no available information regarding human fetal or teratogenic toxicities.
Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of
reproductive potential may not participate unless they have agreed to use two
effective methods of birth control, including a medically accepted barrier or
contraceptive method (e.g., male or female condom) for the duration of therapy and at
least 90 days after final dose of tiragolumab and 150 days after final dose of
atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
• It is not known if atezolizumab or tiragolumab are present in breast milk;
however, IgG immunoglobulins are found in milk. Due to the potential for serious
adverse reactions in the breastfed infant, breastfeeding is not recommended
during therapy and for at least 150 days after the last dose of atezolizumab and
90 days after the last dose of tiragolumab, whichever is later
• Concomitant medications:
• Corticosteroids:
• Patients must not be receiving concomitant systemic steroid medications and
>= 14 days must have elapsed since last dose of systemic corticosteroid with
the following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10
mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are
acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g. 48
hours of corticosteroids for a contrast allergy) are acceptable
• Investigational drugs: Patients who are currently receiving another
investigational drug are not eligible
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
are not eligible
• Systemic immunosuppressive medications (including, but not limited to,
cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study
treatment because these agents could potentially alter the efficacy and safety of
study treatments would not be eligible
• Patients must not have a known hypersensitivity to any component of tiragolumab or
atezolizumab injection
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab or tiragolumab formulation
• Patients who have undergone allogeneic bone marrow or stem cell transplant are not
eligible
• Patients with known, untreated CNS metastases will be excluded with the following
exceptions:
• Patients with a history of CNS metastases that have been previously treated may
enroll if sequential imaging shows no evidence for active disease in the CNS
• Patients must not have active autoimmune disease that has required systemic treatment
in the past 12 months, or a documented history of clinically severe autoimmune
disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
Subjects with vitiligo or resolved childhood asthma/atopy are not excluded.
Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment and these patients are eligible
• Patients who have active immune deficiency are not eligible
• Patients who have known active tuberculosis are not eligible
• Hepatitis B or C infection:
• Patients < 18 years old at enrollment, who have known hepatitis B or C
• Patients >= 18 years old at enrollment with:
• Positive hepatitis B surface antigen (HBsAg), OR
• Positive total hepatitis B core antibody (HBcAb) who have a quantitative
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) >= 500 IU/mL, OR
• Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid
(RNA) test
• Note: For adults (>= 18 years old at enrollment), hepatitis B serology testing is
required to determine eligibility. The HBV DNA test is required only for patients
who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb
test. For adults (>= 18 years old at enrollment), hepatitis C serology testing is
required to determine eligibility. The HCV RNA test is required only for patients
who have a positive HCV antibody test
• Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history
of chronic, active infection are not eligible
• Patients who have history of or active human immunodeficiency virus (HIV) are not
eligible except patients who are stable on anti-retroviral therapy, have a CD4 count
>= 200/uL, and have an undetectable viral load
• Patients who have significant cardiovascular disease (such as New York Heart
Association class III or IV congestive heart failure, myocardial infarction, or
cerebrovascular accident) within 3 months prior to study enrollment, unstable
arrhythmia, or unstable angina are not eligible
• Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks
prior to study enrollment, or the anticipation of the need for a major surgical
procedure during the study are not eligible
• Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia,
drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not
eligible. History of radiation pneumonitis in the radiation field is permitted
• Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites
requiring recurrent drainage procedures (once monthly or more frequently) are not
eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible
Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Participants With Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease (EBV+ PTLD) After Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)
The purpose of this study is to determine the clinical benefit and characterize the safety
profile of tabelecleucel for the treatment of Epstein-Barr virus-associated post-transplant
lymphoproliferative disease (EBV+ PTLD) in the setting of (1) solid organ transplant (SOT)
after failure of rituximab and rituximab plus chemotherapy or (2) allogeneic hematopoietic
cell transplant (HCT) after failure of rituximab.
1. Prior SOT of kidney, liver, heart, lung, pancreas, small bowel, or any combination of
these (SOT cohort); or prior allogeneic HCT (HCT cohort)
2. A diagnosis of locally-assessed, biopsy-proven EBV+ PTLD
3. Availability of appropriate partially HLA-matched and restricted tabelecleucel has
been confirmed by the sponsor
4. Measurable, 18F-deoxyglucose (FDG)-avid (Deauville score ≥ 3) systemic disease using
Lugano Classification response criteria by positron emission tomography
(PET)-diagnostic computed tomography (CT), except when contraindicated or mandated by
local practice, then magnetic resonance imaging (MRI) may be used.For subjects with
treated central nervous system (CNS) disease, a head CT and/or brain/spinal MRI as
clinically appropriate will be required to follow CNS disease response per Lugano
Classification response criteria.
5. Treatment failure of rituximab or interchangeable commercially available biosimilar
monotherapy (SOT subgroup A or HCT cohort) or rituximab plus any concurrent or
sequentially administered chemotherapy regimen (SOT subgroup B) for treatment of PTLD.
6. Eastern Cooperative Oncology Group performance status ≤ 3 for subjects aged ≥ 16
years; Lansky score ≥ 20 for subjects < 16 years
7. For HCT cohort only: If allogeneic HCT was performed as treatment for an acute
lymphoid or myeloid malignancy, the underlying primary disease for which the subject
underwent transplant must be in morphologic remission
8. Adequate organ function
1. Absolute neutrophil count ≥ 1000/μL, (SOT cohort) or ≥ 500/μL (HCT cohort), with
or without cytokine support
2. Platelet count ≥ 50,000/μL, with or without transfusion or cytokine support. For
HCT cohort, platelet count < 50,000/μL but ≥ 20,000/μL, with or without
transfusion support, is permissible if the subject has not had grade ≥ 2 bleeding
in the prior 4 weeks (where grading of the bleeding is determined per the
National Cancer Institute's Common Terminology Criteria for Adverse Events
[CTCAE], version 5.0)
3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total
bilirubin each < 5 × the upper limit of normal; however, ALT, AST, and total
bilirubin each ≤ 10 × upper limit of normal is acceptable if the elevation is
considered by the investigator to be due to EBV and/or PTLD involvement of the
liver as long as there is no known evidence of significant liver dysfunction
9. Subject or subject's representative is willing and able to provide written informed
consent
Exclusion Criteria:
1. Burkitt lymphoma, classical Hodgkin lymphoma, or any T cell lymphoma
2. Daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing
methotrexate, or extracorporeal photopheresis
3. Untreated CNS PTLD or CNS PTLD for which the subject is actively receiving
CNS-directed chemotherapy (systemic or intrathecal) or radiotherapy at enrollment.
NOTE:Subjects with previously treated CNS PTLD may enroll if CNS-directed therapy is
complete.
4. Suspected or confirmed grade ≥ 2 graft-versus-host disease (GvHD) per the Center for
International Blood and Marrow Transplant Research consensus grading system at
enrollment
5. Ongoing or recent use of a checkpoint inhibitor agent (eg, ipilimumab, pembrolizumab,
nivolumab) within 3 drug half-lives from the most recent dose to enrollment
6. For HCT cohort: active adenovirus viremia
7. Need for vasopressor or ventilatory support
8. Antithymocyte globulin or similar anti-T cell antibody therapy ≤ 4 weeks prior to
enrollment
9. Treatment with Epstein-Barr virus cytotoxic T lymphocytes or chimeric antigen receptor
T cells directed against B cells within 8 weeks of enrollment (SOT or HCT cohorts), or
unselected donor lymphocyte infusion within 8 weeks of enrollment (HCT cohort only)
10. Female who is breastfeeding or pregnant or female of childbearing potential or male
with a female partner of childbearing potential unwilling to use a highly effective
method of contraception
11. Inability to comply with study-related procedures
Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score (TEAMMATE)
The TEAMMATE Trial will enroll 210 pediatric heart transplant patients from 25 centers at 6
months post-transplant and follow each patient for 2.5 years. Half of the participants will
receive everolimus and low-dose tacrolimus and the other half will receive tacrolimus and
mycophenolate mofetil. The trial will determine which treatment is better at reducing the
cumulative risk of coronary artery vasculopathy, chronic kidney disease and biopsy
proven-acute cellular rejection without an increase in graft loss due to all causes (e.g.
infection, PTLD, antibody mediated rejection).
1. Orthotopic heart transplantation
2. Age < 21 years at time of transplant
3. Stable immunosuppression at the time of randomization with no contraindication to
everolimus, tacrolimus, or mycophenolate mofetil
4. Planned follow-up at a study site for the 30 month duration of the study.
5. Subject or legal adult representative capable of providing informed consent (in
general, assent will be sought for children aged 12 years or older).
Exclusion Criteria:
1. Multi-organ transplant (e.g. heart-lung or heart-liver).
2. Known hypersensitivity to everolimus, sirolimus, tacrolimus or mycophenolate mofetil
(MMF), or to components of the drug products.
3. Patients on maintenance corticosteroid therapy exceeding a dose equivalent of
prednisone 0.1 mg/kg/day at randomization.
4. High-risk for rejection defined as active rejection, recurrent (≥ 2 episodes of grade
2R rejection) cellular rejection, recurrent rejection (≥ 2 episodes of any grade) with
hemodynamic compromise, steroid-resistant rejection or unresolved antibody-mediated
rejection during the first 6 months post-heart transplant
5. Graft dysfunction (LVEF <40% or wedge pressure >22 mmHg or cardiac index <2.2
L/min/m2)
6. Stage 4 or 5 CKD (eGFR <30 ml/min/1.73 m2) or moderate proteinuria (urine protein to
urine creatinine ratio >0.5 mg/mg).
7. Active infection requiring hospitalization or treatment dose medical therapy.
8. Patients with ongoing wound healing problems, clinically significant wound infection
requiring continued therapy or other severe surgical complication in the opinion of
the Site Principal Investigator.
9. Fasting Serum Cholesterol ≥300 mg/dL OR greater than or equal to 7.75 mmol/L, AND
fasting triglycerides ≥2.5x the upper limit of normal (ULN). Note: In case one or both
of these thresholds are exceeded, the patient can only be included after initiation of
appropriate lipid lowering medication, and reduction of serum cholesterol and
triglyceride levels to below exclusion ranges is confirmed.
10. Uncontrolled diabetes mellitus.
11. Diagnosis of post-transplant lymphoproliferative disorder (PTLD) during the first 6
months post-heart transplant.
12. History of non-adherence to medical regimens.
13. Patients who are treated with drugs that are strong inducers or inhibitors of
cytochrome P450 3A4 (CYP3A4) and cannot discontinue the treatment
14. Patients who are pregnant or breast-feeding or intend to get pregnant during the study
period.
Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors
This phase II trial studies how well cabozantinib works in combination with nivolumab and
ipilimumab in treating patients with rare genitourinary (GU) tumors that that has spread from
where it first started (primary site) to other places in the body. Cabozantinib may stop the
growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy
with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune
system attack the cancer, and may interfere with the ability of tumor cells to grow and
spread. Giving cabozantinib, nivolumab, and ipilimumab may work better in treating patients
with genitourinary tumors that have no treatment options compared to giving cabozantinib,
nivolumab, or ipilimumab alone.
• Metastatic disease defined as new or progressive lesions on cross-sectional imaging or
bone scan. Patients must have at least:
• One measurable site of disease as per Response Evaluation Criteria in Solid
Tumors (RECIST) version (v) 1.1
• One bone lesion on bone scan (tec99 or sodium fluoride [NaF] PET/CT, CT or MRI)
for the bone-only cohort.
• Histologically confirmed diagnosis of one of the following metastatic cohorts:
• Small cell/ neuroendocrine carcinoma of the bladder- All urothelial
carcinomas with any amount of neuroendocrine differentiation (including
small cell differentiation) will be included. If the tumor is purely
neuroendocrine, metastasis from another site of origin should be clinically
excluded
• Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra
clear cell adenocarcinoma •must be pure (per World Health Organization
[WHO] definition), (i.e. urothelial carcinoma with glandular differentiation
is not considered a pure adenocarcinoma
• Squamous cell carcinoma of the bladder •must be pure (i.e. urothelial
carcinoma with squamous differentiation is not considered a pure squamous
cell carcinoma)
• Plasmacytoid urothelial carcinoma •Tumor should show predominantly > or
equal ~ 50% plasmacytoid histology (including all types of discohesive
growth, such as tumors with signet-ring and/or rhabdoid features as well)
• Any penile cancer
• Sarcomatoid renal cell carcinoma •Tumor should be predominantly sarcomatoid
~ 50% (including rhabdoid differentiation) is also unclassified renal cell
carcinomas (RCCs): all (assuming they are high grade with metastasis)
malignant angiomyolipomas are allowed
• Sarcomatoid urothelial carcinoma •Tumor should show predominantly ~ 50%
sarcomatoid differentiation
• Renal medullary carcinoma •Per WHO definition, ideally confirmed with
immunostains
• Renal collecting duct carcinoma •Per WHO definition (medullary involvement,
predominant tubular morphology, desmoplastic stromal reaction, high grade
cytology, infiltrative growth pattern, and absence of other renal cell
carcinoma subtype or urothelial carcinoma)
• Bone only urothelial carcinoma or other non-prostate GU tumor
• Urethra carcinoma- May be of any histology but if urothelial carcinoma then
must be isolated to the urethra and not have metachronous or synchronous
urothelial carcinoma of the bladder
• Other miscellaneous histologic variants of the urothelial carcinoma, such
as, but not limited to : micropapillary (Tumor should show predominantly >
or equal 50% micropapillary architecture), giant cell, lipid-rich, clear
cell and nested variants (Tumor should predominantly > or equal 50% show
these features), large cell neuroendocrine carcinoma, lymphoepithelioma-like
carcinoma and mixed patterns will be considered, as well as small cell
neuroendocrine prostate cancer (Only treatment-naïve primary small cell of
prostate with any amount of small cell component allowed. Post-treatment
small cell prostatic carcinomas are not allowed), Malignant testicular
Sertoli or Leydig cell tumors, and papillary and chromophobe RCC
• Note: Translocation positive renal cell carcinoma patients are
eligible. However, AREN1721 should be considered before this trial
• Hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective
central pathology review
• Patients may have received up to 2 systemic anti-cancer treatments or be treatment
naive. Patients with small cell carcinoma should have received a platinum-based
combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients
in the bone-only cohort may be urothelial carcinoma histology but must receive
standard cisplatin-based chemotherapy (if cisplatin-eligible)
• Age >= 18 years
• Patients must be able to swallow oral formulation of the tablets
• Karnofsky performance status >= 80%
• Absolute neutrophil count (ANC) >= 1,000/mcL
• Platelet count >= 75,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal (ULN). For subjects with known
Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total
bilirubin =< 3.0 mg/dL
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional
upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastases or
Gilbert's disease)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40
mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology [CKD-EPI]
equation or Cockcroft-Gault formula) for patients with creatinine levels above
institutional normal
• Hemoglobin >= 9 g/dL (transfusion of packed red blood cells [PRBCs] allowed)
• Serum albumin >= 3.2 g/dL
• Lipase and amylase =< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or
clinical evidence of pancreatitis
• Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib
will not be allowed. Also, patients that have received both prior MET or VEGF and
prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed
• Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4
inhibitors is allowed, either in the perioperative or in the metastatic setting.
However, patients that have received both prior MET or VEGF and prior
PD-1/PD-L1/CTLA-4 (sequentially or in combination) are not allowed
• Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of
highly active antiretroviral therapy (HAART), no clinically significant drug-drug
interactions are anticipated with the current HAART regimen, CD4 counts are greater
than 350 and viral load is undetectable
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's
syndrome and psoriasis controlled with topical medication only and patients with
positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc.
are eligible but should be considered for rheumatologic evaluation for the presence of
target organ involvement and potential need for systemic treatment
• Patients with vitiligo, endocrine deficiencies including thyroiditis managed with
replacement hormones or medications (e.g. thyroiditis managed with propylthiouracil
[PTU] or methimazole) including physiologic oral corticosteroids are eligible
• Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess,
and gastrointestinal (GI) obstruction, within 12 months are not eligible
• Women of childbearing potential must have a negative pregnancy test =< 7 days prior to
registration
• Women of childbearing potential include women who have experienced menarche and
who have not undergone successful surgical sterilization (hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post
menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have
been amenorrheic for 12 or more months are still considered to be of childbearing
potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,
ovarian suppression or any other reversible reason
• Pregnant women may not participate in this study because with cabozantinib, nivolumab,
and ipilimumab have potential for teratogenic or abortifacient effects. Because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with cabozantinib, nivolumab, and ipilimumab, breastfeeding
should be discontinued if the mother is treated with these agents
• The patient has received no cytotoxic chemotherapy (including investigational
cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2
weeks before the first dose of study treatment
• The patient has received no radiation therapy:
• To the lungs and mediastinum or abdomen within 4 weeks before the first dose of
study treatment, or has ongoing complications, or is healing from prior radiation
therapy
• To brain metastasis within 3 weeks for whole-brain radiotherapy (WBXRT), and 2
weeks for stereotactic body radiation therapy (SBRT) before the first dose of
study treatment
• To the abdomen within 4 weeks before the first dose of study treatment, or has
ongoing complications, or is healing from prior radiation therapy
• To any other site(s) within 2 weeks before the first dose of study treatment
• The patient has received no radionuclide treatment within 6 weeks of the first dose of
study treatment
• The patient has received no prior treatment with a small molecule kinase inhibitor
within 14 days or five half-lives of the compound or active metabolites, whichever is
longer, before the first dose of study treatment
• The patient has received no prior treatment with hormonal therapy within 14 days or
five half-lives of the compound or active metabolites, whichever is longer, before the
first dose of study treatment. Subjects receiving gonadotropin-releasing hormone
(GnRH) agonists and antagonists are allowed to participate
• The patient has not received any other type of investigational agent within 14 days
before the first dose of study treatment
• The patient must have recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia,
neuropathy and other non-clinically significant adverse events (AEs) defined as lab
elevation with no associated symptoms or sequelae
• The patient may not have active brain metastases or epidural disease. Patients with
brain metastases previously treated with whole brain radiation or radiosurgery who are
asymptomatic and do not require steroid treatment for at least 2 weeks before starting
study treatment are eligible. Neurosurgical resection of brain metastases or brain
biopsy is permitted if completed at least 3 months before starting study treatment.
Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known
brain metastases is required to confirm eligibility
• No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor
Xa inhibitors, low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low
molecular weight heparin (LMWH) are permitted
• No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St.
John's wort) or strong CYP3A4 inhibitors
• Because the lists of these agents are constantly changing, it is important to
regularly consult medical reference texts such as the Physicians' Desk Reference
may also provide this information. As part of the enrollment/informed consent
procedures, the patient will be counseled on the risk of interactions with other
agents, and what to do if new medications need to be prescribed or if the patient
is considering a new over-the-counter medicine or herbal product
• The patient has not experienced any of the following:
• Clinically-significant gastrointestinal bleeding within 6 months before the first
dose of study treatment
• Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood per day within 1 months
before the first dose of study treatment
• Any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment
• The patient has no tumor invading any major blood vessels
• The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small
or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial
tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor
masses are not eligible
• The patient has no uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) class III
(moderate) or class IV (severe) at the time of screening.
• Concurrent uncontrolled hypertension defined as sustained blood pressure
(BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study
treatment
• The subject has a corrected QT interval calculated by the Fridericia formula
(QTcF) > 500 ms within 28 days before randomization. Note: if initial QTcF
is found to be > 500 ms, two additional electrocardiograms (EKGs) separated
by at least 3 minutes should be performed. If the average of these three
consecutive results for QTcF is =< 500 ms, the subject meets eligibility in
this regard
• Any history of congenital long QT syndrome
• Any of the following within 6 months before registration of study treatment:
• Unstable angina pectoris
• Clinically-significant cardiac arrhythmias (patients with atrial
fibrillation are eligible)
• Stroke (including transient ischemic attack [TIA], or other ischemic
event)
• Myocardial infarction
• Cardiomyopathy
• No significant gastrointestinal disorders particularly those associated with a
high risk of perforation or fistula formation including:
• Any of the following that have not resolved within 28 days before the first
dose of study treatment:
• Active peptic ulcer disease
• Acute diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, or malabsorption syndrome
• None of the following within 2 years before the first dose of study
treatment:
• Abdominal fistula or genitourinary fistula
• Gastrointestinal perforation
• Bowel obstruction or gastric outlet obstruction
• Intra-abdominal abscess. Note: Complete resolution of an
intra-abdominal abscess must be confirmed prior to initiating treatment
with cabozantinib even if the abscess occurred more than 2 years before
the first dose of study treatment
• Disorders associated with a high risk of fistula formation including percutaneous
endoscopic gastrostomy (PEG) tube placement are not eligible
• No other clinically significant disorders such as:
• Severe active infection requiring IV systemic treatment within 14 days
before the first dose of study treatment
• Serious non-healing wound/ulcer/bone fracture within 28 days before the
first dose of study treatment
• History of organ or allogeneic stem cell transplant
• Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
before the first dose of study treatment (for asymptomatic patients with an
elevated thyroid-stimulating hormone [TSH], thyroid replacement may be
initiated if clinically indicated without delaying the start of study
treatment)
• No history of major surgery as follows:
• Major surgery within 3 months of the first dose of cabozantinib; however, if
there were no wound healing complications, patients with rapidly growing
aggressive cancers, may start as soon as 6 weeks if wound has completely
healed post-surgery
• Minor surgery within 1 month of the first dose of cabozantinib if there were
no wound healing complications or within 3 months of the first dose of
cabozantinib if there were wound complications excluding core biopsies and
mediport placement
• Complete wound healing from prior surgery must be confirmed before the first
dose of cabozantinib irrespective of the time from surgery
• No history of severe hypersensitivity reaction to any monoclonal antibody
• No evidence of active malignancy, requiring systemic treatment within 2 years of
registration
• No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in
study
• No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
ribonucleic acid (HCV antibody) indicating acute or chronic infection. If HBV sAG is
positive, subsequent ribonucleic acid (RNA) polymerase chain reaction (PCR) must be
negative
• No patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids. These include, but are not limited to patients
with a history of immune related neurologic disease, multiple sclerosis, autoimmune
(demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic
autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue
diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis,
hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the
risk of recurrence or exacerbation of disease
Study of Ravulizumab in Pediatric Participants With HSCT-TMA
This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of
ravulizumab administered by intravenous infusion to pediatric participants, from 1 month to <
18 years of age, with HSCT-TMA. The treatment period is 26 weeks, followed by a 26-week
off-treatment follow-up period.
1. 1 month of age up to < 18 years of age at the time of signing the informed consent.
2. Received HSCT within the past 6 months.
3. Diagnosis of TMA that persists despite initial management of any triggering condition.
4. Body weight ≥ 5 kilograms.
5. Female participants of childbearing potential and male participants with female
partners of childbearing potential must use highly effective contraception starting at
Screening and continuing until at least 8 months after the last dose of ravulizumab.
6. Participants must be vaccinated against meningococcal infections if clinically
feasible, according to institutional guidelines for immune reconstitution after HSCT.
Participants must be re-vaccinated against Haemophilus influenzae type b and
Streptococcus pneumoniae if clinically feasible, according to institutional guidelines
for immune reconstitution after HSCT. All participants should be administered coverage
with prophylactic antibiotics according to institutional post-transplant infection
prophylaxis guidances, including coverage against Neisseria meningitidis for at least
2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal
vaccine should receive antibiotic prophylaxis coverage against Neisseria meningitidis
the entire Treatment Period and for 8 months following the final dose of ravulizumab.
Exclusion Criteria:
1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13' deficiency (activity < 5%).
2. Known Shiga toxin-related hemolytic uremic syndrome.
3. Positive direct Coombs test.
4. Diagnosis or suspicion of disseminated intravascular coagulation.
5. Known bone marrow/graft failure.
6. Diagnosis of veno-occlusive disease.
7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody
titer).
8. Unresolved meningococcal disease.
9. Presence or suspicion of sepsis (treated or untreated) within 7 days prior to
Screening.
10. Pregnancy or breastfeeding.
11. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
12. Previously or currently treated with a complement inhibitor.
Drug: Ravulizumab, Other: Best Supportive Care
Brain and Nervous System, Kidney, Leukemia, Other, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Thrombotic Microangiopathy
• Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancy.
• Progressed or was intolerant to all available therapies known to confer clinical
benefit appropriate for their tumor type, and for which the patient was eligible and
willing to receive, or refused SOC treatments that are perceived to have marginal
clinical benefit.
• Adequate bone marrow, kidney and liver function.
• Performance status of 0 or 1.
• Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1
except for AEs not constituting a safety risk by Investigator judgement.
Exclusion Criteria:
• Prior treatment targeting ILT2 and/or ILT4 or targeting HLA-G.
Drug: NGM707, Drug: NGM707 plus pembrolizumab, Drug: NGM707, Drug: NGM707, Drug: NGM707, Drug: NGM707 plus pembrolizumab, Drug: NGM707 plus pembrolizumab
Esophageal Cancer, Breast Cancer, Melanoma, Gastric Cancer, Colorectal Cancer, Ovarian Cancer, Glioblastoma, Cervical Cancer, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Mesothelioma, Cholangiocarcinoma, Pancreatic Ductal Adenocarcinoma, Brain and Nervous System, Breast - Female, Breast - Male, Kidney, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Skin, Ovary, Pancreas, Squamous Cell Carcinoma of Head and Neck, Endocervical Cancer
Testing the Addition of an Anti-Cancer Immunotherapy Drug, Avelumab, to Gemcitabine and Carboplatin Chemotherapy Prior to Surgery in Muscle Invasive Urinary Tract Cancer vs. Surgery Alone in Patients Who Are Not Able to Receive Cisplatin Therapy (SWOG GAP TRIAL)
This phase II trial studies the effect of avelumab, gemcitabine and carboplatin before
surgery compared with surgery alone in treating patients with muscle invasive bladder or
upper urinary tract cancer who are not able to receive cisplatin therapy. Immunotherapy with
monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer,
and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs,
such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. Giving avelumab together with gemcitabine and carboplatin before surgery may work
better in lowering the chance of muscle invasive urinary tract cancer growing or spreading,
in patients who cannot receive cisplatin therapy compared to surgery alone.
• Participants must have one of the following:
• Histologically documented muscle-invasive bladder carcinoma (MIBC) from
transurethral resection of bladder tumor (TURBT) within 56 days prior to
registration
• Histologically confirmed high grade upper tract urothelial carcinoma (UTUC)
within 56 days prior to registration, with invasion confirmed by either a mass on
cross-sectional imaging or a tumor directly visualized during upper urinary tract
endoscopy within 56 days prior to registration
• Participants diagnosed with mixed urothelial carcinoma and variant histology
within 56 days prior to registration may be eligible if the majority (> 50%) of
the tumor consists of urothelial carcinoma. Participants with pure non-urothelial
variant histologies or any small cell histology are not eligible
• Participants must have clinical stage T2-T4aN0M0 bladder or upper tract cancer
confirmed by radiologic staging (computed tomography [CT] scan/magnetic resonance
imaging [MRI] abdomen and pelvis, and CT scan/x-ray of the chest) within 56 days prior
to registration
• Participants must have a bone scan within 56 days prior to registration if they have
bone pain or elevated serum alkaline phosphatase
• Participants must have a bimanual examination under anesthesia within 56 days prior to
registration
• Participants must not have received prior systemic chemotherapy, immunotherapy or
radiotherapy for the treatment of muscle invasive bladder cancer (MIBC) or upper tract
urothelial carcinoma (UTUC). Other prior pelvic radiotherapy is allowed if it does not
preclude surgery (radical cystectomy, nephroureterectomy or ureterectomy, based on
location of primary tumor). Prior intravesical therapy is allowed
• Participants must not have received immunosuppressive medication within 14 days prior
to registration, with the exception of intranasal, inhaled, topical steroids, or local
steroid injections (e.g., intra-articular injection) systemic corticosteroids at
physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Participants must be >= 18 years of age
• Participants must have Zubrod performance status 0-2
• Participants must have history and physical examination within 28 days prior to
registration
• Participants must be surgical candidates as deemed by the local site oncologic surgeon
within 28 days prior to registration. This must be clearly documented
• Participants must have a serum creatinine =< the institutional upper limit of normal
(IULN) OR measured OR calculated creatinine clearance >= 30 mL/min using the
Crockroft-Gault Formula. This specimen must have been drawn and processed within 28
days prior to registration
• Participants must be deemed cisplatin-ineligible based on greater than or equal to 1
of the following:
• Zubrod performance status = 2
• Creatinine clearance (calculated by Crockroft-Gault formula or measured) 30 to <
60 ml/min,
• Neuropathy > grade 1
• Hearing loss > grade 1
• Congestive heart failure > grade 2
• Hemoglobin >= 9.0 g/dL (within 28 days prior to registration)
• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to registration)
• Platelets >= 100,000/mcL (within 28 days prior to registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days
prior to registration)
• Aspartate aminotransferase (AST) =< 2.5 x institutional ULN (within 28 days prior to
registration)
• Alanine aminotransferase (ALT) =< 2.5 x institutional ULN (within 28 days prior to
registration)
• Participants with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification and be class
2B or better
• Participants with known human immunodeficiency virus (HIV) must be on effective
anti-retroviral therapy and have undetectable viral load at their most recent viral
load test and within 6 months prior to registration
Exclusion Criteria:
• Participant must not have any other prior malignancy except for the following:
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
prostate cancer Gleason score =< 3+4 in active surveillance, adequately treated stage
I or II cancer from which the participant is currently in complete remission, or any
other cancer from which the participant has been disease free for two years
• Participants must not be pregnant or nursing due to the risk of harm to a fetus or
nursing infant. Women/men of reproductive potential must have a negative serum or
urine pregnancy test within 28 days prior to registration and must have agreed to use
an effective contraceptive method. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
In addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
bilateral tubal ligation. However, if at any point a previously celibate participant
chooses to become heterosexually active during the time period for use of
contraceptive measures outlined in the protocol, he/she is responsible for beginning
contraceptive measures
• Participants must not have a history of active primary immunodeficiency
• Participants must not have a history of or active autoimmune or inflammatory disorder,
with the exception of vitiligo, alopecia, hypothyroidism (stable on hormone
replacement), or chronic skin condition that does not require systemic therapy
Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall, Stage II Bladder Cancer AJCC v8, Urinary Bladder, Infiltrating Renal Pelvis and Ureter Urothelial Carcinoma
Evaluation of [18F]FLT PET/CT as an Early Predictor of Outcome in Pediatric Solid Tumors
The experimental [18F]FLT-PET/CT will be completed before initiation of chemotherapy at
either diagnosis or initiation of salvage chemotherapy at relapse and prior to the third
cycle (or month) of chemotherapy. Laboratory analysis and correlative radiology, as directed
per clinical care based on the primary diagnosis, are required within 30 days of the baseline
[18F]FLT PET/CT. Follow-up will comprise 24 months of standard practice treatment and follow
up.
• Patients with histologically confirmed solid tumor malignancies with residual tumors
present that require standard of care chemotherapy for a minimum number of cycles. All
anatomical sites and all tumor histologies are eligible including central nervous
system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8 •25 years
• In the opinion of the investigator, patients must be thought to be able to lie still
for imaging without sedation for 20 •30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test
as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
Exclusion Criteria:
• Patients with known allergic or hypersensitivity reactions to previously administered
radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment
in the study. Relapsed patients are eligible prior to starting their relapsed
chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).
Drug: [18F]FLT-PET/CT
Sarcoma, Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Breast - Female, Breast - Male, Carcinoid Tumor, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Small Intestine, Soft Tissue
A Study to Evaluate the Effectiveness and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis
AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and
create free light chains that cannot be broken down. These free light chains bind together to
form amyloid fibrils that build up in the extracellular space of organs, affecting the
kidneys, heart, liver, spleen, nervous system and digestive tract.
The primary purpose of this study is to determine if CAEL-101 improves the overall survival
in Patients with cardiac AL Amyloidosis.
• Each patient must meet the following criteria to be enrolled in this study.
1. Be able to and provide written informed consent and be willing and able to comply
with all study procedures
2. Adult, 18 years and older
3. AL amyloidosis Mayo stage IIIb based on the 2013 European Modification of the
2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement
at the time of Screening
4. Measurable hematologic disease at Screening as defined by at least one of the
following:
1. Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or
2. Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or
3. Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL
5. Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid
deposits by at least one of the following:
1. Immunohistochemistry or
2. Mass spectrometry or
3. Characteristic electron microscopy appearance
6. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart
failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence
of an alternative explanation for heart failure AND b. At least one of the
following: i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or
ii. Echocardiogram demonstrating a mean left ventricular wall thickness
(calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other
causes (e.g., severe hypertension, aortic stenosis), which would adequately
explain the degree of wall thickening or
iii. Cardiac MRI with gadolinium contrast agent diagnostic or cardiac amyloidosis
7. Planned first-line treatment for plasma cell disorder is a CyBorD-based regimen
administered as Standard of Care (SoC)
8. Adequate bone marrow reserve and hepatic function as demonstrated by:
1. Absolute neutrophil count ≥ 1.0 x 109/L
2. Platelet count ≥ 75 x 109/L
3. Hemoglobin ≥ 9 g/dL
4. Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless
due to Gilbert's syndrome.
5. Aspartate aminotransferase (AST) ≤ 3 x ULN
6. Alanine aminotransferase (ALT) ≤ 3 x ULN
7. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly
and isozymes specific to liver, rather than bone)
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test
during Screening and must agree to use highly effective physician approved
contraception from Screening to at least 5 months following the last study drug
administration or 12 months following the last dose of her PCD therapy, whichever
is longer
10. Men must be surgically sterile or must agree to use effective physician approved
contraception and refrain from donating sperm from Screening to at least 5 months
following the last study drug administration or 12 months following the last dose
of his PCD therapy, whichever is longer.
Exclusion Criteria:
• Patients who meet any of the following criteria will not be permitted entry to the
study.
1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure
of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are
obtained and prior to randomization is allowed.
3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells
> 10% or biopsy-proven bony or extramedullary plasmacytoma AND any one or more of
the following CRAB features:
a. Evidence of end organ damage that can be attributed to the underlying plasma
cell proliferative disorder, specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the ULN or >
2.75 mmol/L (> 11mg/dL)
ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum
creatinine > 177mol/L (> 2mg/dL)
iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a
hemoglobin value < 100g/L
iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or
PET/CT. If bone marrow has < 10% clonal plasma cells, more than one bone lesion
is required to distinguish from solitary plasmacytoma with minimal marrow
involvement
OR
b. Any one of the following biomarkers of malignancy:
i. 60% or greater clonal plasma cells on bone marrow examination
ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic
hypotension, defined as a decrease in systolic blood pressure upon standing of >
30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the
absence of volume depletion
5. Taking prednisone or its equivalent > 10 mg/day
6. Taking doxycycline
7. Receiving dialysis
8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem
cell collection during the protocol therapy is permitted.
9. Have had myocardial infarction, uncontrolled angina, severe uncontrolled
ventricular arrhythmias within 6 months prior to screening or percutaneous
cardiac intervention with recent stent or coronary artery bypass grafting within
4 months prior to screening. Exacerbation of chronic condition or new acute
condition will require discussion and approval by the Medical Monitor.
10. Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening
11. Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area
< 1.0 cm2) or severe congenital heart disease
12. Have history of sustained ventricular tachycardia or aborted ventricular
fibrillation or a history of atrioventricular nodal or sinoatrial nodal
dysfunction for which a pacemaker/implantable cardioverter-defibrillator (ICD) is
indicated but not placed. (Participants who do have a pacemaker or ICD are
allowed in the study.)
13. QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a
pacemaker may be included regardless of calculated QTc interval.
14. There is evidence of acute ischemia or active conduction system abnormalities
with the exception of any of the following:
1. First degree Atrioventricular (AV)-block
2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
3. Right or left bundle branch block
4. Atrial fibrillation with a controlled ventricular rate. (An uncontrolled
ventricular rate [i.e., > 110 beats per minute] determined by an average of
three beats in lead II or representative beats in lead II is not allowed)
15. Have had major surgery within 4 weeks of randomization or is planning major
surgery during the study. Patients with surgical procedures conducted under local
anesthesia may participate
16. There is active malignancy (including lymphoma) with the exception of any of the
following:
1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ
cervical cancer
2. Adequately treated stage I cancer from which the patient is currently in
remission and has been in remission for > 2 years
3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific
antigen < 10 mg/mL
4. Other localized and/or low risk malignancies may be permitted with Medical
Monitor approval.
17. Have received an investigational drug/device in another clinical investigational
study within 60 days before Screening
18. Hypersensitivity to the study drug
19. Have received a live vaccine within 4 weeks prior to first dose of CyBorD
20. Women who are breast feeding
21. Have any other medical, social or psychological factors that could affect the
patient's safety or ability to consent personally or comply with study
procedures.
A Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors (PIKASSO-01)
The main purpose of this study is to learn more about the safety, side effects, and
effectiveness of LOXO-783. LOXO-783 may be used to treat breast cancer and other solid tumors
that have a change in a particular gene (known as the PIK3CA gene). Participation could last
up to 36 months (3 years) and possibly longer if the disease does not get worse.
• Have advanced breast cancer or another solid tumor with the presence of a PIK3CA
H1047R mutation (or other Sponsor and SRC-approved, activating PIK3CA mutations other
than H1047R mutation)
• Have adequate archival tumor tissue sample available or be approved by the Sponsor for
enrollment if no tumor sample is available.
• Have stopped all cancer treatment and have recovered from the major side effects
• Have adequate organ function, as measured by blood tests
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
scale
• Patients must have
• Measurable disease
--- Patients with non-breast tumor types must have at least 1 measurable lesion
• Non-measurable bone disease (at least one bone lesion in breast cancer patients
only)
• For patients with an ER+ breast cancer diagnosis:
• If female, must be postmenopausal
• If male, must agree to use hormone suppression
• Phase 1a:
-- Dose escalation and backfill patients:
• Advanced solid tumor
• Patients may have had up to 5 prior regimens for advanced disease
• Phase 1b:
• Part A:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease
• Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required
• Part B:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease.
• Part C:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease.
---- Prior CDK4/6 inhibitor therapy required.
• Have a diagnosis of diabetes mellitus Type 2
• Part D:
• Advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease.
• Part E:
• Advanced solid tumor
• Patients may have had up to 3 prior regimens for advanced disease
Exclusion Criteria:
• Medical Conditions
• Colorectal cancer
• Endometrial cancers with specific concurrent oncogenic alterations
• A history of known active or suspected
• Diabetes mellitus Type 1 or
• Diabetes mellitus Type 2 requiring antidiabetic medication (Phase 1a and all
parts of Phase 1b except Part C).
• Serious concomitant systemic disorder
• Known or suspected history of untreated or uncontrolled central nervous system (CNS)
involvement.
• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection, or
other clinically significant active disease process
• Prior exposure to PI3K/AKT/mTOR inhibitor(s), except in certain circumstances
Breast Cancer, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Kaposis sarcoma, Small Intestine, Soft Tissue, Unknown Sites
A Study to Evaluate the Effectiveness and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis
AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and
create free light chains that cannot be broken down. These free light chains bind together to
form amyloid fibrils that build up in the extracellular space of organs, affecting the
kidneys, heart, liver, spleen, nervous system and digestive tract.
The primary purpose of this study is to determine if CAEL-101 improves the overall survival
in Patients with cardiac AL Amyloidosis.
• Each patient must meet the following criteria to be enrolled in this study.
1. Be able to and provide written informed consent and be willing and able to comply
with all study procedures
2. Adult, 18 years and older
3. AL amyloidosis Mayo stage IIIa based on the 2013 European Modification of the
2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement
at the time of Screening
4. Measurable hematologic disease at Screening as defined by at least one of the
following:
1. Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or
2. Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or
3. Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL
5. Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid
deposits by at least one of the following:
1. Immunohistochemistry or
2. Mass spectrometry or
3. Characteristic electron microscopy appearance
6. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart
failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence
of an alternative explanation for heart failure AND b. At least one of the
following: i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or
ii. Echocardiogram demonstrating a mean left ventricular wall thickness
(calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other
causes (e.g., severe hypertension, aortic stenosis), which would adequately
explain the degree of wall thickening or
iii. Cardiac MRI with gadolinium contrast agent diagnostic or cardiac amyloidosis
7. Planned first-line treatment for plasma cell dyscrasia is a CyBorD-based regimen
administered as Standard of Care (SoC)
8. Adequate bone marrow reserve and hepatic function as demonstrated by:
1. Absolute neutrophil count ≥ 1.0 x 109/L
2. Platelet count ≥ 75 x 109/L
3. Hemoglobin ≥ 9 g/dL
4. Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless
due to Gilbert's syndrome.
5. Aspartate aminotransferase (AST) ≤ 3 x ULN
6. Alanine aminotransferase (ALT) ≤ 3 x ULN
7. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly
and isozymes specific to liver, rather than bone)
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test
during Screening and must agree to use highly effective physician approved
contraception from Screening to at least 5 months following the last study drug
administration or 12 months following the last dose of her PCD therapy, whichever
is longer
10. Men must be surgically sterile or must agree to use effective physician approved
contraception and refrain from donating sperm from Screening to at least 5 months
following the last study drug administration or 12 months following the last dose
of his PCD therapy, whichever is longer
Exclusion Criteria:
• Patients who meet any of the following criteria will not be permitted entry to the
study.
1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure
of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are
obtained and prior to randomization is allowed.
3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells
> 10% or biopsy-proven bony or extramedullary plasmacytoma AND any one or more of
the following CRAB features:
a. Evidence of end organ damage that can be attributed to the underlying plasma
cell proliferative disorder, specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the ULN or >
2.75 mmol/L (> 11mg/dL)
ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum
creatinine > 177mol/L (> 2mg/dL)
iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a
hemoglobin value < 100g/L
iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or
PET/CT. If bone marrow has < 10% clonal plasma cells, more than one bone lesion
is required to distinguish from solitary plasmacytoma with minimal marrow
involvement
OR
b. Any one of the following biomarkers of malignancy:
i. 60% or greater clonal plasma cells on bone marrow examination
ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic
hypotension, defined as a decrease in systolic blood pressure upon standing of >
30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the
absence of volume depletion
5. Taking prednisone or its equivalent > 10 mg/day
6. Taking doxycycline
7. Receiving dialysis
8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem
cell collection during the protocol therapy is permitted.
9. Have had myocardial infarction, uncontrolled angina, severe uncontrolled
ventricular arrhythmias within 6 months prior to screening or percutaneous
cardiac intervention with recent stent or coronary artery bypass grafting within
4 months prior to screening. Exacerbation of chronic condition or new acute
condition will require discussion and approval by the Medical Monitor.
10. Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening
11. Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area
< 1.0 cm2) or severe congenital heart disease
12. Have history of sustained ventricular tachycardia or aborted ventricular
fibrillation or a history of atrioventricular nodal or sinoatrial nodal
dysfunction for which a pacemaker/implantable cardioverter-defibrillator (ICD) is
indicated but not placed. (Participants who do have a pacemaker or ICD are
allowed in the study.)
13. QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a
pacemaker may be included regardless of calculated QTc interval.
14. There is evidence of acute ischemia or active conduction system abnormalities
with the exception of any of the following:
1. First degree Atrioventricular (AV)-block
2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
3. Right or left bundle branch block
4. Atrial fibrillation with a controlled ventricular rate. (An uncontrolled
ventricular rate [i.e., > 110 beats per minute] determined by an average of
three beats in lead II or representative beats in lead II is not allowed)
15. Have had major surgery within 4 weeks of randomization or is planning major
surgery during the study. Patients with surgical procedures conducted under local
anesthesia may participate
16. There is active malignancy (including lymphoma) with the exception of any of the
following:
1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ
cervical cancer
2. Adequately treated stage I cancer from which the patient is currently in
remission and has been in remission for > 2 years
3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific
antigen < 10 mg/mL
4. Other localized and/or low risk malignancies may be permitted with Medical
Monitor approval.
17. Have received an investigational drug/device in another clinical investigational
study within 60 days before Screening
18. Hypersensitivity to the study drug
19. Have received a live vaccine within 4 weeks prior to first dose of CyBorD
20. Women who are breast feeding
21. Have any other medical, social or psychological factors that could affect the
patient's safety or ability to consent personally or comply with study
procedures.