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.
Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS) (DUPLEX)
To determine the long-term nephroprotective potential of treatment with sparsentan as
compared to an angiotensin receptor blocker in patients with primary focal segmental
glomerulosclerosis (FSGS).
1. The patient or parent/legal guardian (as appropriate) is willing and able to provide
signed informed consent, and where required, the patient is willing to provide assent,
prior to any screening procedures.
2. The patient has biopsy-proven primary focal segmental glomerulosclerosis (FSGS) or
documentation of a genetic mutation in a podocyte protein associated with FSGS.
3. Sites within the US: The patient is male or female aged 8 to 75 years, inclusive.
Sites outside the US: The patient is male or female aged 18 to 75 years, inclusive.
4. The patient has a urine protein/creatinine (Up/C) ≥1.5 g/g at screening.
5. The patient has an eGFR ≥30 mL/min/1.73 m2 at screening.
6. Women of childbearing potential (WOCBP) must agree to the simultaneous use of 2
medically accepted methods of contraception from Day 1/Randomization until 90 days
after the last dose of study medication.
7. Males must be surgically sterile (more than 3 months post-vasectomy) or must agree to
the use of medically accepted methods of contraception that are considered highly
reliable from Day 1/Randomization until 90 days after the last dose of study
medication.
Key
Exclusion Criteria:
1. The patient has FSGS secondary to another condition.
2. The patient has positive serological tests of primary or secondary glomerular injury
not consistent with a diagnosis of primary or genetic FSGS.
3. The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes
mellitus.
4. The patient has undergone any organ transplantation, with the exception of corneal
transplants, or has received certain immunosuppressive medications.
5. The patient has a documented history of heart failure, coronary artery disease or
cerebrovascular disease.
6. The patient has significant liver disease.
7. The patient is positive at screening for the human immunodeficiency virus (HIV) or
markers indicating acute or chronic hepatitis B infection or hepatitis C infection.
8. The patient has a history of malignancy other than adequately treated basal cell or
squamous cell skin cancer or cervical carcinoma within the past 2 years.
9. The patient has disqualifying laboratory abnormalities during a screening.
10. The patient is >18 years of age with a body mass index (BMI) >40, or is ≤18 years of
age with a BMI in the 99th percentile plus 5 units at screening.
11. The patient has a history of alcohol or illicit drug use disorder.
12. The patient has a history of serious side effect or allergic response to any
angiotensin II antagonist or endothelin receptor antagonist.
13. The female patient is pregnant, plans to become pregnant during the course of the
study, or is breastfeeding.
14. The male patient plans to father a child during the course of the study.
15. The patient, in the opinion of the Investigator, is unable to adhere to the
requirements of the study, including the ability to swallow the study medication
capsules whole.
INTERCEPT Blood System for RBCs Study in Regions at Potential Risk for Zika Virus Transfusion-Transmitted Infections (RedeS)
Stage A: To evaluate the safety and efficacy of red blood cells (RBCs) prepared with the
INTERCEPT Blood System for Red Blood Cells Pathogen Reduction Treatment (PRT) in comparison
to conventional RBCs in patients who require RBC transfusion support.
Stage B: To provide early access to the INTERCEPT pathogen reduction system for RBC in
regions where a substantial proportion of the population has been infected or is at risk of a
transfusion-transmissible infection.
The objectives and design of Stage B will be reassessed on the completion of Stage A, in
consultation with the FDA.
• Age ≥ 4 years.
• Patients who require or are expected to require a transfusion of RBC component(s),
including red cell exchange transfusion
• Signed and dated informed consent form.
• Female patients of child-bearing potential must:
• Have negative serum or urine pregnancy tests prior to study treatment to rule out
pregnancy, and
• Agree to use to use at least one method of birth control that results in a low
failure rate (i.e., less than 1% per year) when used consistently and correctly
such as implants, injectables, combined oral contraceptives, some intrauterine
devices (IUDs), sexual abstinence or vasectomized partner for the duration of
study participation and an additional 28 days.
For 28-day +6-month extension study in chronically transfused patients:
• A diagnosis of a bone marrow failure syndrome requiring repeated RBC transfusion for
congenital or acquired chronic anemia (e.g., sickle cell anemia, thalassemia, other
hemoglobinopathies, myelodysplastic syndrome, aplastic anemia, chemotherapy or stem cell
transplant etc.)
For 28-day +6-month extension study in SCD patients requiring regular repeated RCE.
• Diagnosis of SCD, either HbSS, HbSC or HbSB0 thalassemia, confirmed by Hb
electrophoresis, deoxyribonucleic acid (DNA) analysis or high-performance liquid
chromatography (HPLC)
• Currently participating in an automated RCE transfusion program (for at least 3 months
prior to enrollment) with 3-to-8 week intervals between RCE transfusion episodes
Stage A: Exclusion Criteria
• Confirmed positive baseline serum/plasma antibody specific to IBS RBC (S 303 treated
RBC) as determined by INTERCEPT S 303 antibody screening panel prior to receiving the
first study transfusion
• Pregnant or breast feeding.
• Presence of an RBC warm autoantibody with evidence of active hemolysis.
• Positive DAT as defined below:
• A polyspecific-DAT reaction strength > 2+, or
• A polyspecific-DAT (any strength) in conjunction with pan-reactivity with a
commercial IAT antibody screening panel that precludes the identification of
underlying alloantibodies or indicates the presence of autoantibody.
• Have had an RBC transfusion within 7 days prior to randomization.
• Have received investigational products, including investigational blood products,
pharmacologic agents or imaging materials, within 28 days prior to randomization.
Prior receipt of conventional blood products tested with an investigational NAT test
is not considered ground for exclusion.
• Patients presenting with or expected to have massive hemorrhage (≥10 RBC units within
24 hours) or expected to require massive transfusion protocols. Planned red cell
exchange does not apply.
• Patients who require neonatal transfusions and intrauterine transfusions.
• Pre-existing antibody to RBC antigens that may make the provision of compatible study
RBC components difficult.
• History of transfusion reactions requiring washed RBCs, volume reduced RBC, or RBCs
with additive solution removed.
• Patients with documented IgA deficiency or a history of severe allergic reactions to
blood products.
• For SCD patients to be enrolled into the repeated RCE 28-day +6-month arm of the
study:
• A history of acute chest syndrome in the last 6 months, or hyperhemolysis
syndrome at any time.
• Clinical evidence of splenic hyperfunction or splenic enlargement: ≥18 cm in
longitudinal diameter (diagnosed at the Investigator's discretion according to
the data available, with ultrasound data being preferable).
• Currently receiving chemotherapy for treatment of cancer. Hydroxyurea for SCD is
acceptable if subject has been on stable therapy for 3 months and no changes to
dosage are planned.
• Subject is in active treatment with renal dialysis.
• Any subject for whom a substantial change in the number of RBC components
transfused is anticipated due to anticipated splenectomy, bone marrow transplant,
surgery or other change in clinical status.
• Subject with known G6PD deficiency or requiring treatment with medications that
are known to adversely affect RBC viability or bone marrow function.
Device: INTERCEPT Blood System for Red Blood Cells, Device: Conventional (Control)
A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW)
The researchers are doing this study to see if semaglutide can slow down the growth and
worsening of chronic kidney disease in people with type 2 diabetes. Participants will get
semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants'
study medicine - which treatment participants get is decided by chance. Semaglutide is a
medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes.
Participants will get the study medicine in a pen. Participants will use the pen to inject
the medicine in a skin fold once a week. The study will close when there is enough
information collected to show clear result of the study. The total time participants will be
in this study is about 3 to 5 years, but it could be longer.
• Male or female, age above or equal to 18 years at the time of signing informed
consent. Japan: Male or female, age above or equal to 20 years at the time of signing
informed consent
• Diagnosed with type 2 diabetes mellitus
• HbA1c less than or equal to 10% (less than or equal to 86 mmol/mol)
• Renal impairment defined either by:
1. serum creatinine-based eGFR greater than or equal to 50 and less than or equal to
75 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 300 and less than 5000 mg/g or
2. serum creatinine-based eGFR greater than or equal to 25 and less than 50
mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 100 and less than 5000 mg/g
• Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone
system (RAAS) blocking agent including an angiotensin converting enzyme (ACE)
inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment is
contraindicated or not tolerated. Treatment dose must be stable for at least 4 weeks
prior to the date of the laboratory assessments used for determination of the
inclusion criteria for renal impairment and kept stable until screening
Exclusion Criteria:
• Congenital or hereditary kidney diseases including polycystic kidney disease,
autoimmune kidney diseases including glomerulonephritis or congenital urinary tract
malformations
• Use of any glucagon-like peptide-1 (GLP-1) receptor agonist within 30 days prior to
screening
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or
transient ischaemic attack within 60 days prior to the day of screening
• Presently classified as being in New York Heart Association (NYHA) Class IV heart
failure
• Planned coronary, carotid or peripheral artery revascularisation
• Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal
dialysis
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by
a fundus examination performed within the past 90 days prior to screening or in the
period between screening and randomisation. Pharmacological pupil-dilation is a
requirement unless using a digital fundus photography camera specified for non-dilated
examination
Drug: Semaglutide, Drug: Placebo (semaglutide)
Diabetes Mellitus, Type 2, Kidney
UT Southwestern; Parkland Health & Hospital System
Irinotecan Hydrochloride, Temozolomide, and Dinutuximab With or Without Eflornithine in Treating Patients With Relapsed or Refractory Neuroblastoma
This phase II trial studies how well irinotecan hydrochloride, temozolomide, and dinutuximab
work with or without eflornithine in treating patients with neuroblastoma that has come back
(relapsed) or that isn't responding to treatment (refractory). Drugs used in chemotherapy,
such as irinotecan hydrochloride and temozolomide, 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. Immunotherapy with monoclonal antibodies, such as dinutuximab, may
induce changes in the body's immune system and may interfere with the ability of tumor cells
to grow and spread. Eflornithine blocks the production of chemicals called polyamines that
are important in the growth of cancer cells. Giving eflornithine with irinotecan
hydrochloride, temozolomide, and dinutuximab, may work better in treating patients with
relapsed or refractory neuroblastoma.
• Patients must have had histologic verification of neuroblastoma or
ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the time
of initial diagnosis.
• For the purposes of this study, aggressive multidrug chemotherapy is defined as
chemotherapy including 2 or more agents that must include an alkylating agent and a
platinum-containing compound as intended to treat high-risk disease. The doses of
chemotherapy must be comparable to those used in frontline high-risk neuroblastoma
therapies (examples include A3973, ANBL0532, ANBL09P1, ANBL12P1, and ANBL1531).
Patients must have ONE of the following:
• First episode of recurrent high-risk disease following completion of aggressive
multi-drug frontline high-risk therapy.
• First episode of progressive high-risk disease during aggressive multi-drug
frontline therapy.
• Primary resistant/refractory disease (less than partial response by International
Neuroblastoma Response Criteria [INRC]) detected at the conclusion of at least 4
cycles of aggressive multidrug induction chemotherapy on or according to a
high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1,
ANBL12P1, ANBL1531, etc.).
• Patients must have at least ONE of the following at the time of enrollment:
• Measurable tumor on magnetic resonance imaging (MRI) or computed tomography (CT)
scan. Measurable is defined as >= 10 mm in at least one dimension on
spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates
increased fludeoxyglucose F-18 (FDG) uptake on positron emission tomography (PET)
scan.
• MIBG-avid lesion detected on MIBG scan with positive uptake at a minimum of one
site. This site must represent disease recurrence after completion of therapy,
progressive disease on therapy, or refractory disease during induction.
• Patients with resistant/refractory soft tissue disease that is not MIBG avid or
does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
document the presence of viable neuroblastoma. Biopsy is not required for
patients who have a new site of soft tissue disease (radiographic evidence of
disease progression) regardless of whether progression occurs while receiving
therapy or after completion of therapy.
• Patients with bone marrow disease only will be eligible if they have more than 5%
disease involvement (documented neuroblastoma cells) in at least one sample from
bilateral bone marrow biopsies.
• Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT
eligible for this study.
• 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.
• Primary refractory/resistant patients must have received at least 4 cycles of
frontline high-risk chemotherapy. Frontline therapy may also have included surgery,
chemotherapy, autologous stem cell transplantation (SCT) +/- MIBG, immunotherapy,
radiotherapy, and retinoids but must NOT have received second line therapy for
resistant/refractory, relapsed, or progressive disease. Patients who received
intensified therapy for poor induction response or refractory disease (e.g. MIBG) will
be considered to have received second line therapy and will not be eligible.
• At least 14 days must have elapsed since completion of myelosuppressive therapy.
• 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.
• 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.
• No interim time prior to study entry is required following prior radiation therapy
(RT) for non-target lesions. However, patients must not have received radiation for a
minimum of 4 weeks prior to study entry at the site of any lesion that will be
identified as a target lesion to measure tumor response. Lesions that have been
previously radiated cannot be used as target lesions unless there is radiographic
evidence of progression at the site following radiation or a biopsy done following
radiation shows viable neuroblastoma. Palliative radiation while on study is not
permitted.
• Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
infusions (including stem cell infusions given as supportive care following 131 I-MIBG
therapy) as long as hematologic and other eligibility criteria have been met.
• Patients are eligible >= 6 weeks after therapeutic 131 I-MIBG provided that all other
eligibility criteria are met.
• Subjects who have previously received anti-GD2 monoclonal antibodies with or without
retinoids for biologic therapy are eligible unless they have had progressive disease
while receiving prior anti-GD2 therapy or progressed/relapsed within 3 months of
receiving anti-GD2 therapy. However, eligible patients may NOT have received anti-GD2
monoclonal antibodies in combination with chemotherapy.
• Subjects who have received autologous marrow infusions or autologous stem cell
infusions that were purged using monoclonal antibody linked to beads are eligible.
• Subjects who have previously received DFMO are eligible for this study provided they
have not had progressive disease while receiving DFMO or progressed/relapsed within 3
months of completing DFMO.
• Patients must not have received long-acting myeloid growth factors (e.g.
pegfilgrastim) within 14 days of entry on this study. Seven days must have elapsed
since administration of a short-acting myeloid growth factor.
• For patients with solid tumors (without marrow involvement) including status post SCT:
peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to
enrollment).
• For patients with solid tumors (without marrow involvement) including status post SCT:
platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to
enrollment).
• Patients known to have bone marrow involvement with neuroblastoma are eligible
provided that minimum ANC and transfusion independent platelet count criteria are met
(as above). However, these patients are not evaluable for hematological toxicity.
• Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 or a serum creatinine
based on age/gender as follows:
• 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
• 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
• 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
• 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
• 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)
• >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to
enrollment).
• Total bilirubin =< 1.5 x ULN for age (within 7 days prior to enrollment).
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
ULN for age (=< 225 U/L). For the purpose of this study, the ULN for SGPT is 45 U/L
(within 7 days prior to enrollment).
• Shortening fraction of >= 27% by echocardiography (ECHO) (within 7 days prior to
enrollment).
• Ejection fraction of >= 50% by ECHO or gated radionuclide study (within 7 days prior
to enrollment).
• No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
requirement, and room air pulse oximetry > 94% if there is a clinical indication for
pulse oximetry. Normal pulmonary function tests in patients who are capable of
cooperating with testing (including diffusion capacity of the lung for carbon monoxide
[DLCO)] are required if there is a clinical indication for determination. For patients
who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT
required.
• Patients with a history of central nervous system (CNS) disease must have no clinical
or radiological evidence of active CNS disease at the time of study enrollment.
• Patients with seizure disorders may be enrolled if seizures are well controlled on
anti-convulsants.
• CNS toxicity =< grade 2.
Exclusion Criteria:
• Men and women of childbearing potential and their partners must agree to use adequate
contraception while enrolled on this study. Based on the established teratogenic
potential of alkylating agents, pregnant women will be excluded from this study.
Because of potential risks to breastfed infants due to drug metabolites that could be
excreted in breast milk, female patients who are lactating must agree to stop
breastfeeding or will otherwise be excluded from this study. Females of childbearing
potential must have a negative pregnancy test to be eligible for this study.
• Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT eligible for this
study.
• Patients must have been off pharmacologic doses of systemic steroids for at least 7
days prior to enrollment. Patients who require or are likely to require pharmacologic
doses of systemic corticosteroids while receiving treatment on this study are
ineligible. The only exception is for patients known to require 2 mg/kg or less of
hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
premedication for blood product administration in order to avoid allergic transfusion
reactions. The use of conventional doses of inhaled steroids for the treatment of
asthma is permitted, as is the use of physiologic doses of steroids for patients with
known adrenal insufficiency.
Patients on any other immunosuppressive medications (e.g. cyclosporine, tacrolimus) are not
eligible.
• Patients must not have received prior treatment with irinotecan and temozolomide.
• Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.
Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic
acid, or levetiracetam will be eligible.
• Patients who have received drugs that are strong inducers or inhibitors of CYP3A4
within 7 days prior to study enrollment are not eligible.
• Patients must not have been diagnosed with myelodysplastic syndrome or with any
malignancy other than neuroblastoma.
• Patients with symptoms of congestive heart failure are not eligible.
• Patients must not have >= grade 2 diarrhea.
• Patients who are unable to tolerate oral/nasogastric/gastrostomy medications will not
be eligible for this trial. Additionally, patients with significant malabsorption will
not be eligible for this trial.
• Patients must not have uncontrolled infection.
• Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required permanent discontinuation of the anti-GD2 therapy are not
eligible.
• Patients with a significant intercurrent illness (any ongoing serious medical problem
unrelated to cancer or its treatment) that is not covered by the detailed exclusion
criteria and that is expected to interfere with the action of study agents or to
significantly increase the severity of the toxicities experienced from study treatment
are not eligible.
A Phase I Dose Escalation Study of Single Fraction Ablative Pre-operative Partial Breast (S-PBI) for Early Stage Breast Cancer
The purpose of this phase I trial is to evaluate dose-limiting toxicity while dose escalating
single-fraction preoperative S-PBI to a presumed radioablative dose over 3 cohorts, starting
with 30Gy in 1 fraction and advancing to 34Gy and 38Gy in 1 fraction.
1. Invasive epithelial (ductal, medullary, lobular, papillary, mucinous (colloid), or
tubular) histologies of the breast 3 cm or less(T1-T2cN0) in women who have not
undergone surgery or neoadjuvant endocrine or chemotherapy for current breast cancer
diagnosis
2. Tumor must not involve the overlying skin based on imaging evaluation and/or clinical
exam
3. Age >/= 18 years old and female
4. Greatest Tumor dimension is 3cm or less based on US. MRI measurements can be included
only if performed BEFORE the biopsy
5. Tumor must be unifocal
6. The tumor must be visible on CT scan and/or preferably marked with clip(s) in tumor
7. Patients must undergo an MRI for work up to aid in tumor delineation and to rule out
additional foci of disease. If additional foci of disease are present, they need to
have a negative biopsy to proceed with treatment.If patient cannot have MRI, contrast
enhanced digital mammography (CEDM) is allowed in place of MRI.
8. Clinically and radiographically node negative on ultrasound of the axilla or MRI
9. Estrogen receptor positive or Progesterone receptor positive and Her2neu negative
10. Ability to understand and the willingness to sign a written informed consent.
11. Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control) prior to the start of study and for the duration 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
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:
1. Multi-centric disease
2. Prior RT to the involved breast
3. Tumor size >3cm
4. 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 the opinion of the
investigator, would limit compliance with study requirements
5. Patients who are pregnant or lactating due to the potential exposure to the fetus to
radiation therapy and unknown effects of radiation therapy to lactating females
6. Patients unable to have an MRI or contrast enhanced digital mammography (CEDM)
7. Prior ipsilateral breast cancer
8. Tumor less than 5mm from the skin surface on clinical exam and/or radiographic imaging
9. Patients with active Lupus or scleroderma
A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of
ralinepag when added to pulmonary arterial hypertension (PAH) standard of care or
PAH-specific background therapy in subjects with World Health Organization (WHO) Group 1 PAH.
1. At least 18 years of age.
2. Evidence of a personally signed and dated informed consent form indicating that the
subject has been informed of all pertinent aspects of the study prior to initiation of
any study-related procedures.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures
4. Primary diagnosis of symptomatic PAH.
5. Has had a right heart catheterization (RHC) performed at or within 3 years prior to
Screening (RHC will be performed during Screening if not available) that is consistent
with the diagnosis of PAH.
6. Has WHO/ NYHA functional class II to IV symptoms.
7. If on PAH-specific background oral therapy, subject is on stable therapy with either
an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor
(PDE5-I) or a soluble guanylate cyclase (sGC) stimulator. Subjects may be naïve to
PAH-specific treatment.
8. Has a 6MWD of ≥150 meters.
9. If taking concomitant medications that may affect the clinical manifestations of PAH
(eg, calcium channel blockers, diuretics, digoxin, or L arginine supplementation, beta
blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor
blockers), must be on a stable dose for at least 30 days prior to the Baseline Visit
and the dosage maintained throughout the study. The exception is that the dose of
diuretics must be stable for at least the 10 days prior to Baseline.
10. Both male and female subjects agree to use a highly effective method of birth control
throughout the entire study period from informed consent through to the 30-Day
Follow-up Visit, if the possibility of conception exists. Eligible male and female
subjects must also agree not to participate in a conception process during the study
and for 30 days after the last dose of IMP. Eligible male subjects must agree not to
participate in sperm donation for 90 days after the last dose of IMP.
Exclusion Criteria:
1. For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell
count <200/mm3 within 90 days of Baseline.
2. Must not have 3 or more left ventricular dysfunction risk factors as defined in the
study protocol.
3. Has evidence of more than mild lung disease on pulmonary function tests performed
within 180 days prior to, or during Screening.
4. Has evidence of thromboembolic disease as determined by a V/Q lung scan or local
standard of care diagnostic evaluation at or after diagnosis of PAH.
5. Current diagnosis of ongoing and clinically significant sleep apnea as defined by the
Investigator.
6. Male subjects with a corrected QT interval using Fridericia's formula (QTcF) >450 msec
and female subjects with a QTcF >470 msec on ECG recorded at Screening and analyzed by
the central ECG laboratory. Subjects with evidence of intraventricular conduction
delay, defined as a QRS interval greater than 110 msec, will be excluded if the QTcF
is >500 msec for both males and females.
7. Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension, cirrhosis
or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage,
encephalopathy).
8. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
9. Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the
upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening.
10. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring
dialysis at Screening.
11. Hemoglobin concentration <9 g/dL at Screening.
12. Subjects treated with an IV or SC prostacyclin pathway agent (eg, epoprostenol,
treprostinil, or iloprost) for PAH at any time prior to Baseline (use in vasoreactive
testing is permitted).
13. Subjects currently on or who were treated with an inhaled or oral prostacyclin pathway
agent (iloprost, treprostinil, beraprost, or selexipag) within 90 days prior to
Baseline.
14. Subject has pulmonary veno-occlusive disease.
15. Malignancy diagnosed and/or treated within 5 years prior to Screening, with the
exception of localized non-metastatic basal cell or squamous cell carcinoma of the
skin or in-situ carcinoma of the cervix excised with curative intent.
16. Subject tests positive for amphetamine, cocaine, methamphetamine,
methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at
Screening, or has a recent history (6 months) of alcohol or drug abuse. A subject will
not be excluded due to a positive drug screen caused by prescribed medications.
17. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon
exercise within 90 days prior to Screening and/or planned during study participation.
18. Prior participation in any study of ralinepag or participation in another
interventional clinical study with medicinal products within 30 days prior to
Screening. Concurrent participation in registry or observational studies is allowed,
as long as the subject can fulfill all other entry criteria and comply with all study
procedures.
19. Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the
subject from participating in the study (eg, any previous or intercurrent medical
condition) that may increase the risk associated with study participation or that
would confound study analysis or impair study participation or cooperation.
20. Known hypersensitivity to ralinepag or any of the excipients.
21. Life expectancy <12 months based on the Investigator's opinion.
22. Women who are pregnant, lactating or breast-feeding.
Prostacyclin, Connective Tissue Disease-Associated, 6 Minute Walk Test, 6 Minute Walk Distance, Pulmonary Vascular Resistance, Right Ventricular Function
A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL)
The researchers are doing this study to look whether the type 2 diabetes medicine,
semaglutide, has a positive effect on heart disease. Participants will either get semaglutide
tablets or placebo tablets ("dummy" medicine) - which treatment is decided by chance.
Participants must take one tablet with water every morning on an empty stomach and not eat or
drink anything for at least 30 minutes. The study will last for about 3.5-5 years.
Participants will have up to 25 clinic visits and 1 phone call with the study doctor. Women
cannot be in the study if pregnant, breast-feeding or if they plan to become pregnant during
the study period.
• Male or female, age equal to or above 50 years at the time of signing informed consent
• Diagnosed with type 2 diabetes mellitus
• HbA1c 6.5% •10.0% (47 •86 mmol/mol) (both inclusive) (latest available and no more
than 30 days old local laboratory assessment based on medical records or point of care
measurement)
• At least one of the below conditions (a-d):
a) Coronary heart disease defined as at least one of the following: i. Prior
myocardial infarction ii. Prior coronary revascularisation procedure iii. 50% or above
stenosis in coronary artery documented by cardiac catheterisation, computerized
tomography coronary angiography iv. Coronary heart disease with ischaemia documented
by stress test with any imaging modality b) Cerebrovascular disease defined as at
least one of the following: i. Prior stroke ii. Prior carotid artery revascularisation
procedure iii.50% or above stenosis in carotid artery documented by X-ray angiography,
magnetic resonance angiography, computerized tomography angiography or Doppler
ultrasound c) Symptomatic peripheral artery disease (PAD) defined as at least one of
the following: i. Intermittent claudication with an Ankle-brachial index (ABI) below
0.85 at rest ii. Intermittent claudication with a 50% or above stenosis in peripheral
artery (excluding carotid) documented by X-ray angiography, magnetic resonance
angiography, computerized tomography angiography or Doppler ultrasound iii. Prior
peripheral artery (excluding carotid) revascularization procedure iv. Lower extremity
amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or
osteomyelitis) d) Chronic kidney disease defined as: i. eGFR below 60 mL/min/1.73 m^2
(based on medical records using latest available and no more than 6 months old
assessment)
Exclusion Criteria:
• Any of the following: myocardial infarction, stroke, hospitalisation for unstable
angina pectoris or transient ischaemic attack within the past 60 days prior to the day
of screening
• Planned coronary, carotid or peripheral artery revascularisation known on the day of
screening
• Heart failure presently classified as being in New York Heart Association Class IV
• Treatment with any glucagon-like peptide-1 receptor agonist within 30 days before
screening
Drug: Semaglutide, Drug: Placebo
Diabetes Mellitus, Type 2
UT Southwestern; Parkland Health & Hospital System
Testing the Timing of Pembrolizumab Alone or With Chemotherapy as First Line Treatment and Maintenance in Non-small Cell Lung Cancer
This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed
by pemetrexed and carboplatin with or without pembrolizumab after disease progression is
superior to induction with pembrolizumab, pemetrexed and carboplatin followed by
pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous
non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab,
may help the body's immune system attack the cancer, and may interfere with the ability of
tumor cells to grow and spread. Drugs used in chemotherapy, such as pemetrexed 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. It is not yet
known whether giving first-line pembrolizumab followed by pemetrexed and carboplatin with or
without pembrolizumab works better in treating patients with non-squamous non-small cell
cancer.
• Patients must have histologically or cytologically confirmed stage IV non-squamous
non-small cell lung cancer (NSCLC) (includes M1a, M1b, and M1c stage disease, American
Joint Committee on Cancer [AJCC] 8th edition). Patients with stage IIIB and IIIC
disease are eligible if they are not candidates for combined chemotherapy and
radiation
• Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells.
If PD-L1 expression TPS is unevaluable or the testing could not be completed, the
patients are not eligible. The assay must have been performed by a Clinical Laboratory
Improvement Act (CLIA) (or equivalent) certified laboratory
• Patients must have measurable or non-measurable disease. The presence of malignant
pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline
imaging assessments and measurements used to evaluate all measurable or non-measurable
sites of disease must be done within 4 weeks prior to study registration
• NOTE: If patient receives pemetrexed, follow institutional guidelines to drain
fluids
• Patients must be >= 18 years of age
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 1
• Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression. CNS
progression counts as progression and patients must move on to the next phase after
CNS treatment. Patients with asymptomatic new (at screening) or progressive brain
metastases (active brain metastases at screening) 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
• Patients are eligible if off steroids for at least 14 days prior to protocol
treatment
• Palliative radiation to non-target lesions (bone metastasis) is allowed if
patient develops symptoms
• Anticonvulsants are allowed
• Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion
of investigators do not need immediate CNS directed therapies are eligible
• Patients with 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 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
• Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception or abstain from sexual intercourse from time of
registration, while on study treatment, and continue for 120 days after the last dose
of study treatment
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of randomization)
• Platelets >= 100,000/mm^3 (within 14 days of randomization)
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 Or if patient on
therapeutic anticoagulation, PT/INR =< 3.0 (within 14 days of randomization)
• Partial thromboplastin time (PTT) =< institutional upper limit of normal (ULN) OR, if
patient is on therapeutic anticoagulation, PTT must be =< 1.5 x ULN (within 14 days of
randomization)
• Total bilirubin =< 1.5 mg/dL (obtained within 14 days of randomization)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5
x upper limit of normal (ULN) (obtained within 14 days of randomization)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x
upper limit of normal (ULN) (obtained within 14 days of randomization)
• Calculated creatinine clearance >= 45 ml/min to be eligible to receive pemetrexed
(obtained within 14 days prior to randomization)
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (obtained within
14 days prior to randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy 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 or on suppressive therapy, 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
Exclusion Criteria:
• Patients must NOT have received the following:
• Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC.
Patients treated with any prior checkpoint inhibitors for metastatic lung cancer
are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy)
or immunotherapy for locally advanced Stage III disease is allowed if at least 6
months have elapsed between the last dose of the prior therapy and study
registration. Local therapy, e.g. palliative radiation, is allowed as long as a
period of 14 days has passed between completion of local therapy and study
registration. Registration prior to treatment during the 14 days is allowed.
Palliative radiation must be to non-target lesions
• Methotrexate (MTX) given in low doses for non-malignant conditions with last dose
at least 14 days prior to date of registration will be allowed. Other low dose
chemotherapeutics for non-malignant conditions will be considered, but review by
the study chair is required
• Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600)
or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors
are excluded
• Patients must not have known pre-existing and clinically active interstitial lung
disease, or a known history of (non infectious) pneumonitis that required steroids, or
current pneumonitis
• Patients must not have significant gastrointestinal disorders with diarrhea as a major
symptom (e.g. Crohn's disease, malabsorption, etc.)
• Patients must not have history of auto-immune condition requiring ongoing or
intermittent systemic treatment in the past 2 years (i.e. with use of disease
modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment
• Patients must not have any other concomitant serious illness or organ system
dysfunction that in the opinion of the investigator would either compromise patient
safety or interfere with the evaluation of the safety of the study drug
• Patients must not receive any other investigational agents during the course of
therapy
• Women must not be pregnant or breast-feeding due to potential harm to the fetus or
infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab).
Patients must also not expect to conceive or father children from the time of
registration, while on study treatment, and until at least 120 days after the last
dose of study treatment
• All females of childbearing potential must have a blood test or urine study
within 72 hours prior to registration to rule out pregnancy
• A female of childbearing potential is 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)
• Patients must not have a known history of active tuberculosis (TB)
• Patients must not have a diagnosis of immunodeficiency or receive systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of protocol treatment
• Patients must not have received a live vaccine within 30 days prior to randomization.
Seasonal flu vaccines that do not contain live virus are permitted
Study of Glycerol Phenylbutyrate & Sodium Phenylbutyrate in Phenylbutyrate Naïve Patients With Urea Cycle Disorders
This is a randomized, controlled, open-label parallel arm study to assess the safety,
tolerability, pharmacokinetics and ammonia control, of RAVICTI® as compared to NaPBA in urea
cycle disorder subjects not currently or previously chronically treated with phenylacetic
acid (phenylacetate; PAA) prodrugs. The study design will include: 1) Baseline Period; 2)
Initial Treatment Period; 3) a RAVICTI only Transition Period 4) a RAVICTI only Maintenance
Period; and 5) a RAVICTI only Safety Extension Period. The study will run for approximately
25 weeks.
• Signed informed consent given by the subject or the subject's parent/legal guardian
for those under 18 years of age or the age of consent by local regulation.
• Male and female subjects with a suspected or confirmed UCD diagnosis of any subtype,
except NAGS deficiency.
• Suspected diagnosis is defined as having experienced a HAC or a documented high
ammonia of >=100 µmol/L
• Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing.
• Requires nitrogen-binding agents according to the judgment of the Investigator
• Birth and older.
• All females of childbearing potential and all sexually active males must agree to
use an acceptable method of contraception from signing the informed consent
throughout the study and for 30 days after the last dose of study drug.
Acceptable forms of contraception are (oral, injected, implanted or transdermal),
tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier
methods. Abstinence is an acceptable form of birth control, though appropriate
contraception must be used if the subject becomes sexually active.
Exclusion Criteria:
• Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, NaPBA,
Pheburane, or other) longer than 14 consecutive days within one year prior to
enrollment.
• Temporary use of NaPBA for acute management of a hyperammonemic crisis in the past is
acceptable.
• Any concomitant illness (e.g., malabsorption or clinically significant liver or
bowel disease) which would preclude the subject's safe participation, as judged
by the Investigator.
• Has undergone liver transplantation, including hepatocellular transplant.
• Subjects on NaBz at Baseline will be excluded if they are viewed by the
Investigator as being unable to undergo NaBz transition to a PAA prodrug during
the Initial Treatment Period.
• Known hypersensitivity to PBA or any excipients of the NaPBA/PBA formulations.
• Pregnant or breast-feeding patients. Women of childbearing potential must have a
pregnancy test performed at the Baseline Visit prior to the start of study drug.
PROSpect: Prone and Oscillation Pediatric Clinical Trial
Severe pediatric acute respiratory distress syndrome (PARDS) is a life-threatening and
frequent problem experienced by thousands of children each year. Little evidence supports
current supportive practices during their critical illness. The overall objective of this
study is to identify the best positional and/or ventilation practice that leads to improved
patient outcomes in these critically ill children. We hypothesize that children with severe
PARDS treated with either prone positioning or high-frequency oscillatory ventilation (HFOV)
will demonstrate more days off the ventilator when compared to children treated with supine
positioning or conventional mechanical ventilation (CMV).
Inclusion criteria:
Intubated and mechanically ventilated with moderate-severe PARDS for <48 hours per PALICC
guidelines (chest imaging consistent with acute pulmonary parenchymal disease and OI ≥12 or
OSI ≥10). We require two blood gases meeting moderate-severe PARDS criteria (separated by
at least 4 ± 2 hours during which time the clinical team is actively working to recruit
lung volume and optimize the patient's hemodynamic status per PALICC guidelines;
specifically, incremental and decremental PEEP changes to optimize lung volume). A second
blood gas is not required for OI ≥16.
Exclusion criteria:
• Perinatal related lung disease
• Congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis
• Respiratory failure explained by cardiac failure or fluid overload
• Cyanotic heart disease
• Cardiomyopathy
• Unilateral lung disease
• Primary pulmonary hypertension
• Intubated for status asthmaticus
• Obstructive airway disease (e.g., Severe airways disease without parenchymal
involvement or disease characterized by hypercapnia with FiO2 <0.30 and/or evidence of
increased resistance visible on the flow •time scalar and/or presence of intrinsic
PEEP)
• Active air leak
• Bronchiolitis obliterans
• Post hematopoietic stem cell transplant; specifically, patients receiving continuous
supplemental oxygen for three or more days prior to intubation; receiving noninvasive
ventilation for more than 24 hours prior to intubation; receiving more than one
vasoactive medication at time of meeting inclusion criteria; spending more than four
days in the PICU prior to intubation; supported on or with immediate plans for renal
replacement therapies; with two or more allogeneic transplants; who relapsed after the
transplant; or with diffuse alveolar hemorrhage
• Post lung transplant
• Home ventilator (including noninvasive) or home oxygen dependent (exception:
night-time noninvasive ventilation (CPAP/BiPAP) or oxygen for obstructive sleep apnea
is permitted)
• Neuromuscular respiratory failure
• Critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical
obstruction of the lower airway (e.g., mediastinal mass)
• Facial surgery or trauma in previous 2 weeks
• Head trauma (managed with hyperventilation)
• Intracranial bleeding
• Unstable spine, femur or pelvic fractures
• Acute abdominal process/open abdomen
• Morbid obesity (2w-24 months: WHO weight-for-length/height z-score ≥+3; ≥2 years: WHO
body mass index (BMI)-for-age z-score ≥+3)
• Currently receiving either prone positioning or any high-frequency mode of MV with
current illness (Up to 4 hours of prone positioning and/or any mode of high-frequency
mode of MV is allowed as long as the therapies are off for least 4 hours prior to the
subject meeting oxygenation criteria.)
• Supported on ECMO during the current admission
• Family/medical team not providing full support (patient treatment considered futile)
• Previously enrolled in current study
• Enrolled in any other interventional clinical trial not approved for co-enrollment
• Known pregnancy
Other: Either supine or prone positioning and either CMV or HFOV
Acute Respiratory Distress Syndrome in Children, Lung/Thoracic
Pediatric Acute Respiratory Distress Syndrome (PARDS), Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, child, pediatric intensive care unit
STRATA: Safe Testing of Risk for AsymptomaTic MicrohematuriA
To evaluate the clinical utility associated with the integration of Cxbladder into the
evaluation of subjects presenting with hematuria for evaluation of urothelial carcinoma (UC)
without compromising detection of UC.
• Patient is undergoing investigation of recent confirmed hematuria, as defined by the
AUA/SUFU Guideline (Barocas DA, Boorjian SA, Alvarez RD et al. Microhematuria:
AUA/SUFU guideline, J Urol 2020; 204:778) (by either flexible or rigid
cystoscopy/TURBT), including hematuria subjects referred due to suspicious/positive
imaging, in order to determine the presence of urothelial carcinoma.
• Able to provide a voided urine sample of the required minimum volume
• Able to give written consent
• Able and willing to comply with study requirements
• Aged 18 years or older
Exclusion Criteria
• Prior history of bladder malignancy or pelvic radiotherapy. Prior history prostate or
renal cell carcinoma within the last 5 years.
• Prior genitourinary manipulation (flexible or rigid cystoscopy / catheterisation,
urethral dilation) in the 14 days before urine collection,
• Known current pregnancy
A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma
This phase III trial compares the effect of selumetinib versus the standard of care treatment
with carboplatin and vincristine (CV) in treating patients with newly diagnosed or previously
untreated low-grade glioma (LGG) that does not have a genetic abnormality called BRAFV600E
mutation and is not associated with systemic neurofibromatosis type 1. Selumetinib works by
blocking some of the enzymes needed for cell growth and may kill tumor cells. Carboplatin and
vincristine are chemotherapy drugs that work in different ways to stop the growth of tumor
cells, either by killing the cells or by stopping them from dividing. The overall goal of
this study is to see if selumetinib works just as well as the standard treatment of CV for
patients with LGG. Another goal of this study is to compare the effects of selumetinib versus
CV in subjects with LGG to find out which is better. Additionally, this trial will also
examine if treatment with selumetinib improves the quality of life for subjects who take it.
• Patients must be >= 2 years and =< 21 years at the time of enrollment
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG)
without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1 (NCT02402244) and that has not been treated
with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously
diagnosed, and there is no required time frame between biopsy/surgery and treatment
initiation.
• Patients with residual tumor after resection or progressive tumor after initial
diagnosis (with or without surgery) who have not received treatment (chemotherapy
and/or radiation) are eligible
• Patients must have two-dimensional measurable tumor >= 1 cm^2 to be eligible
• Eligible histologies will include all tumors considered low-grade glioma or low-grade
astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO
classification of central nervous system (CNS) tumors with the exception of
subependymal giant cell astrocytoma
• Patients with metastatic disease or multiple independent primary LGG are eligible
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (performed within
7 days prior to enrollment):
• Age: Maximum Serum Creatinine (mg/dL)
• 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
• 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
• 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
• 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
• >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 7 days
prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed
on study regardless of their total and indirect [unconjugated] bilirubin levels as
long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(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 (performed within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF
result is given as a range of values, then the upper value of the range will be used)
by echocardiogram (performed within 4 weeks prior to enrollment)
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed within
4 weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days prior to
enrollment)
• Platelets >= 100,000/uL (unsupported) (performed within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (performed within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should not have
experienced a significant increase in seizure frequency within 2 weeks prior to
enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for
age, height, and gender at the time of enrollment (with or without the use of
anti-hypertensive medications)
• Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of
enrollment (with or without the use of anti-hypertensive medications)
• Note for patients of all ages: Adequate blood pressure can be achieved using
medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks
prior to enrollment
• For all patients, a magnetic resonance imaging (MRI) of the brain (with orbital cuts
for optic pathway tumors) and/or spine (depending on the site(s) of primary disease)
with and without contrast must be performed within 4 weeks prior to 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 the ability to swallow whole capsules
• All patients have signed an appropriate consent form and Health Insurance Portability
and Accountability Act (HIPAA) authorization form (if applicable)
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed by
enrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the same
day to complete the Rapid Central Review
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior
surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for
another tumor within the last year are ineligible
• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons
involvement on imaging) are not eligible even if biopsy reveals grade I/II histology
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/condition, including
substance use disorders or ophthalmological conditions, likely in the judgment of the
investigator to interfere or limit compliance with study requirements/treatment
• Patients who, in the opinion of the investigator, are not able to comply with the
study procedures are not eligible
• Female patients who are pregnant are not eligible 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 are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
12 weeks after stopping study therapy are not eligible.
• Note: Women of child-bearing potential and males with sexual partners who are
pregnant or who could become pregnant (i.e., women of child-bearing potential)
should use effective methods of contraception for the duration of the study and
for 12 weeks after stopping study therapy to avoid pregnancy and/or potential
adverse effects on the developing embryo
• Known genetic disorder that increases risk for coronary artery disease. Note: The
presence of dyslipidemia in a family with a history of myocardial infarction is not in
itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Health Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure
(IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
multivitamin containing vitamin E must be stopped prior to study enrollment even if
less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy,
placement of a vascular access device or cerebral spinal fluid (CSF) diverting
procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP)
shunt.
• Note: Patients must have healed from any prior surgery
• Patients who have an uncontrolled infection are not eligible
Genetic Testing in Guiding Treatment for Patients With Brain Metastases
This phase II trial studies how well genetic testing works in guiding treatment for patients
with solid tumors that have spread to the brain. Several genes have been found to be altered
or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these
genes such as abemaciclib, paxalisib, and entrectinib may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor
treatment for each mutation.
PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) • Tissue available for biomarker
testing (any brain metastasis tissue and extracranial site from any prior resection or
biopsy).
REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)
• Participants must have histologically confirmed parenchymal metastatic disease to the
brain from any solid tumor. Note: this includes patients that have controlled
extracranial disease with progressive intracranial metastasis, as well as patients
that have progressive intracranial and extracranial disease.
• New or progressive brain metastases are defined as any one of the following:
• Untreated measurable lesions in patients who have received surgery and/or
stereotactic radiosurgery (SRS) to one or more other lesions.
• Progressive measurable lesions after radiation, surgery, or prior systemic
therapy
• Residual or progressive lesions after surgery if asymptomatic.
• Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then
whose lesions have progressed by BM-RANO criteria or there are new lesions, are
eligible. Lesions treated with SRS may be eligible if there is unequivocal
evidence of progression. For patients with NTRK or ROS1 mutations, entrectinib
may be used for newly diagnosed brain metastases.
• Patients who have not previously been treated with cranial radiation (e.g. WBRT
or SRS) are eligible, but such patients must be asymptomatic or neurologically
stable from their CNS metastases.
• Measurable CNS disease (=> 10 mm).
• Ability to obtain magnetic resonance imaging (MRI)s with contrast
• No surgery within 2 weeks prior to or after registration.
• No chemotherapy within 14 days prior to registration (Note: for abemaciclib arm, a
21-day chemotherapy washout is required).
• For melanoma, patients must have progressed after prior immune checkpoint
blockade or for BRAF positive melanoma, BRAF/MEK inhibitors.
• For lung cancer, EGFR mutant patients must have failed EGFR therapies
• For HER2-positive breast cancer patients (regardless of ER/PR status), patients
must have received at least one prior HER-2 directed therapy in the metastatic
setting.
• For triple negative breast cancer (TNBC), patients must have received at least
one chemotherapy in the metastatic setting.
• For estrogen receptor (ER) and/or progesterone receptor (PR)+ HER2-negative
breast cancer, patients must have received at least one endocrine therapy in the
metastatic setting.
• Patients who have received prior treatment with any of the targeted treatments on
this study are not eligible for that specific treatment arm(s), but could be
eligible for other arms (e.g., a patient who has had prior treatment with
abemaciclib would not be eligible for the abemaciclib arm, but could be eligible
for another arm).
• Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K
pathway in both a brain metastasis and extracranial site per central review.
• Not pregnant and not nursing, because this study involves investigational agents whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown. Therefore, for women of childbearing potential only, a negative pregnancy
test done =< 14 days prior to registration is required (Note: for abemaciclib arm,
pregnancy test is required =< 7 days prior to registration).
• No known current diffuse leptomeningeal involvement (diffuse defined as leptomeningeal
involvement throughout the CNS axis; if there is documented positive CSF cytology,
patient is ineligible).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function.
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's
disease. Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and
direct bilirubin within normal limits are permitted.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN).
• Creatinine =< 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min.
• No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial
lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal
impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical
resection involving the stomach or small bowel, or preexisting Crohn's disease or
ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or
higher diarrhea)
• Radiation to symptomatic non-target sites within neural axis is allowed prior to
registration without washout (provided there is at least one untreated target lesion
for measurement on study and radiation is completed prior to registration).
• Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7
days prior to registration. Baseline doses and changes in steroid dosing will be
captured.
• No concurrent administration of anticancer therapies (except for endocrine therapy or
continuation of hormonal therapy or trastuzumab in breast cancer patients). No
chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the
study (Note: For abemaciclib arm, a 21-day chemotherapy washout is required).
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to
registration on the study.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients
must discontinue the drug 14 days prior to the start of study treatment.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR PAXALISIB ARM
• Urine protein to creatinine (UPC) ratio < 1 or urine protein =< 1.
• Recent acute myocardial infarction in the last 6 months or current angina pectoris are
excluded. Patients with symptomatic bradycardia should have an electrocardiogram at
baseline. If QT interval > 470 msec, the patient is excluded.
• Patients with uncontrolled type I or II diabetes mellitus should be excluded.
Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition
to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to
registration.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ENTRECTINIB ARM
• Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump inhibitors
(PPIs), and/or antacids are prohibited.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ABEMACICLIB ARM
• Hemoglobin >= g/dL. Patients may receive erythrocyte transfusions to achieve this
hemoglobin level at the discretion of the investigator. Initial treatment must not
begin earlier than the day after the erythrocyte transfusion.
• Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for
residual alopecia or Grade 2 peripheral neuropathy prior to registration. A washout
period of at least 21 days is required between last chemotherapy dose and registration
(provided the patient did not receive radiotherapy).
• Patients who received adjuvant radiotherapy must have completed and fully recovered
from the acute effects of radiotherapy. A washout period of at least 14 days is
required between end of radiotherapy and registration.
• Breast cancer patients who have received ribociclib or palbociclib are eligible as
long as there is documentation of CDK4/6 pathway alteration on a biopsy or resection
at the point of progression post-ribociclib or palbociclib.
• For females of childbearing potential: A female of childbearing potential, must have a
negative serum pregnancy test within 7 days prior to registration and agree to use a
highly effective contraception method during the treatment period and for 3 weeks
following the last dose of abemaciclib. Contraceptive methods may include an
intrauterine device [IUD] or barrier method. If condoms are used as a barrier method,
a spermicidal agent should be added as a double barrier protection. Cases of pregnancy
that occur during maternal exposures to abemaciclib should be reported. If a patient
or spouse/partner is determined to be pregnant following abemaciclib initiation, she
must discontinue treatment immediately. Data on fetal outcome and breast-feeding are
to be collected for regulatory reporting and drug safety evaluation.
• Patients with active bacterial infection (requiring intravenous [IV] antibiotics at
time of initiating study treatment), fungal infection, or detectable viral infection
(such as known human immunodeficiency virus positivity or with known active hepatitis
B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is
not required for enrollment.
• Patients with personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest, are excluded.
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
Maximum Tolerated Dose, Safety, and Efficacy of Rhenium Nanoliposomes in Recurrent Glioma (ReSPECT)
This is a multi-center, sequential cohort, open-label, volume and dose escalation study of
the safety, tolerability, and distribution of 186RNL given by convection enhanced delivery to
patients with recurrent or progressive malignant glioma after standard surgical, radiation,
and/or chemotherapy treatment. The study uses a modified Fibonacci dose escalation, followed
by an expansion at the maximum tolerated dose (MTD) to determine efficacy. The starting
absorbed dose is 1mCi in a volume of 0.660mL.
1. At least 18 years of age
2. Ability to understand the purposes and risks of the study and has signed a written
informed consent form approved by the investigator's IRB/Ethics Committee
3. Histologically confirmed glioma
4. Progression by Response Assessment in Neuro-Oncology (RANO) criteria following
standard treatment options with known survival benefit (Temozolomide, Radiation, and
Tumor Treating Fields [unless unwilling])
5. Patients who receive treatment with antiepileptic medications must have a two week
history of stable dose of antiepileptic without seizures prior to dosing
6. Patients with corticosteroid requirements to control cerebral edema must be maintained
at a stable or decreasing dose for a minimum of two weeks without progression of
clinical symptoms
7. A volume of enhancing tumor which falls within the treatment field volume being
evaluated in the respective cohort (see 4.1 Design)
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
9. Life expectancy of at least 2 months
10. Acceptable liver function:
• Bilirubin ≤ 1.5 times upper limit of normal
• AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal (ULN);
11. Acceptable renal function:
• Serum creatinine ≤1.5xULN
12. Acceptable hematologic status (without hematologic support):
• ANC ≥1000 cells/uL
• Platelet count ≥100,000/uL
• Hemoglobin ≥9.0 g/dL
13. All women of childbearing potential must have a negative serum pregnancy test and male
and female subjects must agree to use effective means of contraception (surgical
sterilization or the use or barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel or an IUD) with their partner from entry into the
study through 6 months after the last dose
For part 2:
14. Bevacizumab naïve glioblastoma with no more than 1 recurrence
Exclusion Criteria:
1. The subject has evidence of acute intracranial or intratumoral hemorrhage either by
MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes,
punctate hemorrhage, or hemosiderin are eligible.
2. The subject is unable to undergo MRI scan (eg, has pacemaker).
3. The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia
and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or
other medications that were administered prior to study.
4. The subject is pregnant or breast-feeding.
5. The subject has serious intercurrent illness, as determined by the treating physician,
that would compromise either patient safety or study outcomes such as:
• hypertension (two or more blood pressure readings performed at screening of > 150
mmHg systolic or > 100 mmHg diastolic) despite optimal treatment
• Non-healing wound, ulcer, or bone fracture
• Clinically significant cardiac arrhythmias
• Untreated hypothyroidism
• Uncontrolled systemic infection
• Symptomatic congestive heart failure or unstable angina pectoris within 3 months
prior study drug
• Myocardial infarction, stroke, transient ischemic attack within 6 months
• Known active malignancy (other than glioma) except non-melanoma skin cancer or
carcinoma in-situ in the cervix
6. The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding
7. The subject has received any of the following prior anticancer therapy:
• Non-standard radiation therapy such as brachytherapy, systemic radioisotope
therapy, or intra-operative radiotherapy (IORT) to the target site.
• Radiation therapy within 12 weeks of screening
• Systemic therapy (including investigational agents and small-molecule kinase
inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 14 days or 5
half-lives, whichever is shorter, prior first dose of study drug
• Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21
days prior to first dose of study drug
• Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days,
prior to first dose of study drug
• Prior treatment with carmustine wafers
• Patients who are currently receiving any other investigational agents and/or who
have received an investigational agent in the prior 28 days
8. Multifocal progression or involvement of the leptomeninges
9. Psychiatric illness/social situations that would limit compliance with the study
requirements
10. Infratentorial disease
Pathogenesis of Uric Acid Nephrolithiasis: Role of Pioglitazone/Weight Loss
The investigators will randomize overweight and obese iuan patients to Pio (45 mg/day,
highest approved dose or placebo), WL (10% of body weight, following the established program
used in the Diabetes Prevention Program), or Pio+WL. Participants will be evaluated at
baseline and after 24 weeks of intervention while on a fixed metabolic diet to exclude the
confounding effects of diet and perspiration. The primary endpoint will be change in upH, and
multiple additional endpoints (serum, urine, imaging) will be assessed.
Idiopathic uric acid nephrolithiasis, with last stone analysis showing that stone has >90%
uric acid in composition Age >21 years Any gender, race/ethnicity (from weight loss), but
weight <165 Kg (to fit into MR instrument); eGFR>60ml/min/1.73 m2
Exclusion Criteria:
Bariatric surgery, chronic diarrhea, recurrent UTIs current insulin use use of a
thiazolidinedione in past 2 years contraindication to thiazolidinedione use (liver dz,
pedal edema, CHF NYHA class III/IV, no contraception) Bladder cancer Use of SGLT2-i, GLP-1
analogs, gemfibrozil, topiramate, rifampin Hba1c > 8.5%
A Study of LY3484356 in Participants With Advanced or Metastatic Breast Cancer or Endometrial Cancer (EMBER)
The reason for this study is to see if the study drug LY3484356 alone or in combination with
other anticancer therapies is safe and effective in participants with advanced or metastatic
breast cancer or endometrial cancer.
All study parts:
• Participants must be willing to provide adequate archival tissue sample
• Participants must be willing to use highly effective birth control
• Participants must have adequate organ function
• Participants must be able to swallow capsules
Dose escalation- Participants must have one of the following:
• Parts A and B: ER+ HER2- breast cancer with evidence of locally advanced unresectable
or metastatic disease who have had the following:
• Part A: may have had up to 1 prior regimen of any kind for in the advanced/metastatic
setting and no prior cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy.
• Part B: may have had up to 2 prior regimens, no more than 1 of which may be endocrine
therapy in the advanced/metastatic setting, and must have received a prior CDK4/6
inhibitor
• Cohort E4: No prior everolimus.
• Cohort E5: No prior alpelisib and must have a phosphatidylinositol 3-kinase catalytic
α (PIK3Cα) mutation as determined by local testing.
• Part C: ER+, human epidermal growth factor receptor 2 positive (HER2+) breast cancer
with evidence of locally advanced unresectable or metastatic disease who have had at
least 2 HER2-directed therapies in any setting.
• Part D: ER+, EEC that has progressed after platinum containing chemotherapy and no
prior fulvestrant or aromatase inhibitor therapy.
• Part E: ER+ and HER2+ breast cancer with evidence of locally advanced, unresectable,
or metastatic disease.
• Part E: Participants must have received induction taxane chemotherapy combined with
trastuzumab + pertuzumab as first-line treatment for advanced/metastatic disease and
must not have progressed on this regimen.
• Part E: Participants must not have received more than 1 HER2-directed regimen or any
endocrine therapy for advanced disease or any prior CDK4/6 inhibitor therapy.
Participants with ER+/HER2- breast cancer enrolled in this study must have had evidence of
clinical benefit while on endocrine therapy for at least 24 months in the adjuvant setting
or at least 6 months in the advanced/metastatic setting or have untreated de novo
metastatic breast cancer
Exclusion Criteria:
• Participants must not have certain infections such as hepatitis or tuberculosis or HIV
that are not well controlled
• Participants must not have another serious medical condition
• Participants must not have cancer of the central nervous system that is unstable
• Participants must not be pregnant or breastfeeding
A Study of Selexipag Assessing Right Ventricular Remodeling in Pulmonary Arterial Hypertension by Cardiac Magnetic Resonance Imaging (RESTORE)
The purpose of the study is to assess the effects of selexipag on right ventricular (RV)
function in participants with Pulmonary arterial hypertension (PAH).
• World health organization functional class (WHO FC) II or III. Enrollment will be
stratified by WHO FC II or III. Proportion of participants with WHO FC II and WHO FC
III are expected to be approximately 40 percent (%) and 60%, respectively
• Pulmonary arterial hypertension (PAH) etiology belonging to one of the following
groups according to 6th world symposium of pulmonary hypertension (WSPH)
classification: a) Idiopathic PAH, b) Heritable PAH, c) Drugs or toxins induced d) PAH
associated with connective tissue disease, e) PAH associated with congenital heart
disease, with simple systemic-to-pulmonary shunt at least 1 year after surgical repair
• Patients already receiving PAH-specific oral mono or dual therapy (that is,
phosphodiesterase type 5 inhibitors [PDE-5i] or soluble guanylate cyclase stimulators
[sGCs] and/or endothelin receptor antagonist [ERA]) or patients who are not candidates
for these therapies
• N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP) greater than or equal to
(>=) 300 nanograms per liter (ng/L) (greater than or equal to [>=] 300 picograms per
milliliter [pg/mL]; >=35.5 picomoles per liter [pmol/L]) at screening
• Women of childbearing potential must meet the following criteria: a) Have a negative
serum pregnancy test during screening and a negative urine pregnancy test on Day 1, b)
Agree to use acceptable methods of contraception from Day 1 to at least 30 days after
study intervention discontinuation, c) If only using hormonal contraception, have used
it for at least 1 month (30 days) before Day 1, and d) Agree to perform monthly
pregnancy tests to at least 30 days after study intervention discontinuation
• 6-minute walking distance (6MWD) >=150 meter (m) during screening period
Exclusion Criteria:
• Prior use of Prostacyclin (IP)-receptor agonist, prostacyclin, or prostacyclin analog.
Use of such treatments for vasoreactivity testing is not exclusionary; intermittent
use of such treatments for digital ulcers or Raynaud's phenomenon is not exclusionary
if stopped > 6 months (180 days) prior to Day 1
• Treatment with strong inhibitors of CYP2C8 (example, gemfibrozil) within 4 weeks (28
days) prior to Day 1
• Treatment with another investigational drug planned or taken within 12 weeks (84 days)
prior to Day 1
• Severe coronary heart disease or unstable angina
• Cerebrovascular events (example, transient ischemic attack, stroke) within 3 months
(90 days) prior to Day 1
GEN3013, Epcoritamab Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma EPCORE™ NHL-1
The trial is a global, multi-center safety trial of Epcoritamab, an antibody also known as
GEN3013 (DuoBody®-CD3xCD20). The trial consists of three parts: a dose-escalation part (Phase
1, first-in-human (FIH)), an expansion part (Phase 2a) and a dose optimization part (Phase
2a)
Main Inclusion Criteria Escalation Part (recruitment completed)
• Documented CD20+ mature B-cell neoplasm
1. Diffuse large B-cell lymphoma •de novo or transformed
2. High-grade B-cell lymphoma
3. Primary mediastinal large B-cell lymphoma
4. Follicular lymphoma
5. Mantle cell lymphoma
6. Small lymphocytic lymphoma
7. Marginal zone lymphoma (nodal, extranodal or mucosa associated)
• Relapsed, progressive and/or refractory disease following treatment with an anti-CD20
monoclonal antibody (e.g. rituximab) potentially in combination with chemotherapy
and/or relapsed after autologous stem cell rescue.
• ECOG performance status 0,1 or 2
• Patients must have measurable disease by CT, MRI or PET-CT scan
• Acceptable renal function
• Acceptable liver function
Main Inclusion Criteria Expansion and Optimization Parts
• Documented CD20 positive mature B cell neoplasm or CD20+ MCL
• Diffuse large B cell lymphoma, de novo or transformed (including double hit or triple
hit)
• Primary mediastinal large B cell lymphoma
• Follicular lymphoma grade 3B
• Histologic confirmed follicular lymphoma
• Marginal zone lymphomas
• Small lymphocytic lymphoma
• Mantle Cell Lymphoma (prior BTKi or intolerant to BTKi)
• At least 2 therapies including an anti CD20 monoclonal antibody containing
chemotherapy combination regimen
• Either failed prior autologous hematopoietic stem cell transplantation or ineligible
for autologous stem cell transplantation due to age or comorbidities
• At least 1 measurable site of disease based on CT, MRI or PET-CT scan with involvement
of 2 or more clearly demarcated lesions and or nodes
NOTE: Other protocol defined Inclusion criteria may apply.
Main Exclusion Criteria Escalation, Expansion and Optimization Parts
• Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at
screening
• Known past or current malignancy other than inclusion diagnosis
• AST, and/or ALT >3 × upper limit of normal
• Total bilirubin >1.5 × upper limit of normal, unless bilirubin rise is due to
Gilbert's syndrome or of non-hepatic origin
• Estimated CrCl <45 mL/min
• Known clinically significant cardiovascular disease
• Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
requiring systemic treatment (excluding prophylactic treatment). Past COVID-19
infection may be a risk factor
• Confirmed history or current autoimmune disease or other diseases resulting in
permanent immunosuppression or requiring permanent immunosuppressive therapy
• Seizure disorder requiring therapy (such as steroids or anti-epileptics)
• Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20
• Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days
prior to first epcoritamab administration
• Eligible for curative intensive salvage therapy followed by high dose chemotherapy
with HSCT rescue
• Autologous HSCT within 100 days prior to first epcoritamab administration, or any
prior allogeneic HSCT or solid organ transplantation
• Active hepatitis B (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection).
Subjects with evidence of prior HBV but who are PCR-negative are permitted in
• Known human immunodeficiency virus (HIV) infection
• Exposed to live or live attenuated vaccine within 4 weeks prior to signing ICF
• Pregnancy or breast feeding
• Patient is known or suspected of not being able to comply with the study protocol or
has any condition for which, participation would not be in the best interest of the
patient
• Contraindication to all uric acid lowering agents
Biological: Epcoritamab
Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Non-Hodgkins Lymphoma, High-grade B-cell Lymphoma, Primary Mediastinal Large B-cell Lymphoma
International Penile Advanced Cancer Trial (International Rare Cancers Initiative Study) (InPACT)
This is an international phase III trial, with a Bayesian design, incorporating two
sequential randomisations. It efficiently examines a series of questions that routinely arise
in the sequencing of treatment. The study design has evolved from lengthy international
consultation that has enabled us to build consensus over which questions arise from current
knowledge and practice. It will enable potential randomisation for the majority of patients
with inguinal lymph node metastases and will provide data to inform future clinical
decisions.
InPACT-neoadjuvant patients are stratified by disease burden as assessed by radiological
criteria. Treatment options are then defined according to the disease burden strata.
Treatment is allocated by randomisation. Patients may be allocated to one of three initial
treatments:
A. standard surgery (ILND); B. neoadjuvant chemotherapy followed by standard surgery (ILND);
or C. neoadjuvant chemoradiotherapy followed by standard surgery (ILND).
After ILND, patients are defined as being at low or high risk of recurrence based on
histological interpretation of the ILND specimen. Patients at high risk of relapse are
eligible for InPACT-pelvis, where they are randomised to either:
P. prophylactic PLND Q. no prophylactic PLND
1. Written informed consent
2. Measurable disease as determined by RECIST (version 1.1) criteria;
3. Histologically-proven squamous cell carcinoma of the penis,
4. Stage:
• any T, N1 (i.e. a palpable mobile unilateral inguinal lymph node), M0 or;
• any T, N2 (i.e. palpable mobile multiple or bilateral inguinal lymph nodes), M0
or;
• any T, N3 (i.e. fixed inguinal nodal mass or any pelvic lymphadenopathy), M0
5. Performance Status ECOG 0, 1 or 2.
Exclusion Criteria:
1. Pure verrucous carcinoma of the penis,
2. Nonsquamous malignancy of the penis,
3. Squamous carcinoma of the urethra,
4. Stage M1,
5. Previous chemotherapy or chemoradiotherapy,
6. Concurrent malignancy (other than SCC or Basal Cell Carcinoma of non-penile skin) that
has required surgical or non-surgical treatment in the last 3 years.
Testing the Addition of the Drug Apalutamide to the Usual Hormone Therapy and Radiation Therapy After Surgery for Prostate Cancer (INNOVATE)
This phase III trial studies whether adding apalutamide to the usual treatment improves
outcome in patients with lymph node positive prostate cancer after surgery. Radiation therapy
uses high energy x-ray to kill tumor cells and shrink tumors. Androgens, or male sex
hormones, can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may help
stop or reduce the growth of prostate cancer cell growth by blocking the attachment of
androgen to its receptors on cancer cells, a mechanism similar to stopping the entrance of a
key into its lock. Adding apalutamide to the usual hormone therapy and radiation therapy
after surgery may stabilize prostate cancer and prevent it from spreading and extend time
without disease spreading compared to the usual approach.
• Pathologically (histologically) proven diagnosis of prostate adenocarcinoma. Any type
of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or
robotically assisted
• Any T-stage is eligible (American Joint Committee on Cancer [AJCC] 8th edition [ed])
• Appropriate stage for study entry based on fluciclovine F-18 positron emission
tomography (PET) scan (FACBC, Axumin) within 90 days prior to registration that is
negative for distant metastatic (M1a, M1b, M1c) disease; Note that though every effort
should be made to obtain a fluciclovine F-18 PET (FACBC, Axumin) scan; however, if the
patient has already had a recent F-18 PSMA PET scan or gallium Ga 68-labeled PSMA-11
(Ga-68 PSMA) PET scan or C-11 or F-18 choline PET scan within 90 days prior to
registration (to include scan report) then repeat molecular imaging with a
fluciclovine F-18 PET (FACBC, Axumin) scan will not be required.
• Pathologically node positive disease with nodal involvement only in the pelvis in the
prostatectomy specimen (including external iliacs, internal iliacs, and/or obturator
nodes); peri-rectal nodes can also be considered regional lymphadenopathy and are
allowed
• History/physical examination within 90 days prior to registration
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 90 days
prior to registration
• Detectable PSA after radical prostatectomy. Detectable PSA is defined as serum PSA > 0
ng/mL at least 30 days after prostatectomy and within 180 days of registration and
before start of GnRH agonist/antagonist
• Patients who have already started on post-prostatectomy GnRH agonist/antagonist for =<
180 days prior to registration are eligible (Note: patients who started on an oral
antiandrogen are eligible if started =< 180 days and stopped prior to registration)
• Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors (within 90
days prior to registration)
• Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors
(within 90 days prior to registration)
• Serum potassium >= 3.5 mmol/L within 90 days prior to registration
• Creatinine clearance (CrCl) >= 30 mL/min estimated by Cockcroft-Gault (please use
actual weight for calculation unless greater than 30% above ideal body weight then use
the adjusted body weight) (within 90 days prior to registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Note: In subjects
with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and
indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject is eligible)
(within 90 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN (within 90 days prior to registration)
• Serum albumin >= 3.0 g/dL (within 90 days prior to registration)
• Discontinue or substitute concomitant medications known to lower the seizure threshold
at least 30 days prior to registration
• The patient must agree to use a condom (even men with vasectomies) and another
effective method of birth control if he is having sex with a woman of childbearing
potential or agree to use a condom if he is having sex with a woman who is pregnant
while on study drug and for 3 months following the last dose of study drug
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial and
have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note:
HIV testing is not required for eligibility for this protocol
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy within 30 days prior to registration,
if indicated. Note: HBV viral testing is not required for eligibility for this
protocol
• 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 within 30 days prior to
registration
• 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. Note: Any patient with a cancer
(other than keratinocyte carcinoma or carcinoma in situ) who has no evidence of
disease for < 3 years must contact the principal investigator, Ronald Chen, Doctor of
Medicine (MD)
• The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry
Exclusion Criteria:
• Definitive radiologic evidence of metastatic disease (M1a, M1b or M1c) on molecular
imaging (e.g. fluciclovine F-18 PET, F-18 PSMA, PSMA, F-18 choline 11)
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowed (completed > 3 years prior to registration)
• Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields
• Androgen deprivation therapy (ADT) prior to radical prostatectomy
• Prior treatment with androgen receptor signaling inhibitor (including but not
exclusive to a growing list of: abiraterone acetate, enzalutamide, apalutamide,
darolutamide), unless started =< 180 days and stopped prior to registration, which is
allowed
• Current use of 5-alpha reductase inhibitor. NOTE: if the alpha reductase inhibitor is
stopped prior to randomization the patient is eligible
• History of any of the following:
• Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke
within 1 year prior to registration, brain arteriovenous malformation,
Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal
disease which may require treatment with surgery or radiation therapy)
• Severe or unstable angina, myocardial infarction, arterial or venous
thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident
including transient ischemic attacks), or clinically significant ventricular
arrhythmias within 12 months prior to registration
• New York Heart Association functional classification III/IV (Note: 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.)
• History of any condition that in the opinion of the investigator, would preclude
participation in this study
• Current evidence of any of the following:
• Known gastrointestinal disorder affecting absorption of oral medications
• Active uncontrolled infection
• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >=
160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history of hypertension
are allowed, provided that BP is controlled to within these limits by
anti-hypertensive treatment
• Any chronic medical condition requiring a higher dose of corticosteroid than 10
mg prednisone/prednisolone once daily
• Baseline moderate and severe hepatic impairment (Child-Pugh Class B & C)
• Inability to swallow oral pills
• Any current condition that in the opinion of the investigator, would preclude
participation in this study
• Patients must not plan to participate in any other therapeutic clinical trials while
receiving treatment on this study
• Patients with inflammatory bowel disease
Prostate Adenocarcinoma, Stage IVA Prostate Cancer AJCC v8, Prostate, Stage I Prostate Cancer AJCC v8, Stage II Prostate Cancer AJCC v8, Stage IIA Prostate Cancer AJCC v8, Stage IIB Prostate Cancer AJCC v8, Stage IIC Prostate Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8
Prostate Cancer, Apalutamide, Abiraterone Acetate
UT Southwestern; Parkland Health & Hospital System
A Study To Evaluate The Efficacy And Safety Of Obinutuzumab In Patients With ISN/RPS 2003 Class III Or IV Lupus Nephritis (REGENCY)
This study will evaluate the efficacy, safety, and pharmacokinetics of obinutuzumab compared
with placebo in patients with International Society of Nephrology/Renal Pathology Society
(ISN/RPS) class III or IV lupus nephritis (LN) when added on to standard-of-care therapy
consisting of mycophenolate mofetil (MMF) and corticosteroids.
• Diagnosis of ISN/RPS 2003 Class III or IV LN as evidenced by renal biopsy performed
within 6 months. Participants may co-exhibit Class V disease in addition to either
Class III or Class IV disease
• Urine protein to creatinine ratio greater than or equal to (>/=) 1 on a 24-hour
collection
• Other inclusion criteria may apply
Key
Exclusion Criteria:
• Pregnancy or breastfeeding
• Severe renal impairment or the need for dialysis or renal transplantation
• Receipt of an excluded therapy, including any anti-CD20 therapy less than 9 months
prior to screening or during screening; or cyclophosphamide, tacrolimus, ciclosporin,
or voclosporin during the 2 months prior to screening or during screening
• Significant or uncontrolled medical disease which, in the investigator's opinion,
would preclude patient participation
• Known active infection of any kind or recent major episode of infection
• Intolerance or contraindication to study therapies
• Other exclusion criteria may apply
A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression
The purpose of this study is to evaluate the efficacy of each individual dose of esketamine
nasal spray, 56 milligram (mg) and 84 mg, compared with placebo nasal spray in improving
depressive symptoms in participants with treatment resistant depression (TRD), as assessed by
the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score
from Day 1 (prerandomization) to the end of the 4 week double-blind treatment phase (Day 28).
• Participant must meet the Diagnostic and Statistical Manual of Mental Disorders (5th
edition) (DSM-5) diagnostic criteria for single-episode MDD or recurrent MDD, without
psychotic features, based upon clinical assessment and confirmed by the MINI.
Participants 65 years of age or older must have had the first onset of depression
prior to 55 years of age
• Participant must have had nonresponse (<=25% improvement) to >=2 oral antidepressant
treatments in the current episode of depression, assessed using the MGH-ATRQ, and
confirmed by documented records (example, medical/pharmacy/prescription records or a
letter from a treating physician)
• Participant must have an Inventory of Depressive Symptomatology-Clinician rated,
30-item (IDS-C30) total score of >=34
• The participant's current major depressive episode, depression symptom severity, and
antidepressant treatment response in the current depressive episode, must be confirmed
by the State vs. Trait, Assessibility, Face Validity, Ecological Validity, Rule of
Three P's (SAFER) Interview
• Participant must be medically stable on the basis of physical examination, medical
history, vital signs (including blood pressure), and 12-lead electrocardiogram (ECG)
performed in the screening phase. If there are any abnormalities that are not
specified in the inclusion and exclusion criteria, the determination of their clinical
significance must be determined by the investigator and recorded in the participant's
source documents and initiated by the investigator
• Participant must be medically stable on the basis of clinical laboratory tests
performed in the screening phase. If the results of the serum chemistry panel,
hematology, or urinalysis are outside the normal reference ranges, the participant may
be included only if the investigator judges the abnormalities or deviations from
normal to be not clinically significant or to be appropriate and reasonable for the
population under study. This determination must be recorded in the participant's
source documents and initialed by the investigator: (a) Participants with a
pre-existing history of thyroid disease/disorder who are treated with thyroid hormones
must be on a stable dosage for 3 months prior to the start of the screening phase; (b)
For any participant (regardless of thyroid history), if the thyroid-stimulating
hormone (TSH) value is out of range, a free thyroxine (FT4) will be conducted. If the
FT4 value is abnormal and considered to be clinically significant (after discussion
with the medical monitor), the participant is not eligible
• Participant must be comfortable with self-administration of nasal spray medication and
be able to follow the nasal spray administration instructions provided
Exclusion Criteria:
• The participant has used ketamine/esketamine (lifetime)
• The participant's depressive symptoms have previously demonstrated nonresponse to an
adequate course of treatment with electroconvulsive therapy (ECT) in the current major
depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT
• Participant has received vagal nerve stimulation (VNS) or has received deep brain
stimulation (DBS) in the current episode of depression
• Participant has a current or history of seizures (uncomplicated childhood febrile
seizures with no sequelae are not exclusionary)
• Participant has any anatomical or medical condition that, per the investigator's
clinical judgment based on assessment, may impede delivery or absorption of nasal
spray study drug
Single Cell Immune and Non-immune Correlates of Response to Neoadjuvant Abemaciclib
The purpose of this study is to better understand how the immune system plays a role in
fighting breast cancer and specifically research if the immune system response against breast
cancer can be improved with endocrine therapy and cyclin dependent kinase inhibitor therapy
in patients with hormone receptor positive breast cancer. This will be studied by collecting
tumor tissue and blood samples before and after 2 weeks of study treatment with commonly used
endocrine therapy and cyclin dependent kinase inhibitor therapy.
INCLUSION CRITERIA:
• Clinical stage operable stage I, II, or III invasive mammary carcinoma, which is
estrogen receptor or progesterone receptor positive by immunohistochemistry and HER2
negative by Herceptest (0 or 1+) or not amplified by in situ hybridization as per
routine clinical testing.
• Have post-menopausal status, as defined by any of the following: Subjects at least 55
years of age OR Subjects under 55 years of age and amenorrheic for at least 12 months
OR follicule stimulating hormone (FSH) values ≥ 40 IU/L and estradiol levels ≤ 40
pg/mL (140 pmol/L) or in postmenopausal ranges per local or institutional reference
ranges.
• Breast tumor ≥1cm in diameter by either physical exam or ultrasound and suitable for
pre and post-treatment tissue sampling.
• Meet either of 2 following criteria, for which neoadjuvant endocrine therapy for 2
weeks is deemed suitable: 1) disease that is planned for surgery as initial therapy,
in which 2 weeks of neoadjuvant endocrine therapy is deemed suitable, 2) Disease for
which neoadjuvant systemic therapy (either chemotherapy or endocrine therapy) may be
planned, in which 2 weeks of neoadjuvant endocrine therapy prior to start of systemic
therapy is deemed suitable.
• At least 18 years of age
• Performance status ECOG ≤ 2
• Have adequate organ function (ANC ≥1,500/mcL, Platelets ≥100,000/mcL, Hemoglobin ≥8
g/dL, Total bilirubin ≤1.5 × upper limit of normal, ALT and AST ≤3 × upper limit of
normal, Creatinine clearance >30 mL/minute
• The patient is able to swallow oral medications
• Patients with a prior history of contralateral breast cancer are eligible if they have
no evidence of recurrence of their initial primary breast cancer.
• Women may have been taking tamoxifen or raloxifene as a preventive agent prior to
study entry but must have discontinued the drug for at least 28 days prior to study
enrollment.
• Subjects have ended hormone replacement therapy at least 7 days prior to receiving the
first dose of randomized therapy.
• Ability to understand and the willingness to sign a written informed consent.
• A female of childbearing potential, must have a negative serum pregnancy test within 7
days of the first dose of abemaciclib and agree to use a highly effective
contraception method during the treatment period and for 3 weeks following the last
dose of abemaciclib. These criteria should not apply to most or all patients on the
trial given the inclusion criteria is for post-menopausal patients only who should not
be of childbearing potential.
Note: Contraceptive methods may include an intrauterine device [IUD] or barrier method. If
condoms are used as a barrier method, a spermicidal agent should be added as a double
barrier protection. Cases of pregnancy that occur during maternal exposures to abemaciclib
should be reported. If a patient or spouse/partner is determined to be pregnant following
abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome
and breast-feeding are to be collected for regulatory reporting and drug safety evaluation.
EXCLUSION CRITERIA:
• Active metastatic breast cancer, inflammatory breast cancer, or locally recurrent
breast cancer.
• The patient has serious and/or uncontrolled preexisting medical condition(s) that, in
the judgment of the investigator, would preclude participation in this study (for
example, interstitial lung disease, severe dyspnea at rest or requiring oxygen
therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],
history of major surgical resection involving the stomach or small bowel, or a
preexisting chronic condition resulting in baseline grade 2 or higher diarrhea).
• Females who are pregnant, lactating, or premenopausal.
• Severe uncontrolled malabsorption condition or disease (i.e. grade 2 or higher
diarrhea, severe malnutrition, short gut syndrome).
• Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent.
• Chemotherapy, radiotherapy, or any other cancer therapy for current diagnosis of
breast cancer.
• Subjects may not have received or be receiving any other investigational agents for
the treatment of the cancer under study.
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to abemaciclib or other agents used in study.
• 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 the opinion of the
investigator, would limit compliance with study requirements.
Drug: Letrozole, Drug: Abemaciclib
Breast Cancer, Breast - Female
UT Southwestern; Parkland Health & Hospital System
A Study of TAR-200 in Combination With Cetrelimab, TAR-200 Alone, or Cetrelimab Alone in Participants With Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Intravesical Bacillus Calmette-Guérin Who Are Ineligible for or Elected Not to Undergo Radical Cystectomy (SunRISe-1)
The purpose of this study is to evaluate the overall complete response (CR) rate in
participants treated with TAR-200 in combination with cetrelimab (Cohort 1), or TAR-200 alone
(Cohort 2), or cetrelimab alone (Cohort 3) with Carcinoma in Situ (CIS), with or without
concomitant high-grade Ta or T1 papillary disease.
• Histologically confirmed diagnosis of persistent or recurrent (carcinoma in situ [CIS]
or Tumour in situ [Tis]), with or without papillary disease (T1, high-grade Ta) within
12 months of completion of the last dose of Bacillus Calmette-Guerin (BCG) therapy, in
participants who have received adequate BCG. Mixed histology tumors are allowed if
urothelial differentiation (transitional cell histology) is predominant (example, less
than (<) 20 percent (%) variant histologic subtype). However, the presence of
neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid
features will make a participant ineligible. For participants with lamina propria
invasion (T1) on the screening biopsy/ transurethral resection of bladder tumor
(TURBT), muscularis propria must be present in order to rule out Muscle Invasive
Bladder Cancer (MIBC)
• All visible papillary disease must be fully resected (absent) prior to randomization
(residual CIS acceptable) and documented in the electronic case report form (eCRF) at
screening cystoscopy
• Participants must be ineligible for or have elected not to undergo radical cystectomy
• BCG-unresponsive high-risk NMIBC after treatment with adequate BCG therapy defined as
a minimum of 5 of 6 full doses of an induction course (adequate induction) plus 2 of 3
doses of a maintenance course, or at least 2 of 6 doses of a second induction course
• Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
Exclusion Criteria:
• Histologically confirmed, muscle-invasive, locally advanced, nonresectable, or
metastatic urothelial carcinoma (that is, T2, T3, T4, and/or Stage IV
• Must not have had urothelial carcinoma or histological variant at any site outside of
the urinary bladder. Ta/T1/CIS of the upper urinary tract (including renal pelvis and
ureter) is allowable if treated with complete nephroureterectomy more than 24 months
prior to randomization
• Participants with an active, known or suspected autoimmune disease. Participants with
autoimmune disorders not requiring systemic treatment (example, skin conditions such
as vitiligo, psoriasis, alopecia) or conditions requiring hormonal replacement
therapies such as type 1 diabetes mellitus or hypothyroidism are permitted to enroll
• Active hepatitis B or C infection (for example, participants with history of hepatitis
C infection but undetectable hepatitis C virus polymerase chain reaction (PCR) test
and participants with history of hepatitis B infection with positive hepatitis B
surface antigen (HBsAg) antibody and undetectable PCR are allowed)
• Prior therapy with an anti-programmed-cell death 1 (PD-1), anti-PD-ligand 2 (L2)
agent, or with an agent directed to another co-inhibitory T-cell receptor
Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4A)
This is a randomized, open label, adaptive platform trial to compare the effectiveness of
antithrombotic and additional strategies for prevention of adverse outcomes in COVID-19
positive inpatients
• ≥ 18 years of age
• Hospitalized for COVID-19
• Enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test
• Expected to require hospitalization for > 72 hours
Exclusion Criteria:
• Imminent death
• Requirement for chronic mechanical ventilation via tracheostomy prior to
hospitalization
• Pregnancy
Inclusion Criteria for Arm E
Inclusion criteria contained in the master protocol in addition to the following:
Moderate illness severity •defined as non-ICU level of care at the time of randomization
(not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive
ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)
OR Severe illness severity •defined as ICU level of care at the time of randomization
(receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the
following risk criteria:
1. Age ≥ 65 years or
2. ≥2 of the following -
• O2 supplementation > 2 liters per minute
• BMI ≥ 35
• GFR ≤ 60
• History of Type 2 diabetes
• History of heart failure (regardless of ejection fraction)
• D dimer ≥ 2x the site's upper limit of normal (ULN)
• Troponin ≥ 2x the site's ULN
• BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
• CRP ≥50 mg/L
Exclusion Criteria for Arm E
• Exclusion criteria contained in the master protocol, and
• Any condition that, in the opinion of the investigator, precludes the use of
crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin<4 g/dL)
• Open label treatment with crizanlizumab within the past three months
Inclusion Criteria for Arm F
Inclusion criteria contained in the master protocol in addition to the following:
Moderate illness severity •defined as non-ICU level of care at the time of randomization
(not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive
ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO))
OR Severe illness severity •defined as ICU level of care at the time of randomization
(receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)
For moderate illness severity, participants are required to meet one or more of the
following risk criteria:
1. Age ≥ 65 years or
2. ≥2 of the following-
• O2 supplementation > 2 liters per minute
• BMI ≥ 35
• GFR ≤ 60
• History of Type 2 diabetes
• History of heart failure (regardless of ejection fraction)
• D dimer ≥ 2x the site's upper limit of normal (ULN)
• Troponin ≥ 2x the site's ULN
• BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
• CRP ≥50 mg/L
Exclusion Criteria for Arm F
In addition to the exclusion criteria noted in the master protocol, arm-specific exclusion
criteria are as follows:
• Known hypersensitivity to any SGLT2 inhibitors
• Type 1 diabetes
• History of diabetic ketoacidosis
• eGFR <20 and/or requirement for renal replacement therapy
• Open label treatment with any SGLT2 inhibitor
• Based on a recommendation from the ACTIV4 DSMB on December 19, 2020, enrollment
of patients requiring ICU level of care into the therapeutic anti-coagulation arm
was stopped due to meeting a futility threshold and a potential for harm for this
sub-group could not be excluded. Enrollment continues for moderately ill
hospitalized COVID-19 patients.
• Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of
patients not requiring ICU level of care and randomized to P2Y12 or standard care
was stopped due to meeting a futility threshold. Enrollment continues for
severely ill (ICU level of care) hospitalized COVID-19 patients.
Randomized Study in Children and Adolescents With Migraine: Acute Treatment
The purpose of this study is to test the safety and efficacy of BHV-3000 versus placebo in
the acute treatment of moderate or severe migraine in children and adolescents.
1. History of migraine (with or without aura) for > 6 months before Screening according
to the IHS Classification ICHD-319 specifications for pediatric migraine. History may
be verified using both medical records and recall by the participant and/or
participant's parent(s)/legal representative(s).
2. History of 1 to 8 moderate or severe attacks per month during the 2 months prior to
enrollment, with attacks lasting > 3 hours without treatment, and attacks occurring at
intervals > 24 hours.
3. Prophylactic migraine medication are permitted if the dose has been stable for at
least 12 weeks prior to the Baseline Visit, and the dose is not expected to change
during the course of the study.
1. Participants may remain on one (1) medication with possible migraine prophylactic
effects, excluding CGRP antagonists [biologic or small molecule], during the
treatment phases.
2. Concomitant use of a CGRP antagonist, such as erenumab or fremanezumab, is
prohibited.
3. Previously discontinued prophylactic migraine medication must have done so at
least 90 days prior to the Screening Visit.
4. Verbally distinguish between migraine and other types of headaches.
5. Participants must have a weight > 40 kg at the Screening Visit.
6. Adequate venous access for blood sampling.
7. Male and female participants ≥ 6 to < 18 years of age (participants must not reach
their 18th birthday during the study).
Exclusion Criteria:
1. History of cluster headache or hemiplegic migraine headache.
2. Confounding and clinically significant pain syndrome that may interfere with the
participant's ability to participate in this study.
3. Current psychiatric condition that is uncontrolled and/or untreated for a minimum of 6
months prior to the Screening Visit. Participants with a lifetime history of psychosis
and/or mania.
4. History of suicidal behavior or major psychiatric disorder.
5. Current diagnosis or history of substance abuse; positive drug test at Screening.
6. History of moderate or severe head trauma or other neurological disorder (including
seizure disorder) or systemic medical disease that is likely to affect central nervous
system functioning.
7. Recent or planned surgery, requiring general anesthesia, <8 weeks prior to the
Screening Visit.
8. Participant has had gastrointestinal surgery that interferes with physiological
absorption and motility (i.e., gastric bypass, duodenectomy, or gastric banding).
9. Current diagnosis of viral hepatitis or a history of liver disease.
10. Conditions considered clinically relevant in the context of the study such as
uncontrolled hypertension (high blood pressure), diabetes, a life-threatening allergy
Research Study to Compare Three Doses of Semaglutide Tablets Taken Once Daily in People With Type 2 Diabetes (PIONEER PLUS)
This study compares three doses of once daily semaglutide tablets in people with type 2
diabetes who were previously treated with other oral anti-diabetic medicines. Participants
will be initiated on the lowest starting dose of 3 mg and gradually increased until they
reach the final trial dose of 14 mg, 25 mg or 50 mg once daily semaglutide tablets. The final
three doses will be randomized (i.e., decided by chance). Participants will be administered
one tablet per day for 68 weeks. Women cannot take part if they are pregnant, breast-feeding
or planning to become pregnant during the study period. Women who can get pregnant will be
checked for pregnancy via urine tests. Once daily semaglutide tablets (3 mg, 7 mg and 14 mg)
are approved for the treatment of type 2 diabetes in the US, in the EU and in some other
countries, under the brand name Rybelsus®.
• Male or female, age above or equal to 18 years at the time of signing informed
consent.
• Diagnosed with type 2 diabetes mellitus at least 180 days prior to the day of
screening.
• HbA1c of 8.0-10.5% (64-91 mmol/mol) (both inclusive).
• BMI equal to or above 25 kg/m^2
• Stable daily dose(s) for 90 days prior to the day of screening of any of the following
treatment regimens:
• No more than 3 of the following oral anti-diabetic drugs and at least 1 marked with a
*:
• Metformin (equal to or above1500 mg or maximum tolerated or effective dose).
• Sulfonylureas (SU) (equal to or above half of the maximum approved dose according
to local label or maximum tolerated or effective dose).
• Sodium/glucose cotransporter 2 (SGLT2) inhibitors (maximum tolerated dose).
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (maximally indicated dose as per local
label).
• Subjects, on treatment with stable dose of DPP-4 inhibitors at inclusion, must be
willing to discontinue DPP-4 inhibitor treatment at randomisation (with no wash-out).
Exclusion Criteria:
• Treatment with any medication indicated for the treatment of diabetes or obesity other
than stated in the inclusion criteria within the past 90 days prior to the day of
screening. However, short term insulin treatment for a maximum of 14 days prior to the
day of screening is allowed.
• Renal impairment measured as estimated glomerular filtration rate (eGFR) value of
below 30 mL/min/1.73 m^2 according to Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) creatinine equation as defined by kidney disease improving
global outcomes (KDIGO 2012) classification.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by
a fundus examination performed within the past 90 days prior to screening or in the
period between screening and randomisation. Pharmacological pupil-dilation is a
requirement unless using a digital fundus photography camera specified for non-dilated
examination.
Safeguarding the Brain of Our Smallest Infants Phase III (SafeBoosC)
the SafeBoosC-III trial investigates the benefit and harms of treatment based on
near-infrared spectroscopy monitoring compared with treatment as usual. The hypothesis is
that treatment based on near-infrared spectroscopy monitoring for extremely preterm infants
during the first 72 hours of life will result in a reduction in severe brain injury or death
at 36 weeks postmenstrual age.
• Infants born with postmenstrual age less than 28 weeks
• Signed informed consent, unless the NICU has chosen to use 'opt-out' or deferred
consent as consent method.
Exclusion Criteria:
• Missing written parental informed consent (if the 'opt-out' method is used for
consent, lack of a record that the clinical staff have explained the trial and the
'opt-out' consent process to parents and/or a record in the infant's clinical file of
parents' decision to opt-out, are exclusion criteria)
• Decision not to conduct full life support
• No possibility to place cerebral NIRS oximeter within six hours after birth
Other: Modify cardio-respiratory support to avoid cerebral hypoxia, Other: Treatment as usual
First-in-Human (FIH) Trial of GEN3009 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas
The drug that will be investigated in the study is an antibody, GEN3009. Since this is the
first study of GEN3009 in humans, the main purpose is to evaluate safety. Besides safety, the
study will determine the recommended GEN3009 dose to be tested in a larger group of patients
and assess preliminary clinical activity of GEN3009. GEN3009 will be studied in a broad group
of cancer patients, having different kinds of lymphomas. All patients will get GEN3009 either
as a single treatment (monotherapy) or in combination with another antibody-candidate for
treatment of cancer in the blood. The study consists of two parts: Part 1 tests increasing
doses of GEN3009 ("escalation"), followed by Part 2 which tests the recommended GEN3009 dose
from Part 1 ("expansion").
1. Be at least 18 years of age.
2. Must sign an informed consent form prior to any screening procedures.
3. Dose Escalation: Has histologically or cytologically confirmed relapsed and/or
refractory B-cell NHL with no available standard therapy or is not a candidate for
available standard therapy, and for whom, in the opinion of the investigator, the
experimental therapy may be beneficial. All subjects must have received at least two
prior lines of systemic therapy.
Dose Expansion: Has histologically or cytologically confirmed relapsed or refractory
B-cell NHL. All subjects must have received at least 2 prior lines of systemic
therapy, and,
1. For FL and DLBCL, at least 1 of the 2 prior lines of treatment must have been a
CD20 containing systemic regimen;
2. For CLL, subjects must have received at least one prior line of BTK inhibitor or
BCL 2 inhibitor.
4. Has one of the eligible subtypes of B-cell NHL :
Dose Escalation: (DLBCL, HGBCL, PMBCL, FL, MCL, MZL, SLL, or CLL). Dose Expansion:
(DLBCL, FL, CLL)
5. Has measurable disease for B-cell NHL or has active disease for Chronic Lymphocytic
Leukemia (CLL).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Has adequate hepatic, renal, and bone marrow functions.
8. Before the first dose of GEN3009, during the trial, and for 12 months after the last
dose of GEN3009 and/or the combination, a woman must be either not of childbearing
potential or of childbearing potential and practicing a highly effective method of
birth control, and must have a negative serum beta-human chorionic gonadotropin
(beta-hCG) and urine pregnancy test at screening.
9. A man who is sexually active with a woman of childbearing potential and has not had a
vasectomy must agree to use a barrier method of birth control.
10. Subjects must have a life expectancy of at least 3 months.
Key
Exclusion Criteria:
1. Prior treatment with a CD37-targeting agent.
2. Prior allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
3. Prior treatment with a CD3xCD20 bispecific antibody (Combination Expansion cohort
only).
4. Autologous HSCT within 3 months before the first dose of GEN3009.
5. Lymphomas leukemic phase: high absolute lymphocyte count or the presence of abnormal
cells in the peripheral blood indicating circulating lymphoma cells.
6. Treatment with an anti-cancer biologic including anti-CD20 therapy, radio-conjugated
or toxin-conjugated antibody or chimeric antigen receptor (CAR) T-cell therapy within
4 weeks or 5 half-lives, whichever is shorter, before the first dose of GEN3009.
Treatment with small molecules such as BTK inhibitors, BCL2 inhibitors, or PI3K
inhibitors within 5 half-lives prior to the first dose of GEN3009.
7. Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009.
8. Treatment with an investigational drug or an invasive investigational medical device
within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of
GEN3009, and at any time during the study treatment period.
9. Autoimmune disease or other diseases that require permanent or high-dose
immunosuppressive therapy.
10. Received a cumulative dose of corticosteroids more than the equivalent of 250 mg of
prednisone within the 2-week period before the first dose of GEN3009.
11. Has uncontrolled intercurrent illness.
12. Seizure disorder requiring therapy (such as steroids or anti-epileptics) (Combination
Expansion cohort only).
13. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or
to Grade 1 or less except for alopecia and peripheral neuropathy.
14. Primary central nervous system (CNS) lymphoma or known CNS involvement at screening.
15. Known past or current malignancy other than inclusion diagnosis.
16. Had allergic reactions to anti-CD20 or anti-CD37 monoclonal antibody treatment or
intolerant to GEN3009 or to the combination therapy excipients.
17. Has had major surgery within 4 weeks before screening or will not have fully recovered
from surgery, or has major surgery planned during the time the subject is expected to
participate in the trial (or within 4 weeks after the last dose of GEN3009 and/or the
combination therapy).
18. Known history/positive serology for hepatitis B.
19. Known medical history or ongoing hepatitis C infection that has not been cured.
20. Known history of seropositivity for HIV infection.
21. Is a woman who is pregnant or breast-feeding, or who is planning to become pregnant
while enrolled in this trial or within 12 months after the last dose of GEN3009 and/or
the combination therapy.
22. Is a man who plans to father a child while enrolled in this trial or within 12 months
after the last dose of GEN3009 and/or the combination therapy.
23. Has any condition for which, in the opinion of the investigator, participation would
not be in the best interest of the subject (eg, compromise the well-being) or that
could prevent, limit, or confound the protocol-specified assessments. Additionally,
vulnerable subjects or subjects under guardianship, curatorship, judicial protection
or deprived of liberty), are excluded from participation in this trial.
24. Exposed to live/live attenuated vaccine within 4 weeks prior to initiation of GEN3009
treatment.
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Biological: GEN3009, Biological: Epcoritamab
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Non-Hodgkins Lymphoma, High-grade B-cell Lymphoma, Primary Mediastinal Large B-cell Lymphoma