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.
Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency
Determine the safety, tolerability and pharmacokinetics of single doses of ARCT-810 in
clinically stable patients (stable on standard of care treatment, e.g. diet ± ammonia
scavengers) with ornithine transcarbamylase deficiency (OTCD).
1. Adequate cognitive ability to consent and recall symptoms over a 1-week time period
2. Males and females ≥18 years of age with documented diagnosis of ornithine
transcarbamylase deficiency (OTCD) confirmed with genetic testing, or willing to
consent to OTC gene sequencing and deletion/duplication testing
3. Subject's ornithine transcarbamylase deficiency (OTCD) is stable as evidenced by
1. no clinical symptoms of hyperammonemia AND b,
2. an ammonia level <100 µmol/L (170 µg/dL) at the screening evaluation Subjects
must remain free from symptoms of hyperammonemia throughout the screening period.
4. If using nitrogen ammonia scavenger therapy, must be on a stable regimen (no change in
dose or frequency) for ≥ 28 days prior to providing informed consent and throughout
the screening period
5. Must have maintained a stable protein-restricted diet (+/- amino acid supplementation)
for at least 28 days prior to providing informed consent and continue to maintain a
stable diet for the duration of the study
6. Good general health other than OTCD, in the opinion of the Investigator
7. Willing to refrain from strenuous exercise/activity and alcohol for 72 hours before
study visits
8. Willingness to comply with procedures and visits
9. Willingness to follow contraception guidelines
Exclusion Criteria:
1. History of clinically significant disease(s), in the opinion of the Investigator
2. Clinically significant screening laboratory values
3. Uncontrolled diabetes
4. Clinically significant anemia
5. Subjects who develop infection during screening must be asymptomatic for at least 7
days prior to dosing
6. Unwillingness to comply with study requirements
7. History of positive HIV, hepatitis C, or chronic hepatitis B
8. Uncontrolled hypertension
9. Malignancy within 5 years prior to study
10. Treatment with another investigational drug, biological agent, or device within 30
days of screening, or 5 half-lives of investigational drug
11. Treatment with any oligonucleotide or mRNA within 6 months of screening, with
exceptions for some vaccinations and investigational treatments
12. History of gene therapy, hepatocyte or mesenchymal stem cell transplantation
13. Prior organ transplant
14. History of severe allergic reaction to a liposomal product
15. Recent history of, or current, drug or alcohol abuse
16. Dependence on inhaled (smoked or vaped) or oral cannabis products
17. Systemic corticosteroids within 6 weeks prior to screening
18. Blood donation of 50 to 499 mL within 30 days of screening or of .499 mL within 60
days of screening
19. Other conditions, in the opinion of the Investigator, that would make the subject
unsuitable for participation
Comparing Two Treatment Combinations, Gemcitabine and Nab-Paclitaxel With 5-Fluorouracil, Leucovorin, and Liposomal Irinotecan for Older Patients With Pancreatic Cancer That Has Spread
This phase II trial compares two treatment combinations: gemcitabine hydrochloride and
nab-paclitaxel, or fluorouracil, leucovorin calcium, and liposomal irinotecan in older
patients with pancreatic cancer that has spread to other places in the body (metastatic).
Drugs used in chemotherapy, such as gemcitabine hydrochloride, nab-paclitaxel, fluorouracil,
leucovorin calcium, and liposomal irinotecan, work in different ways to stop the growth of
tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them
from spreading. This study may help doctors find out which treatment combination is better at
prolonging life in older patients with metastatic pancreatic cancer.
• Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous
surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided
radiation therapy is completed at least 2 weeks prior to registration and adjuvant
therapy was administered more than 6 months prior to registration. Patients with the
following histology are excluded: acinar cell; adenosquamous carcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patient is an English speaker with the ability to understand and complete the informed
consent and questionnaires
• Leukocytes >= 3,000/mcL (obtained within 4 weeks of registration)
• Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks of registration)
• Platelets >= 100,000/mcL (obtained within 4 weeks of registration)
• Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks
of registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (obtained within 4 weeks of registration)
• Creatinine =< institutional ULN unless data exists supporting safe use at lower kidney
function values, no lower than 30 mL/min/1.73 m^2 (obtained within 4 weeks of
registration)
• Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 unless data exists supporting
safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (obtained
within 4 weeks of registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of registration are eligible for
this protocol. HIV positive (+) patients who are on ritonavir or/and cobicistat-based
regimen must be switched to alternative anti-retroviral therapy (ART)
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable 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
• Male patients must agree not to father children while on study
• 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 protocol, patients should be class 2B or better
• Patients must have measurable disease and scans must be done within 4 weeks of
registration
• Patients classified to have mild-moderate abnormalities in any of the domains
evaluated in the screening geriatric assessment and are classified as "vulnerable" are
eligible. Patients classified without any abnormalities ("fit") or with severe
cognitive/functional impairment or high co-morbidity score ("frail") on the screening
geriatric assessment are ineligible
• Patients must agree not to take any medications or substances that are strong
inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan
treatment arm should avoid drugs that are UGT1A1 inhibitors
Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) (MK-3475-676/KEYNOTE-676)
This study is designed to assess the antitumor efficacy and safety of pembrolizumab in
combination with BCG, compared to BCG monotherapy, in participants with HR NMIBC that is
either persistent or recurrent following adequate BCG induction (Cohort A), or that is naïve
to BCG treatment (Cohort B). The primary hypothesis for Cohort A is that the combination of
pembrolizumab plus BCG has a superior complete response rate (CRR) as assessed by central
pathology review compared to BCG in participants with carcinoma in situ (CIS). The primary
hypothesis for Cohort B is that the combination of pembrolizumab plus BCG (either reduced
maintenance or full maintenance) has a superior Event Free Survival (EFS) compared to BCG.
• Have locally and blinded independent central review (BICR)-confirmed histological
diagnosis of high-risk non-muscle invasive (T1, high grade Ta and/or CIS) UC of the
bladder
• Has undergone cystoscopy/ transurethral resection of bladder tumor (TURBT) to remove
all resectable disease
• Has provided tissue for biomarker analysis
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Has adequate organ function
• During the treatment period and for ≥7 days after the last dose of BCG, male
participants are EITHER abstinent from heterosexual intercourse as their preferred and
usual lifestyle and agree to remain abstinent, OR, must agree to use contraception
unless confirmed to be azoospermic
• Female participants who are not pregnant, not breastfeeding, and either not a woman of
child bearing potential (WOCBP); or are a WOCBP who agrees to use a contraception
method that is highly effective or remains abstinent from heterosexual intercourse
during the treatment period and for ≥7 days after the last dose of BCG or 120 days
after the last dose of pembrolizumab, whichever comes last
BCG Post-induction Cohort (Cohort A) Only
• Has been treated with one adequate course of BCG induction therapy for the treatment
of HR NMIBC
• Following adequate BCG induction therapy, must have persistent or recurrent HR NMIBC
Exclusion Criteria:
• Has a history of or concurrent locally advanced (i.e., T2, T3, T4) or metastatic UC
• Has concurrent extra-vesical (i.e, urethra, ureter, renal pelvis) non-muscle invasive
urothelial carcinoma or a history of extra-vesical non-muscle invasive UC
• Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor
• Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks of start of study treatment
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks of start of study treatment
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days of start of study
treatment
• Has a known additional malignancy that is progressing or requires active treatment
within the past 3 years
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease
• Has one or more of the following contraindications to BCG: prior BCG sepsis or
systemic infection, total bladder incontinence, or an adverse experience to a previous
BCG instillation that resulted in treatment discontinuation and precludes retreating
with BCG
• Has an active infection or diagnosis requiring systemic antimicrobial therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B or known active Hepatitis C virus infection
• Has current active tuberculosis
• Has had an allogenic-tissue/solid organ transplant
• Has any contraindication(s) to IV contrast or is otherwise unable to have screening
imaging with IV contrast performed
BCG Post-induction Cohort (Cohort A) Only •Has persistent T1 disease following an
induction course of BCG
BCG Naïve Cohort (Cohort B) Only
•Has received any prior treatment with BCG for their NMIBC within the past 2 years prior
to study entry
Biological: Pembrolizumab, Biological: BCG
Urinary Bladder, High-risk Non-muscle Invasive Bladder Cancer
A Research Study to Compare Two Types of Insulin, a New Insulin, Insulin Icodec and an Available Insulin, Insulin Glargine, in People With Type 2 Diabetes Who Have Not Used Insulin Before (ONWARDS 1)
This study compares insulin icodec (a new insulin taken once a week) to insulin glargine (an
insulin taken once daily which is already available on the market) in people with type 2
diabetes.
The study will look at how well insulin icodec taken weekly controls blood sugar compared to
insulin glargine taken daily. Participants will either get insulin icodec that participants
will have to inject once a week on the same day of the week or insulin glargine that
participants will have to inject once a day at the same time every day. Which treatment
participants get is decided by chance.
The insulin is injected with a needle in a skin fold in the thigh, upper arm or stomach. The
study will last for about 1 ½ years. Participants will have 37 clinic visits and 26 phone
calls with the study doctor. At 11 clinic visits participant will have blood samples taken.
At 8 clinic visits participants cannot eat or drink (except for water) for 8 hours before the
visit.
Participants will be asked to wear a sensor that measures the blood sugar all the time in 5
periods of about one month during the study (about 5 months in total). Women cannot take part
if pregnant, breast-feeding or plan to become pregnant during the study period.
• Male or female aged above or equal to 18 years at the time of signing informed
consent.
• Diagnosed with type 2 diabetes mellitus (T2D) 180 days or more prior to the day of
screening.
• HbA1c from 7.0-11.0% (53.0-96.7 mmol/mol) both inclusive at screening confirmed by
central laboratory analysis.
• Insulin naïve. However, short term insulin treatment for a maximum of 14 days prior to
the day of screening is allowed, as is prior insulin treatment for gestational
diabetes.
• Stable daily dose(s) 90 days or more prior to the day of screening of any of the
following anti-diabetic drug(s) or combination regimen(s): a. Any metformin
formulations at least or greater than 1500 mg or maximum tolerated or effective dose.
b. Any metformin combination formulations equal to or above 1500 mg or maximum
tolerated or effective dose. c. Any of the following oral anti-diabetic drug classes
including combinations ((equal to or above half of the maximum approved dose according
to local label or maximum tolerated or effective dose): Sulfonylureas, Meglitinides
(glinides), dipeptidyl peptidase-4 (DPP-4) inhibitors, Sodium-glucose co-transporter-2
(SGLT2) inhibitors, Thiazolidinediones, Alpha-glucosidase inhibitors, Oral combination
products (for the allowed individual oral anti-diabetic drugs), Oral or injectable
glucagon-like peptide 1 (GLP-1) receptor agonists
• Body mass index (BMI) equal to or below 40.0 kg/m^2.
Exclusion Criteria:
• Any episodes (as declared by the subject or in the medical records) of diabetic
ketoacidosis within 90 days prior to the day of screening.
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or
transient ischaemic attack within 180 days prior to the day of screening.
• Chronic heart failure classified as being in New York Heart Association Class IV at
screening.
• Anticipated initiation or change in concomitant medications (for more than 14
consecutive days) known to affect weight or glucose metabolism (e.g. treatment with
orlistat, thyroid hormones, or corticosteroids).
• 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: Insulin icodec, Drug: Insulin glargine
Diabetes Mellitus, Type 2, Other Endocrine System, Pancreas
A Study of Combination Chemotherapy for Patients With Newly Diagnosed DAWT and Relapsed FHWT
This phase II trial studies how well combination chemotherapy works in treating patients with
newly diagnosed stage II-IV diffuse anaplastic Wilms tumors (DAWT) or favorable histology
Wilms tumors (FHWT) that have come back (relapsed). Drugs used in chemotherapy regimens such
as UH-3 (vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan)
and ICE/Cyclo/Topo (ifosfamide, carboplatin, etoposide, cyclophosphamide, and topotecan) work
in different ways to stop the growth of tumor cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. This trial may help doctors find out
what effects, good and/or bad, regimen UH-3 has on patients with newly diagnosed DAWT and
standard risk relapsed FHWT (those treated with only 2 drugs for the initial WT) and regimen
ICE/Cyclo/Topo has on patients with high and very high risk relapsed FHWT (those treated with
3 or more drugs for the initial WT).
• Patients with newly diagnosed stages 2 •4 diffuse anaplastic Wilms tumor must be
enrolled on AREN03B2 and have received an initial risk assignment showing DAWT (if
anaplasia first identified at diagnostic, pre-treatment nephrectomy or biopsy) or a
delayed nephrectomy classification showing DAWT (if anaplasia first noted at delayed
nephrectomy) prior to enrollment on AREN1921. Prior enrollment on AREN03B2 is not an
eligibility requirement for patients with relapsed favorable histology Wilms tumor.
• Patients must be =< 30 years old at study enrollment
• Patients with the following diagnoses are eligible for this study:
• Newly diagnosed stages 2 •4 diffuse anaplastic Wilms tumor as confirmed by
central review
• Favorable histology Wilms tumor at first relapse. Relapsed FHWT patients must
have previously achieved remission for their initial FHWT diagnosis to be
eligible for this study. The relapse risk groups are defined as follows,
regardless of radiation therapy:
• Standard-Risk relapse: Patients who received two chemotherapy agents for
frontline therapy; primarily actinomycin D and vincristine
• High-Risk relapse: Patients who received three chemotherapy agents for
frontline therapy; primarily vincristine, actinomycin D and doxorubicin or
vincristine, actinomycin D and irinotecan
• Very High-Risk relapse: Patients who received four or more chemotherapy
agents as part of initial therapy; primarily regimen M or its variations
• Patients with newly diagnosed DAWT must have had histologic verification of the
malignancy. For relapsed FHWT patients, biopsy to prove recurrence is encouraged, but
not required
• Note: For relapsed FHWT patients, an institutional pathology report confirming
favorable histology Wilms tumor (from relapse, if available, or from original
diagnosis) must be available for upload prior to initiation of protocol therapy
• Patients with newly diagnosed Stages 2 •4 diffuse anaplastic Wilms tumor must be
enrolled on AREN1921 within 2 weeks of the tumor-directed surgery or biopsy procedure
that first confirms a diagnosis of DAWT, whether at initial diagnostic procedure or
delayed nephrectomy (such surgery/biopsy is day 0). For patients who received prior
therapy for presumed favorable histology Wilms tumor, later confirmed to have diffuse
anaplastic Wilms tumor at subsequent review of the initial biopsy
• Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least
1 lymph node sampled prior to study enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
• Patients must have a life expectancy of >= 8 weeks
• Diffuse Anaplastic Wilms Tumor: Patients with diffuse anaplastic histology must have
had no prior systemic therapy, except in the following situations:
• Patients with diffuse anaplastic Wilms tumor who received no more than 12 weeks
of pre nephrectomy chemotherapy for what was originally presumed to be favorable
histology Wilms tumor, subsequently confirmed to be diffuse anaplastic Wilms
tumor at delayed nephrectomy
• Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeks of
chemotherapy following upfront biopsy, initiated within 14 days of biopsy, for
presumed favorable histology Wilms tumor based on institutional review, but
subsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2
initial risk assignment results (if available per current version of AREN03B2)
• Treatment consisting of vincristine/doxorubicin/cyclophosphamide initiated on an
emergent basis and within allowed timing as described
• Note: Patients who received prior therapy for presumed favorable histology Wilms
tumor, later identified to have diffuse anaplastic Wilms tumor as per above, must
begin study treatment starting at cycle 3 (week 7) of regimen UH 3. Patients who
received emergency radiation to preserve organ function are eligible as noted.
Patients who received radiation as part of standard of care for presumed newly
diagnosed favorable histology Wilms tumor, along with chemotherapy as noted
above, prior to identification of diffuse anaplasia, are also eligible
• Relapsed Favorable Histology Wilms Tumor: Patients must not have received prior
chemotherapy for their relapsed favorable histology Wilms tumor diagnosis. In
addition, patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
onto this study
• Radiation therapy (RT): >= 2 weeks (wks) must have elapsed for local palliative
RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >=
50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone
marrow (BM) radiation. Patients with relapsed favorable histology Wilms tumor who
received emergency radiation to preserve organ function are eligible and do not
need to washout with the above criteria
• Patients may not be receiving any other investigational agents (within 4 weeks prior
to study enrollment)
• Peripheral absolute neutrophil count (ANC) >= 750/uL (performed within 7 days prior to
enrollment)
• Platelet count >= 75,000/uL (transfusion independent) (performed within 7 days prior
to enrollment)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performed
within 7 days prior to enrollment)
• Patients with high-risk or very high-risk relapsed FHWT who will be treated with
regimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance or
radioisotope glomerular filtration rate (GFR) and meet the following requirement:
• Creatinine clearance or radioisotope GFR >= 60 mL/min/1.73 m^2 (performed within
7 days prior to enrollment)
• Patients diagnosed with stage 2-4 DAWT or standard risk relapsed FHWT, who will be
treated with regimen UH 3, may either obtain a creatinine clearance, radioisotope GFR
(meeting the above criteria of GFR >= 60 mL/min/1.73 m^2), or an adequate serum
creatinine as per the following table:
• Age: Maximum Serum Creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 0.6 (male and female)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: 1.7 (male), 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age or direct bilirubin =<
ULN for patients whose total bilirubin > 1.5 x ULN (performed within 7 days prior to
enrollment)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age or =< 5 x ULN for patients with liver metastases
(performed within 7 days prior to enrollment)
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
radionuclide angiogram (obtained within 21 days prior to enrollment and start of
protocol therapy)
Exclusion Criteria:
• Patients with a history of bilateral Wilms tumor (synchronous or metachronous)
• Patients with any uncontrolled, intercurrent illness including, but not limited to,
ongoing or active infection, or symptomatic congestive heart failure (defined as grade
2 or higher heart failure per Common Terminology Criteria for Adverse Events [CTCAE]
version 5.0)
• Relapsed FHWT patients who did not receive frontline chemotherapy (e.g., very low risk
FHWT initially observed without chemotherapy) or received only one chemotherapy agent
for frontline therapy
• For patients with high-risk or very high-risk relapsed FHWT:
• Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16
mmol/L and serum phosphate =< 2 mg/dL (or < 0.8 mmol/L) without supplementation
• For stages 2-4 DAWT and standard-risk relapsed FHWT patients:
• Chronic inflammatory bowel disease and/or bowel obstruction
• Concomitant use of St. John's wort, which cannot be stopped prior to the start of
trial treatment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation
RAdium-223 and SABR Versus SABR for Oligometastatic Prostate Cancers (RAVENS)
This is a Phase II non-blinded randomized study evaluating men with oligometastatic prostate
cancer lesions randomized (1:1) to stereotactic ablative radiation therapy (SABR) versus SBAR
+ Radium-223. We are looking to determine the progression-free survival of men who have
oligometastatic prostate cancer with at least one bone metastasis with stereotactic ablative
radiation therapy (SABR) versus SABR + Radium-223.
• Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the
bone or soft tissue (with at least one bone metastasis) develop within the past
6-months that are ≤ 5.0 cm or <250 cm3
• Patient must have had their primary tumor treated with surgery and/or radiation.
• Histologic confirmation of malignancy (primary or metastatic tumor).
• PSADT <15 months. PSA doubling time (PSADT) will be calculated using as many PSA
values that are available from time of relapse (PSA > 0.2). To calculate PSADT, the
Memorial Sloan Kettering Cancer Center Prostate Cancer Prediction Tool will be used.
It can be found at the following web site:
https://www.mskcc.org/nomograms/prostate/psa-doubling-time.
• Patient may have had prior systemic therapy and/or ADT associated with treatment of
their primary prostate cancer. Patient may have had ADT associated with salvage
radiation therapy (to the primary prostate cancer or pelvis is allowed).
• PSA > 0.5 but <50.
• Testosterone > 125 ng/dL.
• Patient must be ≥ 18 years of age.
• Patient must have a life expectancy ≥ 12 months.
• Patient must have an ECOG performance status ≤ 2.
• Patient must have normal organ and marrow function as defined as:
Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥
1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL.
* Patient must have the ability to understand and the willingness to sign a written
informed consent document.
Exclusion Criteria:
• No more than 3 years of ADT is allowed, with the most recent ADT treatment having
occurred greater than 6 months prior to enrollment.
• PSMA-PET/MRI or PSMA-PET/CT scan within the past 6 months with results that
demonstrate more disease lesions than baseline CT/Bone Scan
• Castration-resistant prostate cancer (CRPC).
• Spinal cord compression or impending spinal cord compression.
• Suspected pulmonary and/or liver metastases (greater >10 mm in largest axis).
• Patient receiving any other investigational agents.
• Patient receiving abiraterone and prednisone.
• Patient is participating in a concurrent treatment protocol.
• Serum creatinine > 3 times the upper limit of normal.
• Total bilirubin > 3 times the upper limit of normal.
• Liver Transaminases > 5-times the upper limit of normal.
• Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT.
• Prior salvage treatment to the primary prostate cancer or pelvis is allowed.
• Refusal to sign informed consent.
Ph 1/2 Study Evaluating Safety and Tolerability of Inhaled AP-PA02 in Subjects With Chronic Pseudomonas Aeruginosa Lung Infections and Cystic Fibrosis (SWARM-Pa)
Phase 1b/2a, double-blind, randomized, placebo-controlled, single and multiple ascending dose
study to evaluate the safety, tolerability and phage recovery profile of AP-PA02
multi-bacteriophage therapeutic candidate administered by inhalation in subjects with cystic
fibrosis and chronic pulmonary Pseudomonas aeruginosa (PA) infection.
• ≥ 18 years old
• Body mass index (BMI) of ≥ 18 kg/m2
• Documented diagnosis of CF
• Evidence of chronic pulmonary Pseudomonas aeruginosa infection
• Willing to undergo sputum induction procedures at designated study visits, and willing
to provide expectorated sputum samples at all other timepoints (for subjects who are
able to expectorate)
• FEV1 ≥ 60% of predicted normal [per Global Lung Function Initiative (GLI) standards]
at Screening
• Adequate renal function
Key
Exclusion Criteria:
• Recent significant weight loss
• Abnormal vital signs at Screening
• History of prolonged QT syndrome
• Use of supplemental oxygen during the day at rest
• Abnormal liver function tests greater than 3X the upper limit of normal (ULN)
• Recent oral or IV antibiotics received for acute pulmonary exacerbation. Inhaled
antibiotic use for chronic suppression of P. aeruginosa is acceptable.
• Recent clinically significant infection requiring systemic antimicrobial therapy
• Currently receiving anti-pseudomonal antibiotic treatment for acute sinusitis.
• Currently receiving systemic corticosteroids
• Currently receiving treatment for active infection with nontuberculous mycobacteria
(NTM)
• Currently receiving treatment for aspergillosis or ABPA (allergic bronchopulmonary
aspergillosis)
• Initiation of a CFTR potentiator/corrector therapy, such as Trikafta®, less than 90
days prior to Screening
• Acquired or primary immunodeficiency syndromes
• Active pulmonary malignancy (primary or metastatic)
• History of lung transplantation
• Recent hemoptysis
• Female pregnant or breastfeeding
• Use of tobacco in any form, or use of e-cigarettes/vaping within 6 months prior to
Screening
Celliant Socks to Increase Tissue Oxygenation and Complete Wound Closure in Diabetic Foot Wounds
This study is a prospective, multicenter, double-blind, 1:1 randomized clinical trial. The
purpose of this study is to demonstrate that the use of Celliant Socks increases tissue
oxygenation (via oxygen saturation, StO2) and incidence of wound closure in subjects with
diabetic foot ulcers. This study will use hyperspectral imaging and wound assessment to
measure these outcomes. The study will enroll 254 evaluable subjects total, 127 per arm to
meet the Primary Endpoint. Enrollment may continue up to twenty-five hundred (2500) evaluable
subjects total to meet the Key Secondary Endpoint of complete wound closure.
• Diagnosis of diabetes mellitus
• Subject is willing and able to wear a sports-style tube sock at least 22 hours a day.
• Ankle Brachial Index (ABI) ≥0.5 (bedside ABI is acceptable for screening purposes as
the formal imaging ABI may not be resulted prior to surgery) or toe pressure of
≥30mmHg
• One or more diabetic foot ulcers (only one will be treated) that are located in the
ankle area or below that has persisted a minimum of 30 days prior to the Screening
visit
• Diabetic Foot Ulcers ≥1cm2 and ≤16cm2
• Ulcer grade I or II, Stage A, I or II Stage B, according to University of Texas Wound
Classification System
• 22 years of age or older
Exclusion Criteria:
• Has clinically significant renal disease to require hemo or peritoneal dialysis
• Subject has untreated osteomyelitis
• Ulcers within 5cm of target ulcer or connected by fistulas
• Ulcer has decreased by 30% or more at the end of the run-in period
• Subject has untreated cellulitis
• Subject has untreated charcot
• Major immunodeficiency including HIV
• Is pregnant or plans to become pregnant
• Is nursing or actively lactating
• Developmental disability/significant psychological disorder that in the opinion of the
investigator could impair the subject's ability to provide informed consent,
participate in the study protocol or record study measures, including untreated
schizophrenia, bipolar disorder and psychiatric hospitalization within the last 2
years.
• Active alcohol or substance abuse in the opinion of the investigator that could impair
the subject's ability to provide informed consent, participate in the study protocol
or record study materials
Device: Celliant Diabetic Medical Socks, Device: Control (placebo) Medical Socks
Diabetic Foot Ulcer
UT Southwestern; Parkland Health & Hospital System
EA2176: Phase 3 Clinical Trial of Carboplatin and Paclitaxel +/- Nivolumab in Metastatic Anal Cancer Patients
This phase 3 trial compares the addition of nivolumab to chemotherapy (carboplatin and
paclitaxel) versus usual treatment (chemotherapy alone) for the treatment of anal cancer that
has spread to other places in the body (metastatic). Immunotherapy with monoclonal
antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may
interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as
carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either
by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Giving nivolumab together with carboplatin and paclitaxel may help doctors find out if the
treatment is better or the same as the usual approach.
• Patient must have inoperable, recurrent, or metastatic disease not amenable to
curative therapy
• Patient must have histological or cytological confirmation of anal squamous cell
carcinoma (includes basaloid and cloacogenic lesions) from the primary tumor or a
newly diagnosed recurrent/metastatic lesion
• Patient must be >= 18 years of age
• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =< 0-1
• Patients must have measurable disease according to Response Evaluation Criteria in
Solid Tumors (RECIST) criteria version 1.1 and based on radiologic assessment
performed < 4 weeks prior to randomization
• Patient receiving palliative (limited-field) radiation therapy is allowed, as long as
the lesion treated for palliation is not a target lesion and is > 7 days from
completion from palliative radiation
• Patients with brain metastasis are eligible if patient is asymptomatic and if
treatment ended > 3 months prior to randomization. Patients with treated brain
metastases are eligible if follow-up brain imaging after central nervous system
(CNS)-directed therapy shows no evidence of progression within 4 weeks prior to
randomization
• Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to randomization)
• Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)
• Hemoglobin (Hb) >= 9 g/dL for males and >= 9 g/dL for females (obtained < 14 days
prior to randomization)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days
prior to randomization)
• Aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) /alanine
transferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional
ULN (obtained < 14 days prior to randomization)
• Creatinine =< 1.5 x institutional ULN OR creatinine clearance (CrCl) >= 50 mL/min (if
using the Cockcroft-Gault formula) (obtained < 14 days prior to randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy (ART) with CD4 count >= 200 or have a CD4 count < 200 but an undetectable
viral load are eligible
• All HIV+ patients should be under the care of an infectious diseases specialist.
If a relationship with an infectious diseases specialist is not established, an
infectious disease specialist should be consulted. Records of all viral counts
and peripheral T-cell counts should be documented in order to follow these values
over the course of treatment
• All patients must be willing to undergo testing for HIV testing if not tested
within the past 12 months
• 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
• Patients with known history or current symptoms of cardiac disease, 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. Patients with a history of congestive heart failure (CHF) or who are at
risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs
must be willing to undergo evaluation of cardiac function including electrocardiogram
(EKG) and echocardiogram (ECHO) as clinically indicated
• Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC) who
have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible
• Patients must agree to not receive live vaccines while on this study
Exclusion Criteria:
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used. All females of childbearing potential must have a blood test or
urine study with a minimum sensitivity of 25 IU/L or equivalent units of Bacille
Calmette-Guerin (BCG), within 14 days prior to randomization to rule out pregnancy. A
female of childbearing potential is defined as any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy
or bilateral oophorectomy; or 2) 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).
• Women of childbearing potential and sexually active males must not expect to conceive
or father children by using accepted and effective method(s) of contraception or to
abstain from sexual intercourse for at least one week prior to the start of treatment,
and continue for 5 months after the last dose of protocol treatment for women of
childbearing potential and 7 months after the last dose of protocol treatment for
males who are sexually active with women of childbearing potential (WOCBP)
• Patient must not have had previous use of systemic chemotherapy or other
investigational drugs for the treatment of inoperable recurrent or metastatic anal
cancer (previous use of radiotherapy or chemoradiotherapy in this setting is not an
exclusion criterion if: 1) non-irradiated target tumor lesions are present at
randomization for the purpose of tumor response assessment or 2) in the absence of
non-irradiated target tumor lesions, progression of the irradiated tumor lesions
according to the RECIST criteria version 1.1 is documented)
• Patient must not have current or recent (within 30 days prior to randomization)
treatment with another investigational drug or participation in another
investigational study
• Patient must not have had prior immunotherapy
• Patient must not have a history of known hypersensitivity reaction to any platinum or
taxane-based chemotherapy or monoclonal antibody
• Patient must not have active autoimmune disease or history of autoimmune disease that
might recur, which may affect vital organ function or require immune suppressive
treatment including chronic prolonged systemic corticosteroids (defined as
corticosteroid use of duration one month or greater). These include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patients with any of these
are ineligible because of the risk of recurrence or exacerbation of autoimmune disease
• Patient must not have a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of randomization. Inhaled or topical steroids and adrenal
replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of
active autoimmune disease. Patients are permitted to use topical, ocular,
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
absorption). Physiologic replacement doses of systemic corticosteroids are permitted,
even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions
(e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Patient must not have had major surgery performed =< 28 days prior to randomization
• Patient must not have a history of interstitial lung disease (e.g., pneumonitis or
pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest
computed tomography (CT) scan
• Patient must not have a serious active infection requiring IV antibiotics at time of
randomization
• Patient must not have other primary malignancy within the last 3 years, except for
adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin,
or adequately controlled limited basal cell skin cancer, or any other cancer from
which the patient has been disease-free for at least 3 years
• Patient must not have known peripheral neuropathy > grade 1 at the time of
randomization (absence of deep tendon reflexes as the sole neurological abnormality
does not render the patient ineligible)
Ferric Citrate and Chronic Kidney Disease in Children (FIT4KID)
We will conduct a 12-month, double-blind, randomized, placebo-controlled trial to assess the
effects of therapy with ferric citrate (FC) on changes in intact FGF23 levels (iFGF23,
primary endpoint) in 160 pediatric patients (80 in each of the two arms) aged 6-17 years of
either sex with chronic kidney disease (CKD) stages 3-4 and age-appropriate normal serum
phosphate levels. Participants will be randomized to one of the two groups: 1) FC or 2) FC
placebo. Participants will be recruited from 12 core clinical sites.
1. Ages 6 to 17 years (inclusive);
2. Estimated GFR of 15-59 ml/min per 1.73 m2 by modified CKiD formula;56
3. Serum phosphate within age appropriate normal levels;
4. Serum ferritin <500 ng/ml and TSAT <50%;
5. For those patients treated with growth hormone, calcitriol, nutritional vitamin D,
iron, and/or ESAs such treatments must have stable dosing for at least 2 weeks prior
to screening;
6. Able to swallow tablets;
7. Able to eat at least two meals a day;
8. In the opinion of the investigator, willing and able to follow the study treatment
regimen and comply with the site investigator's recommendations.
Exclusion Criteria:
1. Perform physical exam and obtain vitals.
2. Check urine pregnancy test in menstruating female participants and administer
corresponding questionnaire.
3. Administer GI Symptom questionnaire.
4. Ascertain AEs.
5. Obtain information on concomitant medications.
6. Process 24-hour urine sample for 24 hour urine creatinine and phosphate.
7. Measure run-in adherence using eCAP system and pill count.
8. Administer the Medical Adherence Measure tool.
9. Reinforce adherence.
10. Prepare one month's supply of drug and enter them into eCAP system.
A Study to Compare Treatment With the Drug Selumetinib Alone Versus Selumetinib and Vinblastine in Patients With Recurrent or Progressive Low-Grade Glioma
This phase III trial investigates the best dose of vinblastine in combination with
selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib
alone in treating children and young adults with low-grade glioma (a common type of brain
cancer) that has come back after prior treatment (recurrent) or does not respond to therapy
(progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells
grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill
cancer cells. Giving selumetinib in combination with vinblastine may work better than
selumetinib alone in treating recurrent or progressive low-grade glioma.
• Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of
enrollment
• Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of
enrollment
• All patients > 21 years of age at the time of enrollment must have had initial
diagnosis of low-grade glioma by 21 years of age
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have eligibility confirmed by rapid central pathology and central
molecular screening reviews performed on APEC14B1
• Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC)
low-grade glioma (LGG) without a BRAFV600E or IDH1 mutation
• Patients must have progressive or recurrent LGG. Note: Biopsy may be at either
initial diagnosis or recurrence
• Patients must have measurable disease, defined as having a two-dimensional
measurable tumor volume of >= 1 cm^2
• Tumor size will be measured to include both solid and cystic components of
the tumor (whether or not tumor is enhancing) + fluid attenuated inversion
recovery (FLAIR) signal
• Eligible histologies will include all tumors considered low-grade glioma or
low-grade astrocytoma (World Health Organization [WHO] grade 1 and II) by the WHO
Classification of Tumors of the Central Nervous System •4th Edition Revised,
with the exception of subependymal giant cell astrocytoma
• Patients with metastatic disease or multiple independent primary LGGs are
eligible
• Patients must be progressive or recurrent after having been treated with at least one
prior tumor-directed therapy before enrollment
• Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
onto this study (4 weeks if prior nitrosourea);
• Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent;
• Radiation therapy (RT): >= 2 weeks (wks) for local palliative RT (small port); >=
6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of
pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM)
radiation;
• 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;
• MEK inhibitor or vinblastine: Must not have received treatment with a MEK
inhibitor or vinblastine within 6 months of study enrollment
• 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 (within 7 days
prior to enrollment):
• 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 (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
(within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L
• Albumin >= 2 g/L (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 (within 4 weeks prior to enrollment)
• Corrected QT interval (QTc interval) =< 450 msec by electrocardiogram (EKG) (within 4
weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to
enrollment)
• Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (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
• Stable neurological examination for >= 1 week
• HYPERTENSION:
• 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, an 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
• Note: If surgical resection or biopsy is performed at the time of progression or
recurrence, a post-operative MRI is required
• 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
Exclusion Criteria:
• Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following
exceptions:
• Patients must not have had progressive disease while on therapy with vinblastine
or a MEK inhibitor;
• Patients must not have discontinued vinblastine or selumetinib due to toxicity
• 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 must not have known hypersensitivity to selumetinib, vinblastine, or similar
compounds
• CYP3A4 agents: Patients must not have received fluconazole or drugs that are strong
inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment
• 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
• PRE-EXISTING CONDITIONS (CARDIAC):
• 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 Heart Association (NYHA) class II-IV prior or current
cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• PRE-EXISTING CONDITIONS (OPHTHALMOLOGIC CONDITIONS):
• 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 upper limit of normal (ULN) adjusted by age are
not eligible
• Any multivitamin containing vitamin E must be stopped prior to study enrollment even
if it contains less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy,
placement of a vascular access device or cerebrospinal 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
• 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
• 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
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Use of DNA Testing to Help Transition Kidney Transplant Recipients to Belatacept-only Immunosuppression
The purpose of the study is to identify kidney transplant patients that can be transitioned
from multi-drug immunosuppression therapy to Belatacept monotherapy, using cell free DNA and
gene expression as markers of immune quiescence. The primary objective will be to determine
if donor derived-cell free DNA (AlloSure) can be utilized to facilitate Belatacept
monotherapy, and to determine if Belatacept is safe and effective as immunosuppression in
kidney transplant recipients. The secondary objective is to determine the utility of AlloMap
as a predictor of immune quiescence and tolerance of immunosuppressive de-escalation to
Belatacept monotherapy, and to evaluate the performance of iBox in predicting adverse
outcomes in patients transitioned to Belatacept monotherapy
• Adult (>18 years) recipients of a kidney-only transplant, including re-transplants
• Non-HLA identical Living or Deceased Donor Grafts
• Able to provide informed consent
• Absence of donor specific antigens
• Stable renal function (eGFR>40mL/min for 3 months prior to enrollment)
• Patients treated with Belatacept as part of de novo immunosuppression or converted to
Belatacept with stable kidney function for 3 months (as stated above)
• Patients who underwent kidney transplantation at least 9 months prior to study entry
Exclusion Criteria:
• Prior or concurrent non-kidney organ transplants
• Presence of BK nephropathy in current graft
• Recipient on any other investigational drug in the 12 weeks prior to inclusion
• Patient with history of recent (<3mo), recurrent, or severe (Banff Grade 2 or greater
or unable to be treated with steroids) acute rejection episodes
• Female participant who is pregnant, lactating or planning pregnancy during the course
of the trial
• Significant hepatic impairment
• Bilateral kidney transplantation
• Any other significant disease or disorder which, in the opinion of the Investigator,
may either put the participants at risk because of participation in the trial, or may
influence the result of the trial, or the participant's ability to participate in the
trial
T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial
This phase III trial studies how well trastuzumab emtansine (T-DM1) and tucatinib work in
preventing breast cancer from coming back (relapsing) in patients with high risk, HER2
positive breast cancer. T-DM1 is a monoclonal antibody, called trastuzumab, linked to a
chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches
to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors,
and delivers DM1 to kill them. Tucatinib may stop the growth of tumor cells by blocking some
of the enzymes needed for cell growth. Giving T-DM1 and tucatinib may work better in
preventing breast cancer from relapsing in patients with HER2 positive breast cancer compared
to T-DM1 alone.
• HER2-positive status will be based on pretreatment biopsy material and defined as an
immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH)
according to current American Society of Clinical Oncology (ASCO) College of American
Pathologists (CAP) guidelines. Central testing is not required
* Known hormone receptor (HR) status as defined by ASCO/CAP guidelines (based on
pretreatment biopsy material). Hormone receptor positive status can be determined by
either known positive estrogen receptor (ER) or known positive progesterone receptor
(PR) status; hormone receptor negative status must be determined by both known
negative ER and known negative PR
• Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive
disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0
tumors are not eligible at initial breast cancer diagnosis are not eligible)
• Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or
lymph nodes per the surgical pathology report are eligible; however, patients with HR+
HER2+ cancers must have node-positive residual disease per the surgical pathology
report in order to qualify for the study. The presence of residual invasive disease in
the breast is not mandatory for these patients
• Patients with weakly ER-positive (1-10%) breast cancer (based on the pretreatment core
biopsy) are eligible even if they have node-negative disease per the surgical
pathology report
• The residual disease tissue (breast and/or lymph nodes) is not required to be
HER2-positive, as eligibility for NCI-2020-03770 (A011801) is based on a positive HER2
status at the time of the initial breast cancer diagnosis
* Note: The presence of micrometastases in lymph nodes after preoperative therapy
counts as residual disease, whereas the presence of isolated tumor cells does not
• Patients with synchronous bilateral invasive disease are eligible provided both
lesions were confirmed to be HER2-positive, and at least one of the lesions meets the
criteria outlined above. Multifocal disease is allowed, as long as the largest
biopsied breast tumor was HER2-positive
• Patients must have received neoadjuvant chemotherapy with one of the following
regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin
(TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P));
docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P));
fluorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab
(FAC-TH(P)), or
fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)).
Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is
acceptable
• Prior receipt of T-DM1 in the neoadjuvant setting is not allowed.
• Prior treatment must have consisted of >= 6 cycles of chemotherapy and
HER2-directed therapy, with a total duration of >= 12 weeks, including at least 9
weeks of preoperative taxane and trastuzumab with or without pertuzumab (or Food
and Drug Administration [FDA]-approved biosimilars). Patients who have received
at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also
eligible if they received >= 6 cycles of systemic therapy prior to enrollment.
Note: Patients who complete at least nine of a planned twelve doses of weekly
paclitaxel, or three of a planned four doses of docetaxel, but discontinue
prematurely due to toxicity are eligible. Patients receiving dose-dense
chemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane)
instead of paclitaxel or docetaxel is permitted. Prior use of subcutaneous
trastuzumab (Hylecta) and subcutaneous trastuzumab and pertuzumab (Phesgo) is
also allowed.
• Patients who received neoadjuvant systemic therapy which included experimental
HER2-targeted therapy/therapies are potentially eligible, as long as the
investigational agent was not a HER2-targeted antibody-drug conjugate (e.g.
T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase
inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib).
• Patients may have received =< 1 cycles of T-DM1 in the adjuvant setting. Note: These
patients will be randomized to receive a further 14 cycles of T-DM1 and
tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been
administered =< 5 weeks prior to registration
* Note: Both of the following two criteria need to be met for the patient to be
eligible for this study
• An interval of no more than 12 weeks between the completion date of the last
definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither
given, breast surgical date) and the date of registration. Concurrent radiation
therapy is permitted while receiving study treatment
• Patients must be registered on study within =< 180 days of the date of the most
recent definitive breast cancer surgery (not including reconstructive surgery)
• All systemic chemotherapy should have been completed preoperatively unless
participating in EA1181 (CompassHER2 pathologic complete response [pCR]) or the BIG
DECRESCENDO Trial (which is very similar to CompassHER2 pCR in terms of study design,
drugs, and eligibility). However, patients who received 4 cycles of neoadjuvant THP
off study can receive a further 2-4 cycles of chemotherapy postoperatively to meet
eligibility for A011801. Patients who participated in EA1181 or MA41 and proceeded to
surgery immediately after the de-escalated trial regimen must receive postoperative
chemotherapy to complete a total of >= 6 cycles of systemic treatment prior to
enrollment on A011801, as outlined above (e.g. 4 cycles pre-operatively, and 2 cycles
post-operatively). The postoperative chemotherapy regimen prescribed is at the
discretion of the treating oncologist (i.e. 2-4 cycles AC or THP, other). Continuation
of trastuzumab + pertuzumab (HP) pre- or post-operatively as maintenance therapy
(while awaiting a surgical date or an official pathology report) is allowed for all
study participants
• Toxicities related to prior systemic treatment should have resolved or be at baseline,
apart from alopecia and peripheral neuropathy =< grade 1
• Adequate excision: surgical removal of all clinically evident disease in the breast
and lymph nodes as follows:
• Breast surgery: total mastectomy with no gross residual disease at the margin of
resection, or breast-conserving surgery with histologically negative margins of
excision
• For patients who undergo breast-conserving surgery, the margins of the resected
specimen must be histologically free of invasive tumor and ductal carcinoma in
situ (DCIS) as determined by the local pathologist. If pathologic examination
demonstrates tumor at the line of resection, additional operative procedures may
be performed to obtain clear margins. If tumor is still present at the resected
margin after re-excision(s), the patient must undergo total mastectomy to be
eligible. Patients with margins positive for classic lobular carcinoma in situ
(LCIS) are eligible without additional resection
• Lymph node surgery ** The axilla needs to be evaluated with either sentinel node
biopsy or axillary lymph node dissection. If patients have a sentinel lymph node
biopsy and sentinel nodes are negative, no further axillary treatment is
necessary. If patients have isolated tumor cells (ITCs) in the setting of
residual breast disease, at least one of the following is required: axillary
lymph node dissection (ALND) or planned nodal irradiation. If patients have
micro- or macro-metastatic nodal disease, ALND and planned nodal irradiation are
required. Of note, co-enrollment on Alliance A011202 is not allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted
to achieve eligibility)
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.0 x upper limit of normal (ULN) or direct bilirubin within the
institutional normal range for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN)
• Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or
multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no
decrease in LVEF by more than 15% absolute percentage points from the pre-chemotherapy
LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55%
after completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated
once up to 3 weeks following the initial screening assessment to assess eligibility
Exclusion Criteria:
• No adjuvant treatment with any anti-cancer investigational drug within 28 days prior
to registration
• 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 pregnancy test done =< 7 days prior to registration
is required
• Patients with known active and/or untreated hepatitis B or hepatitis C or chronic
liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has
been treated and cleared and normal liver function are eligible to participate in the
study if the other eligibility parameters are met
• Stage IV (metastatic) breast cancer
• History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of
registration
• Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the
surgical pathology report
• Evidence of recurrent disease following preoperative therapy and surgery
• Patients for whom radiotherapy would be recommended for breast cancer treatment but
for whom it is contraindicated because of medical reasons (e.g., connective tissue
disorder or prior ipsilateral breast radiation)
• History of exposure to the following cumulative doses of anthracyclines: doxorubicin >
240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2.
For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2
• Cardiopulmonary dysfunction as defined by any of the following:
• History of National Cancer Institute (NCI) CTCAE version (v) 5.0 grade >= 3
symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA)
criteria class >= II
• Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not
controlled by adequate medication, severe conduction abnormality, or clinically
significant valvular disease
• High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate >
100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or
higher-grade atrioventricular block (AV)-block (second degree AV-block type 2
[Mobitz 2] or third degree AV-block)
• Significant symptoms (grade >= 2) relating to left ventricular dysfunction,
cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative
therapy
• History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with
prior trastuzumab treatment (e.g., during preoperative therapy)
• Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure > 100 mmHg)
• Current severe, uncontrolled systemic disease
• Major surgical procedure unrelated to breast cancer or significant traumatic injury
within 28 days prior to registration or anticipation of the need for major surgery
during the course of study treatment
• History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity
to trastuzumab or murine proteins or any components of the product
• Peripheral neuropathy of any etiology that exceeds grade 1
• Assessment by the investigator as being unable or unwilling to comply with the
requirements of the protocol
• Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4
or CYP2C8 inducer within 5 days prior to registration is prohibited.
• Please note that use of sensitive CYP3A substrates should be avoided two weeks
before registration and during study treatment. Additionally, CYP3A4 or CYP2C8
inducers are prohibited as concomitant medications within 5 days following
discontinuation of tucatinib treatment. Patients who require medications that are
known to be sensitive substrates of CYP3A4 with a narrow therapeutic window
should be excluded.
Invasive Breast Carcinoma, HER2 Positive Breast Carcinoma, Multifocal Breast Carcinoma, Synchronous Bilateral Breast Carcinoma, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Breast - Female, Breast - Male, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8
UT Southwestern; Parkland Health & Hospital System
A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation (RAMP-201)
This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy and in
combination with Defactinib in subjects with recurrent Low-Grade Serous Ovarian Cancer
(LGSOC)
• Histologically proven LGSOC (ovarian, peritoneal)
• In Part A KRAS mutation, KRAS wt
• Progression or recurrence of LGSOC after at least one prior systemic therapy for
metastatic disease.
• Measurable disease according to RECIST 1.1
• An Eastern Cooperative Group (ECOG) performance status ≤ 1.
• Adequate organ function
• Adequate recovery from toxicities related to prior treatments
• Agreement to use highly effective method of contraceptive
Exclusion Criteria:
• Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy
• Co-existing high-grade ovarian cancer or another histology
• History of prior malignancy with recurrence <3 years from the time of enrollment
• Major surgery within 4 weeks
• Symptomatic brain metastases requiring steroids or other interventions
• Known SARS-Cov2 infection (clinical symptoms) ≤28 days prior to first dose of study
therapy
• For subjects with prior MEK exposure, Grade 4 toxicity deemed related to the MEK
inhibitor
• Active skin disorder that has required systemic therapy within the past year
• History of rhabdomyolysis
• Concurrent ocular disorders
• Concurrent heart disease or severe obstructive pulmonary disease
• Subjects with the inability to swallow oral medications
Drug: avutometinib (VS-6766), Drug: avutometinib (VS-6766) and Defactinib
Nivolumab or Nivolumab and Azacitidine in Patients With Recurrent, Resectable Osteosarcoma
The purpose of this study is to evaluate the safety and efficacy of nivolumab, or nivolumab
in combination with azacitidine in participants with recurrent, resectable osteosarcoma
• Participants must have had a histologic diagnosis of osteosarcoma at original
diagnosis
• Disease Status: Patients with an isolated pulmonary recurrence of osteosarcoma can be
enrolled on this study.
• Any history of metastatic disease at a site other than lung would make the
patient ineligible for this study.
• The patient's treating team must consider the patient's disease to be resectable
and the patient must be willing to undergo resection of all disease, including
any lung lesion meeting criteria for likely metastatic disease, defined as: 3 or
more lesions ≥ 3 mm in diameter OR a single lesion ≥ 5 mm.
• Patients with bilateral disease are eligible provided their disease is considered
resectable. Resectable pulmonary nodules are defined as nodules that can be
removed without performing a pneumonectomy (e.g., nodules immediately adjacent to
the main stem bronchus or main pulmonary vessels).
• Must have a performance status corresponding to Eastern Cooperative Oncology Group
(ECOG) scores of 0, 1 or 2, using the Karnofsky scale for patients > 16 years of age
and the Lansky scale for patients ≤ 16 years of age
• Prior Therapy: Participants must have fully recovered from the acute toxic effects of
all prior chemotherapy, immunotherapy, or radiotherapy prior to the start of protocol
therapy.
• Participants must have normal organ and marrow function within 7 days of starting
protocol therapy
• All participants and/or their parents or legal guardians must have the ability to
understand and the willingness to sign a written informed consent/assent document
• Additional criteria may apply
Exclusion Criteria:
• Pregnancy or Breast Feeding
• Males and females of reproductive potential may not participate unless they have
agreed to the use of, at minimum, two methods of contraception, with one method being
highly effective and the other method being either highly effective or less effective
as outlined in study protocol documentation
• Concomitant Medications: Patients receiving the following are not eligible:
• Corticosteroids or other immunosuppressive medications
• Patients who are currently receiving other investigational agents or other anti-cancer
therapy
• Intercurrent Illnesses: Patients with uncontrolled intercurrent illness including, but
not limited to:
• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study
requirements
• Autoimmune disorders: Patients with a history of any Grade autoimmune disorder are not
eligible.
• Asymptomatic laboratory abnormalities (e.g., ANA, rheumatoid factor, altered thyroid
function studies) will not render a patient ineligible in the absence of a diagnosis
of an autoimmune disorder.
• Patients with ≥ Grade 2 hypothyroidism due to history of autoimmunity are not
eligible. Note: Hypothyroidism due to previous irradiation or thyroidectomy will not
impact eligibility
• Allergies: Patients with a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to Nivolumab (e.g., another humanized
antibody) or Azacitidine are not eligible
• Safety and Monitoring: Patients who are considered unable to comply with the safety
monitoring requirements of the study are not eligible
• Patients with known HIV or hepatitis B or C are excluded
• Patients who have received prior solid organ transplantation are not eligible
• Patients who have received prior anti-PD-1 directed therapy (mAb or small molecule)
are not eligible
Drug: Nivolumab, Drug: Azacitidine, Procedure: Post Treatment Surgery
Sarcoma, Osteosarcoma, Soft Tissue, Osteosarcoma in Children, Osteosarcoma Recurrent
Nivolumab in Treating Patients With Autoimmune Disorders and Advanced, Metastatic, or Unresectable Cancer
This phase Ib trial studies the side effects of nivolumab and to see how well it works in
treating patients with autoimmune disorders and cancer that has spread to other places in the
body or cannot removed by surgery. Immunotherapy with monoclonal antibodies, such as
nivolumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread.
• Patients can have either histologically confirmed malignancy that is radiologically
evaluable and metastatic or unresectable, or have a malignancy for which a PD-1/PD-L1
inhibitor has been approved in the adjuvant setting. Eligible tumor types include
solid tumors and malignancies in which there is known evidence of clinical activity
for single agent PD-1 or PD-L1 antibodies. Nivolumab is Food and Drug Administration
(FDA)-approved for the treatment of melanoma, non-small cell lung cancer (NSCLC),
Merkel cell cancer, bladder cancer, renal cell carcinoma (RCC), gastric cancer,
hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer, Hodgkin
lymphoma (HL), metastatic small cell lung cancer (SCLC), and any solid tumor with
microsatellite instability (MSI)-high status confirmed. Patients with HL are eligible
but must follow standard response criteria. Additional tumor types may be eligible on
a case by case basis upon discussion with principal investigator (PI). Patients
enrolling on the trial for adjuvant use will be restricted to those with histology for
which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting including but
not limited to NSCLC, melanoma, RCC, cervical cancer, and bladder cancer
• Patients who have previously received other forms of immunotherapy (high-dose [HD]
IL-2, IFN, CTLA-4) are allowed. Patients must not have received cytokine immunotherapy
for at least 4 weeks before nivolumab administration. Patients who have received prior
anti-CTLA4 will be allowed and the washout period is 6 weeks
• Age >= 18 years; children are excluded from this study but may be eligible for future
pediatric phase 1 combination trials
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >=
60)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 1,000/mcL
• Absolute neutrophil count >= 500/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x institutional ULN or < 8 x institutional ULN for patients with liver metastases
or an autoimmune disease that is contributing to the elevation of these values
• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using the
Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
viral load
• Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate central nervous system (CNS) specific treatment is not required and is
unlikely to be required for at least 4 weeks (or scheduled assessment after the first
cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the
investigator favors participation in the clinical trial
• The effects of nivolumab on the developing human fetus are unknown. For this reason,
women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. WOCBP receiving nivolumab will be
instructed to adhere to contraception for a period of 5 months after the last dose of
investigational product. Men receiving nivolumab and who are sexually active with
WOCBP will be instructed to adhere to contraception for a period of 7 months after the
last dose of investigational product. Women of childbearing potential must have a
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of
nivolumab. Women must not be breastfeeding. Women who are not of childbearing
potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic
men) do not require contraception. WOCBP is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. These durations
have been calculated using the upper limit of the half-life for nivolumab (25 days)
and are based on the protocol requirement that WOCBP use contraception for 5
half-lives plus 30 days, and men who are sexually active with WOCBP use contraception
for 5 half-lives plus 90 days. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she (or the
participating partner) should inform the treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients with more than one autoimmune disease are eligible. The treating physician
would determine which autoimmune disease is dominant and the patient would be treated
under that specific cohort
Exclusion Criteria:
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (AEs) due to agents administered more than 4 weeks
earlier have not resolved or stabilized. Palliative (limited-field) radiation therapy
(RT) is permitted (2 week washout from start of treatment), if all of the following
criteria are met:
• Repeat imaging demonstrates no new sites of bone metastases
• The lesion being considered for palliative radiation is not a target lesion
• Patients with prior therapy with an anti-PD-1 or anti-PD-L1
• Patients with prior allogeneic hematologic transplant
• Patients who are receiving any other anticancer investigational agents
• 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 would limit compliance with
study requirements
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) bleeding, obstruction, and abdominal carcinomatosis
which are known risk factors for bowel perforation should be evaluated for the
potential need for additional treatment before coming on study. For the IBD (UC and
CD) cohort, an endoscopic assessment, disease activity index, and disease specific
inclusion/exclusion criteria will substitute for these factors in determining
eligibility with the exception of abdominal carcinomatosis, which should prompt
further evaluation
Global Safety and Efficacy Registration Study of Crinecerfont for Congenital Adrenal Hyperplasia (CAHtalyst)
This is a Phase 3 study to evaluate the efficacy, safety, and tolerability of crinecerfont
versus placebo administered for 24 weeks in approximately 165 adult subjects with classic CAH
due to 21-hydroxylase deficiency. The study consists of a 6 month randomized, double blind,
placebo-controlled period, followed by 1 year of treatment with crinecerfont. Duration of
participation is approximately 20 months.
1. Be willing and able to adhere to the study procedures, including all requirements at
the study center and return for the follow-up visit.
2. Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH.
3. Be on a stable regimen of steroidal treatment for CAH.
4. Patients of childbearing potential must agree to use hormonal or two forms of
nonhormonal contraception (dual contraception) or other highly effective contraception
during the study.
Exclusion Criteria:
1. Have a diagnosis of any of the other known forms of classic CAH.
2. Have a history of bilateral adrenalectomy, hypopituitarism, or other condition
requiring chronic glucocorticoid therapy.
3. Have a clinically significant unstable medical condition or chronic disease other than
CAH.
4. Have a history of cancer unless considered cured.
5. Are pregnant.
6. Have a known history of clinically significant arrhythmia or abnormalities on ECG.
7. Have a known hypersensitivity to any corticotropin releasing hormone antagonists.
8. Have received any other investigational drug within 30 days before initial screening
or plan to use an investigational drug (other than the study drug) during the study.
9. Have current substance dependence, or current substance (drug) or alcohol abuse.
10. Have had a blood loss ≥550 mL or donated blood or blood products within 8 weeks prior
to the study.
A Study of AKCEA-APOCIII-LRx Administered to Patients With Familial Chylomicronemia Syndrome (FCS) (BALANCE)
The purpose of the study is to evaluate the efficacy of AKCEA-APOCIII-LRx as compared to
placebo on the percent change in fasting triglycerides (TG) from baseline.
• A diagnosis of genetically confirmed Familial Chylomicronemia Syndrome (type 1
Hyperlipoproteinemia)
• Fasting TG ≥ 880 mg/dL (10 millimoles per liter (mmol/L)) at Screening
• History of pancreatitis
• Stable doses of statins, omega-3 fatty acids, fibrates, or other lipid-lowering
medications are allowed
Key
Exclusion Criteria:
• Acute coronary syndrome within 6 months of Screening
• Major surgery within 3 months of Screening
• Have any other conditions, which, in the opinion of the Investigator would make the
participant unsuitable for inclusion, or could interfere with participating in or
completing the study
Assessment of ANK-700 in Patients With Relapsing Remitting Multiple Sclerosis (MoveS-it)
A safety study of ANK-700 in patients with relapsing remitting multiple sclerosis. The study
has two parts:
Part A - first in human study in which patients receive a single dose of ANK-700 Part B -
patients will receive three doses of either ANK-700 or placebo
• Diagnosed with RRMS per revised McDonald criteria (2017) with an EDSS score ≤ 6.5 at
screening
• Neurologically stable with no evidence of relapse within the 28 days before signing
the informed consent form (ICF)
• Either not currently receiving disease modifying MS therapy, or currently using
fumarate drugs (dimethyl fumarate or diroximel fumarate)
• Patients must use a highly effective method of birth control or are sterile or
postmenopausal as confirmed by study Investigator
• Patient has signed and understands the ICF
Exclusion Criteria:
• Diagnosis of primary progressive MS or secondary progressive MS
• Uncontrolled or significant medical conditions (including active infection or chronic
hepatitis) which, in the opinion of the Investigator, preclude participation
• Patients treated with glatiramer acetate, parenteral steroids or adrenocorticotropic
hormone, β-interferon, plasma exchange, fingolimod, ozanimod, or siponimod within the
3 months prior to first dose
• Patients treated with cytotoxic agents (including, but not limited to, cladribine,
mitoxantrone, cyclophosphamide, azathioprine, and methotrexate), laquinimod,
teriflunomide, or IV gamma globulin within 12 months prior to first dose
• Patients treated with monoclonal antibody therapy (including natalizumab, daclizumab,
rituximab, ofatumumab, and ocrelizumab) within 24 months prior to first dose
• Patients previously treated with alemtuzumab, total lymphoid irradiation, mesenchymal
stem cell or hematopoietic stem cell transplantation, or tolerance-inducing therapies
for MS
• Contraindication to or inability to undergo gadolinium-enhanced magnetic resonance
imaging (MRI) scan
• Use of any investigational drug or experimental procedure within previous 6 months
that would interfere with the assessment of ANK-700
• Patients who are pregnant or breastfeeding
A Trial to Compare the Efficacy and Safety of Once-weekly Lonapegsomatropin With Placebo and a Daily Somatropin Product in Adults With Growth Hormone Deficiency (foresiGHt)
A 38 week dosing trial of lonapegsomatropin, a long-acting growth hormone product,
administered once-a-week versus placebo-control. A daily somatropin product arm is also
included to assist clinical judgement on the trial results. Approximately 240 adults (males
and females) with growth hormone deficiency will be included. Randomization will occur in a
1:1:1 ratio (lonapegsomatropin : placebo : daily somatropin product). This is a global trial
that will be conducted in, but not limited to, the United States, Europe, and Asia.
Inclusion Criteria
1. Age between 23 and 75 years, inclusive, at screening.
2. AGHD Diagnosis Criteria
For adult-onset AGHD: documented history of structural hypothalamic-pituitary disease,
hypothalamic-pituitary surgery, cranial irradiation, 1-4 non-GH pituitary hormone
deficiencies, a proven genetic cause of GHD, or traumatic brain injury (TBI).
A. For all countries except Japan: Subjects must satisfy at least one of the following
criteria:
1. Insulin tolerance test: peak GH ≤5 ng/mL
2. Glucagon stimulation test according to body mass index (BMI)
• i. BMI ≤30 kg/m2: peak GH ≤3 ng/mL
• ii. BMI >30 kg/m2: peak GH ≤1 ng/mL
3. Three or four pituitary axis deficiencies (i.e., adrenal, thyroid, gonadal,
and/or vasopressin; not including GH) with IGF-1 SDS ≤ -2.0 at screening
4. Macimorelin test: peak GH ≤2.8 ng/mL
5. Growth hormone releasing hormone (GHRH) + arginine test according to BMI:
• i. BMI <25 kg/m2, peak GH <11 ng/mL
• ii. BMI ≥25-≤30 kg/m2, peak GH <8 ng/mL
• iii. BMI >30 kg/m2, peak GH <4 ng/mL
B. For Japan only: Subjects with adult onset AGHD and deficiency of one or more other
pituitary hormones need to satisfy at least one of the following criteria, while
subjects with isolated GHD and no evidence of intracranial structure disorder
(structural hypothalamic-pituitary disease) or with adult onset AGHD without
deficiency of other pituitary hormones need to satisfy at least 2 of the following
criteria:
1. Insulin tolerance test: peak GH ≤1.8 ng/mL
2. Glucagon test: peak GH ≤1.8 ng/mL
3. Growth Hormone Releasing Peptide-2 (GHRP-2) tolerance test: peak GH ≤9 ng/mL
3. IGF-1 SDS ≤ -1.0 at screening as measured by central laboratory.
4. hGH treatment naïve or no exposure to hGH therapy or GH secretagogue for at least 12
months prior to screening.
5. For subjects on hormone replacement therapies for any hormone deficiencies other than
GH (e.g., adrenal, thyroid, estrogen, testosterone) must be on adequate and stable
doses for ≥6 weeks prior to and throughout screening.
6. For subjects not on glucocorticoid replacement therapy, documentation of adequate
adrenal function at screening defined.
7. For males not on testosterone replacement therapy: morning (6:00 •10:00AM) total
testosterone within normal limits for age.
8. On a stable diet and exercise regime at screening with no intention to modify diet or
exercise pattern during the trial, i.e., no weight reduction program intended during
the trial or within the last 90 days prior to or through screening.
9. No plans to undergo bariatric surgery during the trial.
10. Normal fundoscopy at screening (without signs/symptoms of intracranial hypertension or
diabetic retinopathy above stage 2 / moderate). For subjects with a diagnosis of
diabetes mellitus at screening, this must be documented with a fundus photograph.
11. Able and willing to provide a written informed consent and authorization for protected
health information (PHI) disclosure in accordance with Good Clinical Practice (GCP).
Exclusion Criteria
1. Known Prader-Willi Syndrome and/or other genetic diseases that may have an impact on
an endpoint.
2. Diabetes mellitus at screening if any of the following criteria are met:
1. Poorly controlled diabetes, defined as HbA1c >7.5% at screening.
2. Diabetes mellitus (defined as HbA1c ≥6.5% and/or fasting plasma glucose ≥126
mg/dL and/or plasma glucose ≥200 mg/dL two hours after oral glucose tolerance
test) diagnosed <26 weeks prior to screening
3. Change in diabetes regimen (includes dose adjustment) within <90 days prior and
throughout screening
4. Use of any diabetes drugs other than metformin and/or DPP-4 inhibitors for a
cumulative duration of greater than 4 weeks within 12 months prior to screening
5. Diabetes-related complications at screening (i.e., nephropathy as judged by the
investigator, neuropathy requiring pharmacological treatment, retinopathy stage 2
/ moderate and above within 90 days prior to screening or during screening)
3. Active malignant disease or history of malignancy. Exceptions to this exclusion
criterion:
1. Resection of in situ carcinoma of the cervix uteri
2. Complete eradication of squamous cell or basal cell carcinoma of the skin
3. Subjects with GHD attributed to treatment of intracranial malignant tumors or
leukemia, provided that a recurrence-free survival period of at least 5 years
prior to screening is documented in the subject's file based on a Magnetic
Resonance Imaging (MRI) result
4. Evidence of growth of pituitary adenoma or other benign intracranial tumor within the
last 12 months before screening.
5. Subjects with acromegaly without remission / with documented remission less than 24
months prior to screening.
6. Subjects with Cushing's disease without remission / with documented remission less
than 24 months prior to screening.
7. Subjects with prior cranial irradiation or hypothalamic-pituitary surgery: the
procedure took place less than 12 months prior to screening.
8. eGFR <60 mL/min/1.73m2 determined based on Modification of Diet in Renal Disease
(MDRD) equation.
9. Hepatic transaminases (i.e., AST or ALT) >3 times the upper limit of normal.
10. Heart failure NYHA class 3 or greater (NYHA 1994).
11. QTcF ≥ 451 milliseconds on 12-lead ECG at screening.
12. Poorly controlled hypertension.
13. Cerebrovascular accident within 5 years prior to screening.
14. Anabolic steroids (other than gonadal steroid replacement therapy) or
oral/intravenous/intramuscular corticosteroids within 90 days prior to or throughout
screening.
15. Currently using or have used within 26 weeks prior to screening any weight-loss or
appetite-suppressive medications.
16. Known history of hypersensitivity and/or idiosyncrasy to any of the test compounds
(somatropin) or excipients employed in this trial.
17. Known history of neutralizing anti-hGH antibodies.
18. Inability to undergo scanning by DXA or a non-interpretable DXA scan at screening.
19. Female who is pregnant, breast-feeding or intends to become pregnant or is of
childbearing potential and not using adequate contraceptive methods
20. Male subjects must use a condom, or his female partner of childbearing potential must
use an effective form of contraception as described above, from the beginning of
screening to the last trial visit.
21. Known substance abuse or known (or previous) eating disorders, including anorexia
nervosa, bulimia and severe gastrointestinal disease affecting normal eating (as
judged by the investigator).
22. Any disease or condition that, in the judgement of the investigator, may make the
subject unlikely to comply with the requirements of the trial or any condition that
presents undue risk from the investigational product or procedures.
23. Participation in another interventional clinical trial involving an investigational
compound within 26 weeks prior to screening or in parallel to this trial.
Study to Assess the Efficacy and Safety of MT-3921 in Subjects With Acute Traumatic Cervical Spinal Cord Injury
The purpose of this study is to compare the efficacy and safety of intravenous (IV) infusions
of MT-3921 to placebo in subjects with acute traumatic cervical spinal cord injury.
Subjects meeting eligibility criteria will enter the 6-month double-blind period. Subjects
will be randomized in a 2:1 ratio to receive MT-3921 or placebo in a double blind manner.
Additional screening criteria check may apply for qualification:
• Provide written informed consent prior to beginning any study procedures
• Cervical spinal cord injury that meet all of the following criteria:
• Classified as AIS A, AIS B or AIS C
• ISNCSCI neurological level of injury between C4 and C7 (for C4, the subject must
have at least 1 point of motor activity between C5 to C7)
• UEMS ≤28 at Screening
• Body mass index (BMI) <40
Exclusion Criteria:
Additional screening criteria check may apply for qualification:
• Any concomitant injury that interferes with the procedures and examinations required
by study protocol, including performance, interpretation or validity of neurological
examinations
• Poly-traumatic Injury as defined by Injury Severity Score (ISS) values > 25
• Penetrating spinal cord injuries
• Complete transection of the spinal cord
• Any other significant pre-existing medical conditions prior to spinal cord injury or
current conditions that, in the judgement of the iInvestigator, may increase the risks
associated with study participation
• History of anaphylaxis or clinically significant allergic reactions to any medication
• History or presence of malignancy within the last 3 years prior to screening
• Subjects with current SARS-CoV-2 infection (COVID-19)
• Subjects with hereditary fructose intolerance
• Psychoactive substance use disorder
• Participation in any clinical trial of a new chemical entity within 12 weeks prior to
Screening
• Female subjects who are pregnant or lactating
To assess toxicity with use of Ruxolitinib in NSCLC cachexia patients; to associate levels of
JAK/STAT signaling in blood, adipose, and muscle pre- and post-ruxolitinib treatment with
changes in cachexia and anorexia.
1. Male or female subjects at least 18 years of age;
2. Ability to understand and the willingness to sign a written informed consent;
3. Histological or biopsy proven Non-Small Cell Lung Cancer (squamous or non-squamous);
4. ECOG performance status of 0-2;
5. Patients with evidence of:
• cancer cachexia, defined by the International Cancer Cachexia Consensus
Definition (>5% weight loss over the preceding 6 months prior to diagnosis); OR
• Patients with evidence of cancer pre-cachexia, defined by the International
Cancer Cachexia Consensus Definition (0 to <=5% weight loss over the preceding 6
months prior to diagnosis);
6. Any de novo stage IV NSCLC disease diagnosis as defined by AJCC 8th edition staging.
Staged with PET/CT, MRI brain, or other acceptable staging tool; measurable disease as
defined by RECIST 1.1;
7. Adequate end-organ function, based on routine clinical and laboratory workup and
institutional guidelines, as determined by oncology team offering patient standard of
care therapy, including:
1. ANC >1,000 cells/µl, Platelets > 100,000 cells/µl, Hemoglobin > 10.0 g/dl;
2. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 45 ml/min;
3. Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤
2.5 x ULN;
4. International normalized ratio (INR) (or prothrombin time (PT)) and activated
partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving
anticoagulant therapy, if values are within the intended therapeutic range;
8. Women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation, and for 90 days following completion
of therapy. 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: a. Has not undergone a hysterectomy or bilateral oophorectomy; or
b. 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);
9. Male subjects who are surgically sterile or are using a medically acceptable form of
contraception for 90 days following the completion of therapy;
10. Life expectancy anticipated to be 6 months or greater;
11. No prior therapy for advanced lung cancer.
Exclusion Criteria:
1. Subjects with confirmed stage I-III NSCLC;
2. Patients whose tumors have actionable mutations treatable with targeted therapies;
3. Patients with no evidence of cancer cachexia, defined by the International Cancer
Cachexia Consensus Definition (>5% weight loss over the preceding 6 months prior to
diagnosis); OR Patients with no evidence of cancer pre-cachexia, defined by the
International Cancer Cachexia Consensus Definition (0 to <=5% weight loss over the
preceding 6 months prior to diagnosis);
4. Active malignancy other than lung cancer that requires concurrent treatment other than
hormonal therapy and is deemed by the treating physicians to be likely to affect the
subject's survival duration;
5. Subjects who have not recovered or have disease control from prior treatment-related
to toxicities judged by treating physician;
6. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ruxolitinib or other agents used in study;
7. Uncontrolled intercurrent illness including, but not limited to, serious 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;
8. Inadequate liver or renal function, if out of the acceptable ranges of the inclusion
criteria;
9. Significant bacterial, fungal, parasitic, or viral infection requiring treatment;
10. Previous treatment with a JAK inhibitor;
11. Uncontrolled congestive heart failure (New York Heart Association Classification 3 or
4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral
artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3
months prior to initiation of ruxolitinib;
12. Females who are pregnant, breast-feeding or plan to become pregnant;
13. Participation in other clinical trials either to treat diagnosed lung or other cancers
(patients on registry trials are eligible);
14. Requirement for treatment with drugs that may, in the judgment of the treating
investigator, create a risk for a precipitous change in patient's health;
15. Any other conditions that, in the Investigator's opinion, might indicate the subject
to be unsuitable for the study;
16. Life expectancy of less than 6 months;
17. Prior therapy for the newly diagnosed advanced lung cancer.
18. Patients taking therapies that are strong CYP3A4 inhibitors and fluconazole.
Drug: Identify any dose-limiting toxicity (DLT) when ruxolitinib is administered to NSCLC cachexia patients.
A Study of the Efficacy and Safety of 24 Week Treatment With REN001 in Patients With Primary Mitochondrial Myopathy (STRIDE)
This is a randomized, double-blind, placebo-controlled, parallel group, multi-centre, study
designed to investigate the efficacy and safety of REN001 administered once daily over a
24-week period to patients with PMM.
1. Subjects age 18 years or older with PMM as defined by the International Workshop:
Outcome measures and clinical trial readiness in primary mitochondrial myopathies in
children and adult (Mancuso et al 2017).
2. A confirmed PMM diagnosis due to known pathogenic gene mutation or deletion of the
mitochondrial genome. The Sponsor may authorize local genetic testing at Screening, if
required, but results must be available prior to randomization of the subject.
3. Documented PMM primarily characterized by exercise intolerance or active muscle pain.
4. Subjects must be ambulatory and able to perform the walking tests independently
(walking aids are allowed).
5. Have no changes to any therapeutic exercise regimen within 30 days prior to Day 1 and
be willing to remain on the same therapeutic exercise regimen for the duration of the
study.
6. Females should be either of non-child-bearing potential or must agree to use highly
effective methods of contraception from Screening through to 30 days after last dose
in the study. Males with partners who are WOCBP must also use contraception.
7. Concomitant medications (including supplements) must be stable for at least 1 month
prior to enrolment and throughout participation in the study.
8. Evidence of a personally signed and dated informed consent document indicating that
the subject has been informed of all pertinent aspects of the study.
Exclusion:
1. Participation in a prior REN001 (previously known as HPP-593) study.
2. Currently taking or anticipated to need a PPAR agonist during the study.
3. Subjects with bone deformities or motor abnormalities other than related to the
mitochondrial myopathy that may interfere with the outcome measures.
4. Clinically significant kidney disease or impairment calculated as eGFR Grade 2 or
above <60ml/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) creatinine equation at Screening.
5. Clinically significant liver disease or impairment of AST or ALT Grade 2 or above
(>2.5 x ULN), or Total bilirubin > 1.6 x ULN or >ULN with other signs and symptoms of
hepatotoxicity at Screening.
6. Subjects with uncontrolled diabetes and/or a Screening HbA1c of ≥11%.
7. Evidence of significant concomitant clinical disease that may need a change in
management during the study or could interfere with the conduct or safety of this
study. (Stable well-controlled chronic conditions such hypercholesterolemia,
gastroesophageal reflux, or depression under control with medication (other than
tricyclic antidepressants), are acceptable provided the symptoms and medications would
not be predicted to compromise safety or interfere with the tests and interpretations
of this study.)
8. Subjects with a history of cancer. A history of in situ basal cell carcinoma in the
skin is allowed.
9. Clinically significant cardiac disease and/or clinically significant ECG abnormalities
such as 2nd degree heart block, symptomatic tachyarrhythmia or unstable arrythmia
(right bundle branch block, left fascicular block and long PR interval are not
excluded) that in the opinion of the Investigator should exclude the subject from
completing exercise tests.
10. Evidence of hospitalization for rhabdomyolysis within the year prior to enrolment.
11. Pregnant or nursing females.
12. History of sensitivity to PPAR agonists.
Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
This phase III trial compares the effects of nivolumab with chemo-immunotherapy versus
chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal
B-cell lymphoma (PMBCL). Immunotherapy with monoclonal antibodies, such as nivolumab, may
help the body's immune system attack the cancer, and may interfere with the ability of cancer
cells to grow and spread. Treatment for PMBCL involves chemotherapy combined with an
immunotherapy called rituximab. Chemotherapy drugs work in different ways to stop the growth
of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping
them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20,
which is found on B cells (a type of white blood cell) and some types of cancer cells. This
may help the immune system kill cancer cells. Giving nivolumab with chemo-immunotherapy may
help treat patients with PMBCL.
• Age >= 2 years
• Patient must have histologically confirmed primary mediastinal B-cell lymphoma (PMBCL)
as defined by World Health Organization (WHO) criteria
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or ECOG
performance status of 3 if poor performance is related to lymphoma
• Children's Oncology Group (COG) Institutions: Use Karnofsky for patients >= 17
and < 18 years of age and Lansky for patients < 17 years of age
• Adults (age 18 or older): Creatinine clearance >= 30 mL/min, as estimated by the
Cockcroft and Gault formula. The creatinine value used in the calculation must have
been obtained within 28 days prior to registration. Estimated creatinine clearance is
based on actual body weight
• Pediatric Patients (age < 18 years): The following must have been obtained within 14
days prior to registration:
• Measured or calculated (based on institutional standard) creatinine clearance or
radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2, or
• Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a serum
creatinine based on age/gender as follows:
• Age : 2 to < 6 year; Maximum serum creatinine (mg/dL): 0.8 (male; 0.8
(female)
• Age : 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1
(female)
• Age : 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2
(female)
• Age : 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4
(female)
• Age : >= 16 years to < 18 years; Maximum serum creatinine (mg/dL): 1.7
(male); 1.4 (female)
• Patients with abnormal liver function will be eligible to enroll if the lab
abnormality is thought to be due to the lymphoma or Gilbert's syndrome
• Age >= 18 years: Ejection fraction of >= 50% by echocardiogram
• Age < 18 years: Shortening fraction of >= 27% by echocardiogram, or ejection fraction
of >= 50% by radionuclide angiogram
• 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 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
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Administration of prior anti-cancer therapy except as outlined below:
• A short course (=< 2 weeks) of corticosteroids for the relief of lymphoma-related
symptoms
• A single course of COP (cyclophosphamide, vincristine, and prednisone)
• One cycle of chemo-immunotherapy including R-CHOP, DA-EPOCH-R, a pediatric mature
B-cell non-Hodgkin lymphoma (B-NHL) induction therapy (such as ANHL1131), or
intrathecal chemotherapy that has not started more than 21 days prior to
enrollment
• Active ischemic heart disease or heart failure
• Active uncontrolled infection
• Central nervous system (CNS) involvement of lymphoma
• Previous cancer that required systemic chemotherapy and/or thoracic radiation. Other
cancers will be permitted if in remission x 3 years
• Active autoimmune disease that has required systemic treatment (such as disease
modifying agents, corticosteroids, or immunosuppressive agents) in the past 2 years.
Replacement therapy such as thyroxine, insulin or physiologic corticosteroid for
adrenal or pituitary insufficiency is not considered a form of systemic treatment
• In patients < 18 years of age hepatitis B serologies consistent with past or current
infections
• Patients with severe hepatic impairment (Child-Pugh class C or serum total bilirubin >
5.0 mg/dL) unless thought to be due to lymphoma or Gilbert's syndrome
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential
• Sexually active patients of reproductive potential who have not agreed to use a highly
effective contraceptive method (failure rate of < 1% per year when used consistently
and correctly) for the duration of their study participation
• Lactating females are not eligible unless they have agreed not to breastfeed their
infants starting with the first dose of study therapy and for at least 6 months after
the last dose of rituximab
Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B)
Substudy 03B is part of a larger research study that is testing experimental treatments for
renal cell carcinoma (RCC). The larger study is the umbrella study (U03).
The goal of substudy 03B is to evaluate the safety and efficacy of experimental combinations
of investigational agents in participants with advanced second line plus (2L+) clear cell
renal cell carcinoma (ccRCC).
This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety
lead-in phase will be used to demonstrate a tolerable safety profile for the combination of
investigational agents. There will be no hypothesis testing in this study.
• Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
• Has experienced disease progression on or after having received systemic treatment for
locally advanced or metastatic RCC with a PD-(L)1 checkpoint inhibitor (in sequence or
in combination with a vascular endothelial growth factor •tyrosine kinase inhibitor
[VEGF-TKI]) where PD-(L)1 checkpoint inhibitor treatment progression is defined by
meeting ALL of the following criteria: (a) has received ≥2 doses of an anti-PD-(L)1
monoclonal antibody (mAb) (b) has shown radiographic disease progression during or
after an anti-PD-(L)1 mAb as defined by RECIST 1.1 by investigator (c) disease
progression has been documented within 12 weeks from the last dose of an anti-PD-(L)1
mAb
• Has experienced disease progression on or after having received systemic treatment for
locally advanced or metastatic RCC with a VEGF-TKI (in sequence or in combination with
a PD-[L]1 checkpoint inhibitor) where VEGF-TKI treatment progression is defined by
meeting the following criterion: has shown radiographic disease progression during or
after a treatment with a VEGF-TKI as defined by RECIST 1.1 by investigator
• Is able to swallow oral medication
• Has adequate organ function
• Participants receiving bone resorptive therapy must have therapy initiated at least 2
weeks before randomization/allocation
• Has resolution of toxic effects of the most recent prior therapy to ≤Grade 1
• If participants receive major surgery or radiation therapy, they must have recovered
from complications from the intervention
• Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change in
hypertensive medications within 1 week before randomization/allocation
• Male participants are abstinent from heterosexual intercourse or agree to use
contraception during treatment with and for at least 7 days after the last dose of
lenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped,
if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab,
favezelimab/pembrolizumab, MK-4830 or a combination of the aforementioned drugs, no
contraception is needed
• Female participant is not pregnant or breastfeeding and is not a woman of childbearing
potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using
contraception during the intervention period and for at least 120 days after the last
dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab, MK-4830
or 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last
Exclusion Criteria:
• Has urine protein ≥1 g/24 hours and has any of the following: (a) hypoxia defined as a
pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen,
or (c) requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 12 months from the first dose
of study intervention administration
• Has had major surgery within 3 weeks before first dose of study interventions
• Has a history of lung disease
• Has a history of inflammatory bowel disease
• Has preexisting gastrointestinal (GI) or non-GI fistula
• Has malabsorption due to prior GI surgery or disease
• Has previously received treatment with a combination of pembrolizumab plus lenvatinib
• Has received prior treatment with belzutifan
• Has received prior radiotherapy within 2 weeks of start of study intervention
• Has received a live or live attenuated vaccine within 30 days before the first dose of
study intervention; killed vaccines are allowed
• Has received more than 4 previous systemic anticancer treatment regimens
• Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive
therapy within 7 days prior to the first dose of study intervention
• Has known additional malignancy that is progressing or has required active treatment
within the past 3 years
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2
years; replacement therapy is not considered a form of systemic treatment and is
allowed
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B
• Has had an allogenic tissue/solid organ transplant
A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT
This phase II trial studies the best approach to combine chemotherapy and radiation therapy
(RT) based on the patient's response to induction chemotherapy in patients with
non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain
or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond
well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose
chemotherapy followed by conventional RT in patients who did not respond to induction
chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa,
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. Radiation therapy uses high
energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have
shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to
chemotherapy before receiving radiation therapy, are more likely to be free of the disease
for a longer time than are patients for whom the chemotherapy does not efficiently eliminate
or reduce the size of the tumor. The purpose of this study is to see how well the tumors
respond to induction chemotherapy to decide what treatment to give next. Some patients will
be given RT to the spine and a portion of the brain. Others will be given high dose
chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving
treatment based on the response to induction chemotherapy may lower the side effects of
radiation in some patients and adjust the therapy to a more efficient one for other patients
with localized NGGCT.
• Patients must be >= 3 years and < 30 years at the time of study enrollment
• Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar
and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation
of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG)
beta > 100 mIU/mL. Suprasellar, pineal and bifocal tumors are included. (CSF tumor
markers and cytology must be within 21 days prior to enrollment and within 35 days
prior to start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and
hCGbeta must be within 7 days prior to enrollment and start of protocol therapy
[repeat if necessary]). Basal ganglia or other primary sites are excluded
• Patients with any of the following pathological elements are eligible: endodermal
sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma
and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant
elements listed above are present. Patients with only mature teratoma are excluded.
Patients with pure germinoma admixed with mature teratoma are excluded (would be
eligible for pure germinoma protocols)
• Patients must have a cranial magnetic resonance imaging (MRI) with and without
gadolinium at diagnosis/prior to enrollment. If surgical resection is performed,
patients must have pre-operative and post operative brain MRI with and without
gadolinium. The post operative brain MRI should be obtained within 72 hours of
surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not
required (within 14 days prior to study enrollment)
• Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to
enrollment. Spine MRI with and without gadolinium is recommended (within 14 days prior
to study enrollment)
• Lumbar CSF must be obtained prior to study enrollment unless medically
contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be
obtained at the time of surgery, then it should be performed at least 10 days
following surgery and prior to study enrollment. False positive cytology can occur
within 10 days of surgery
• Patients must have CSF tumor markers obtained prior to enrollment unless medically
contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if
performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF
diversion and biopsy/surgery are combined, CSF tumor markers should be collected first
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment)
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days
prior to enrollment)
• 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 (within 7 days
prior to enrollment):
• Age: Maximum serum creatinine (mg/dL)
• 3 to < 6 years: 0.8 (male), 0.8 (female)
• 6 to < 10 years: 1 (male), 1 (female)
• 10 to < 13 years: 1.2 (male), 1.2 (female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: male (1.7), 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L
• Central nervous system function defined as:
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled
• Patients must not be in status epilepticus, coma or assisted ventilation prior to
study enrollment
• Protocol therapy must begin within 31 calendar days of definitive surgery or clinical
diagnosis. If a biopsy only was performed, the biopsy date will be considered the date
of definitive surgery. For patients who have a biopsy or incomplete resection at
diagnosis followed by additional surgery, the date of the last resection will be
considered the date of definitive surgery.
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
• NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
• English-, Spanish-, or French- speaking
• Note: Patients who speak a language other than English, Spanish, or French will
be allowed to participate in ACNS2021 but will not complete the neurocognitive
and quality of life assessments
• No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g.,
Down syndrome, fragile X, William syndrome, intellectual disability). Patients with
NF1 will be allowed to participate
• Additional eligibility criteria for the COG Standardized Neuropsychological Battery
only: must be at a site that has a psychologist to administer the battery
• Note: If not eligible for the COG Standardized Battery, patients should still
complete the Behavior Rating Inventory of Executive Function, Second Edition
(BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior
Assessment System Third Edition (ABAS-3), and Behavior Assessment System for
Children, Third Edition (BASC-3) questionnaires
Exclusion Criteria:
• Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
• Patients with only mature teratoma and non-elevated markers upon tumor sampling at
diagnosis
• Patients who have received any prior tumor-directed therapy for their diagnosis of
NGGCT other than surgical intervention and corticosteroids
• Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or
intraoperative evidence of dissemination)
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have
been noted for several of the study drugs
• Note: Serum and urine pregnancy tests may be falsely positive due to
HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by
institutional standards
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation
Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC
This research study will assess whether cabozantinib, nivolumab and ipilimumab in combination
are safe and effective in slowing down the growth of kidney cancer(renal cell carcinoma or
RCC) that has advanced or spread to other areas the body.
• histologically or cytologically confirmed unresectable advanced or metastatic nccRCC,
including but not limited to:
• Papillary RCC, any type
• Unclassified RCC
• Translocation RCC
• Chromophobe RCC
• Collecting duct RCC
• Medullary RCC
• Renal cell carcinoma with 80% or more sarcomatoid features on primary nephrectomy
specimen or a biopsy
• Other nccRCC histologies
• Measurable disease as per RECIST 1.1. See Section 11 for the evaluation of measurable
disease.
• Age ≥ 18 years
• ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A)
• Participants must undergo fresh tumor biopsy after registration but prior to the start
of treatment unless medically unsafe or not feasible. If a fresh tumor biopsy is not
medically safe or not feasible, confirmation of the availability of archival tumor
tissue is required. For archival tissue, a recommended minimum of 20 unstained slides
should be obtained.
• Normal organ and marrow function as defined below:
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• hemoglobin ≥9g/dL (transfusions allowed)
• total bilirubin ≤2.0 x institutional upper limit of normal with the following
exception: patients with known Gilbert disease should have a serum bilirubin ≤ 3
x ULN
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal with the following
exception: patients with known liver metastases should have AST and ALT ≤ 5 x ULN
• creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault equation.
• Normal coagulation INR ≤ 1.5
• Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
5 months after the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 7 months after completion of cabozantinib,
nivolumab or ipilimumab administration.
• Ability to understand and willingness to sign a written informed consent document
Exclusion Criteria:
•Patients could be untreated or have received prior lines of therapies. Patients who
receive prior therapy may receive only one VEGF based therapy. A combination therapy (e.g.
lenvatinib+everolimus) is considered 1 line of therapy.
• Previous therapy with CD137 agonists and immune checkpoint inhibitors, including but
not limited to inhibitors of the PD-1/PD-L1 and/or CTLA-4 axes. Previous treatment
with IFNα or IL-2 is allowed if received > 4 weeks from enrollment.
• Treatment with small molecule tyrosine kinase inhibitors within 2 weeks of enrollment,
or any other anticancer agent within 4 weeks of enrollment.
• Prior therapy with cabozantinib
• Patients receiving any other therapeutic investigational agents.
• Treatment with hydroxychloroquine within two weeks of treatment start.
• Radiotherapy for nccRCC within 14 days of first study treatment with the exception of
a single fraction of radiation administered for palliation of symptoms.
• Untreated brain metastases. Patients might be included if they underwent radiation
therapy or surgery at least 4 weeks prior enrollment. Stability of the central nervous
system disease should be confirmed by brain MRI or CT-scan or as determined by
treating investigator. Patients should not be receiving prednisone dose >10 mg/d at
C1D1.
• Other malignancy diagnosed within 2 years of first study treatment unless negligible
risk of metastases or death (included but not limited to carcinoma in situ of the
cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal
carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma, or other
malignancy not deemed to impact patients 5-year life expectancy).
• Significant cardiovascular disorders including:
• Significant cardiovascular disease including dyspnea of New York Heart
Association (NYHA) class II or greater, myocardial infarction within the previous
3 months of first study treatment, unstable arrhythmias, unstable angina.
Patients with known coronary artery disease or congestive heart failure not
meeting the above criteria, or left ventricular ejection fraction < 50%, must be
on a stable and optimized in the opinion of the treating physician, in
consultation with a cardiologist when appropriate.
• Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or
diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy is allowed.
• Personal history of hypertensive crisis or hypertensive encephalopathy within the
previous 3 months of registration.
• Personal history of stroke or transient ischemic attack within 3 months of
registration.
• Significant vascular disease, such as but not limited to aortic aneurysm
requiring surgical repair or recent peripheral arterial thrombosis, within 6
months of registration.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG). Furthermore, subjects with a history of additional risk
factors for torsades de pointes (eg, long QT syndrome) are also excluded.
• Known history of severe allergic reactions attributed to compounds of similar chemical
or biologic composition human antibodies, or known hypersensitivity to any component
of cabozantinib, nivolumab or ipilimumab products.
• Systemic immunosuppressive medications including but not limited to: Corticosteroids
at a dose > 10mg equivalent prednisone daily, cyclosporin, azathioprine, methotrexate,
thalidomide, anti-tumor necrosis factor (TNF) agents, hydroxychloroquine, within 2
weeks of first study dose.
• Patients who have received acute, low-dose systemic immunosuppressant medications
may be enrolled.
• Patients with adrenal insufficiency on physiologic replacement doses of steroids
may be enrolled.
• The use of inhaled, topical, intraocular, or intraarticular corticosteroids or
mineralocorticoids are allowed
• Prior allogenic stem cell or solid organ transplant.
• Personal history of autoimmune disease including: myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,
Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple
sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis. Patients with
a history of autoimmune-related hypothyroidism on thyroid replacement hormone, or
those with autoimmune dermatologic conditions not requiring the use of prednisone > 10
mg or equivalent are eligible.
• History of idiopathic pulmonary fibrosis, organized pneumonia, or evidence of active
pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in
the radiation field is permitted.
• History of following infectious diseases:
• Active or chronic hepatitis B (defined as having a positive hepatitis B surface
antigen [HBsAg] test at screening).
• Active hepatitis C infection. Patients with positive hepatitis C antibody test
are eligible if PCR is negative for hepatitis C viral DNA.
• Infection requiring therapeutic oral or IV anti-microbials within 2 weeks of
first study treatment. Patients receiving routine antimicrobial prophylaxis for
dental procedures are eligible.
• Known positive test for HIV.
• Administration of a live, attenuated vaccine within 3 weeks for first study treatment.
• Bleeding diathesis, or significant coagulopathy in the absence of therapeutic
anticoagulation.
• Use of strong inhibitors and inducers of CYP3A4
• Significant bleeding, including but not limited to hematemesis, hematuria, hemoptysis
of > 0.5 teaspoon (2.5 mL), within 3 months before registration.
• Invasion of major pulmonary blood vessels. A discussion with PI may be needed if
invading lesions are suspected.
• Concomitant use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded.
Aspirin (≤ 325 mg per day) is allowed. Prophylactic anticoagulation with oral or
parenteral anticoagulants for the patency of venous access devices or other
indications is allowed.
Therapeutic use of low-molecular weight heparin (such as enoxaparin) and subcutaneous or
oral Factor Xa inhibitors are allowed. Use of warfarin is prohibited.
• Significant GI conditions at risk of perforation or bleeding, including but not
limited to:
• Active GI obstruction or requirement of routine parenteral nutrition or tube
feedings.
• Personal history of abdominal or tracheoesophageal fistula or GI perforation
within 6 months of registration.
• Evidence of abdominal free air not explained by paracentesis or recent surgical
procedure.
• Serious, non-healing or dehiscing wound or active ulcer.
• Major surgical procedure to include major dental, oral or maxillofacial procedures
within 14 days of first study treatment.
• Proteinuria as demonstrated by > 1.5 gram of protein in a 24-hour urine collection.
All patients with ≥ 2+ protein on urinalysis must undergo 24-hour urine collection for
protein.
• Unable to swallow pills.
• Malabsorption syndrome.
• Inability to receive IV medications
• Pregnant or lactating women.
Tractography Guided Subcallosal Cingulate Deep Brain Stimulation for Treatment Resistant Depression
Treatment resistant depression remains a major problem for individuals and society. Surgical
procedures may provide relief for some of these patients. The most frequently considered
surgical approach is deep brain stimulation (DBS) of a part of the brain called the
subcallosal cingulate region. However, the effectiveness and safety is not well established.
The investigators will use a novel approach using advanced imaging technique (magnetic
resonance tractography) to evaluate the feasibility and safety of this surgical approach. An
innovative method for the definition of DBS target will be applied that redefines the concept
of targeting as one of targeting a symptomatic network rather than a structural brain region
using subject-based brain anatomy to define the target location. The correlation between
imaging findings at baseline with the mood score changes at different time points of the
study will be investigated.
• Men and women (non-pregnant) between ages 21 and 70;
• DSM-5 diagnosis a current major depressive episode (MDE) for 10 years of less,
recurrent or single episode with first episode after adulthood and did not start
during childhood or adolescence, secondary to nonpsychotic unipolar major depressive
disorder;
• Current index MDE ≥24 months duration and/or recurrent illness with at least a total
of 2 lifetime episodes (including current episode >12 months);
• Treatment resistance (defined by criteria on the Antidepressant Treatment History Form
(ATHF)28): Failure to respond to a minimum of four adequate depression treatments from
different categories;
• Symptom severity for Screening: Hamilton Depression Rating Scale-17 item (HDRS17) ≥20;
• Symptom severity for Outcome: Montgomery Asberg Rating Scale (MADRS) ≥27 to be met at
assessment one week pre-op;
• Normal brain MRI within 3 months of surgery;
• Antidepressant medication regimen has been held stable for ≥ 30 days prior to the
study screening MADRS;
• Remain on stable antidepressant medication throughout the study, unless there are
safety concerns;
• Montreal Cognitive Assessment (MoCA) >25;
• Able and willing to give informed consent and agree to attend regular clinic visits
for at least 12 months.
Exclusion Criteria:
• DSM-5 Axis I Disorders: any lifetime history of psychotic disorder or bipolar
disorder;
• Alcohol or substance use disorder within 6 months, excluding nicotine;
• History of childhood abuse (physical or sexual) 18
• Personality disorders;
• Seeking disability during the trial;
• Current substantial suicidal risk as defined by a plan or clear immediate intent for
self-harm, or made any suicide attempt within the last year; (MADRS ≥ 5 including the
day of surgery);
• No stable work history;
• Neurological/Medical condition that makes the patient, in the opinion of the surgeon,
a poor candidate;
1. Pregnant or has plans to become pregnant in the next 36 months;
2. Unable/unable to practice birth control through the period of randomization and
withdrawal of therapy;
• Subjects who have a history of a seizure disorder;
• Subjects who will be exposed to diathermy;
• Subjects who have any medical contraindications to undergoing DBS surgery (e.g.
infection, coagulopathy, or significant cardiac or other medical risk factors for
surgery);
• Subjects with another implanted device such as a cardiac pacemaker, defibrillator or
neurostimulator;
• Subjects who have a history of hemorrhagic stroke;
• Subjects who are unable to undergo MRI;
• Subjects who are at increased risk of hemorrhage due to underlying medical conditions
or medication.
Device: Abbott Laboratories Infinity™ implantable deep brain stimulation system
Treatment Resistant Depression, Undergoing Deep Brain Stimulation (DBS) Surgery
To observe the effects of radiofrequency ablation on adenomyosis through the pathological
analysis of treated tissue that has been removed during planned hysterectomy.
• planning to undergo an abdominal, laparoscopic, or robotic-assisted hysterectomy due
to benign conditions
• uterus < 16 weeks gestational size if undergoing a laparoscopic or robotic procedure
(no size limit for patients planning to undergo a transabdominal hysterectomy)
• at least one area of focal or diffuse adenomyosis or adenomyomas that is/are
contralateral to any fibroids as determined by MRI
• able to provide informed consent
• suitable candidates for surgery (have passed a standard pre-operative health
assessment)
• English speaking
Exclusion Criteria:
• require emergent hysterectomy or vaginal hysterectomy
• have a uterus > 16 weeks gestational size if undergoing a laparoscopic or robotic
procedure (no size limit for patients planning to undergo a transabdominal
hysterectomy)
• have fibroids in the proximity of the target adenomyosis (same side, similar location)
• are not appropriate surgical candidates as determined during pre-operative health
assessment
• are unable or unwilling to undergo a hysterectomy
• are pregnant or lactating
• are under the age of 18 years
• have active pelvic inflammatory disease
• have a history of gynecologic malignancy within the past 3 years
• are unable to give informed consent
• have an implantable uterine or fallopian tube device for contraception
• are not English speaking
A Study of the Efficacy and Safety of MK-5475 in Participants With Pulmonary Arterial Hypertension (INSIGNIA-PAH: Phase 2/3 Study of an Inhaled sGC Stimulator in PAH) (MK-5475-007)
This is a two-part (Phase 2/Phase 3) study of MK-5475, an inhaled soluble guanylate cyclase
stimulator, in participants with pulmonary arterial hypertension (PAH).
The first part (Phase 2) will assess three different doses of MK-5475 compared to placebo in
a base period of 12 weeks, followed by comparison of three different doses of MK-5475 during
an optional 24 month extension period. The treatment dose with the best efficacy and safety
profile in the phase 2 cohort base period will be selected for use in the second part (Phase
3) of the study. The primary hypothesis of Phase 2 is that at least one MK-5475 dose is
superior to placebo in reducing pulmonary vascular resistance (PVR) from baseline at week 12.
The purpose of the second part (Phase 3) of the study is to confirm the efficacy, safety, and
tolerability of MK-5475 at the selected dose compared to placebo during a 12 week base period
followed by an extension period of up to 5 years. The primary hypothesis of Phase 3 is that
MK-5475 is superior to placebo in increasing 6-minute walk distance (6MWD) from baseline at
week 12.
• Pulmonary arterial hypertension (PAH) in one of the following groups:
• Idiopathic PAH
• Heritable PAH
• Drug and toxin-induced PAH
• PAH associated with connective tissue disease, HIV infection, or congenital heart
disease.
• Diagnosis of PAH documented by right heart catheterization (RHC).
• Eligibility RHC meeting all of the following criteria:
• Mean pulmonary artery pressure (mPAP) ≥25 mmHg
• Pulmonary vascular resistance (PVR) of ≥3 Wood units
• Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic
pressure (LVEDP) ≤15 mmHg.
• World Health Organization functional class (WHO-FC) symptoms between Class II and IV.
• Two 6-Minute walk distance (6MWD) measurements between 150 and 500 meters, one at
screening and one at randomization.
• Stable concomitant background PAH-specific therapy.
• Body Mass Index (BMI) between 18.5 kg/m² and 40 kg/m² .
• Agree to be abstinent from heterosexual intercourse or use contraception during the
intervention period and for at least 14 days after the last dose of study
intervention.
• Female participants may not be pregnant or breastfeeding.
Exclusion Criteria:
• Group 2 to 5 pulmonary hypertension.
• PAH in one of the following groups:
• Long term responders to calcium channel blockers
• Overt features of venous/capillary involvement
• Evidence of more-than-mild obstructive lung disease.
• Evidence of more-than-mild parenchymal lung disease.
• Evidence of more-than-mild obstructive sleep apnea (OSA) that is untreated.
• Evidence or history of left heart disease, including any of the following:
• Left ventricular ejection fraction (LVEF) ≤45%
• Moderate or severe left-sided valvular disease (aortic or mitral valve stenosis
or regurgitation)
• Significant left ventricular diastolic dysfunction on echocardiographic
evaluation
• Presence of 3 or more of the following risk factors for heart failure with preserved
ejection fraction: BMI>30 kg/m², essential systemic hypertension, diabetes mellitus of
any type, or coronary artery disease.
• Oxygen saturation measured by pulse oximetry (SpO₂) <90%, despite supplemental oxygen
therapy.
• Chronic renal insufficiency (eGFR <30 mL/min)
• Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis, or
significant hepatic laboratory abnormalities.
• Current smoker or currently uses electronic cigarettes (vapes).
• History of cancer, except: nonmelanomatous skin carcinoma or carcinoma in situ of the
cervix or other malignancies which have been successfully treated, with appropriate
follow up, and unlikely to recur for the duration of the study.