IRB Study Number 25-649
Status Recruiting
Phase Phase 3
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
The primary objectives of the PEAK-1 study aim to evaluate the efficacy and safety of combining casdatifan (a HIF-2α inhibitor) with cabozantinib (a VEGFR-TKI) compared to cabozantinib alone with placebo in patients with advanced clear cell renal cell carcinoma (ccRCC) who have progressed after prior anti-PD-1/PD-L1 therapy. This Phase 3 trial is designed to assess progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response (DOR), and disease control rate (DCR), along with safety and tolerability of the treatments. Exploratory objectives include studying pharmacokinetics (PK), tumor and blood biomarkers, and patient-reported outcomes related to quality of life.
Key points:
Study Design: This is a randomized, double-blind, placebo-controlled trial with two arms:
- Arm A: Casdatifan (100 mg daily) + Cabozantinib (60 mg daily).
- Arm B: Placebo + Cabozantinib (60 mg daily).
Patients will be stratified by region, prior VEGFR-TKI therapy, and IMDC risk score.
Endpoints:
- Primary Endpoint: PFS, defined as time from randomization to progression or death, assessed by Blinded Independent Central Review (BICR).
- Secondary Endpoints: Include OS, ORR, DOR, DCR, safety measures, and patient-reported outcomes.
- Exploratory Endpoints: PK profile, biomarker correlations, and progression-free survival-2 (PFS2).
3 . Patient Eligibility: Adults with unresectable locally advanced or metastatic ccRCC who received prior anti-PD-1/PD-L1 therapy. Exclusions include prior treatment with HIF-2α inhibitors or cabozantinib, uncontrolled health conditions, or use of certain medications.
Treatment Modifications: Guidelines are provided for managing adverse events (AEs), including dose reductions, interruptions, or permanent discontinuation of study drugs.
Safety Monitoring: An Independent Data Monitoring Committee (IDMC) will oversee patient safety and interim efficacy analyses.
Statistical Considerations:
- Sample size: Approximately 720 patients.
- Primary endpoint analysis: PFS comparison using stratified log-rank tests and Cox regression models.
- Interim analyses planned for OS at 50% and 85% information fractions.
Study Duration: The study will run for approximately five years, with patient follow-ups every three months for survival and subsequent therapy data collection.
Ethics and Compliance: Conducted in accordance with GCP, ICH guidelines, and applicable regulations. Patients will provide informed consent before participation.
This study seeks to provide insights into the potential benefits of combining casdatifan and cabozantinib for patients with limited treatment options and aims to establish a new standard of care for post-immune oncology ccRCC.
Inclusion Criteria
Patients are eligible for study inclusion if all the following criteria apply:
Age ≥ 18 years (or age ≥ regionally approved age of consent for participation in investigational clinical studies) at the time of signing the informed consent form (ICF).
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Unresectable locally advanced or metastatic renal cell carcinoma with a clear cell component.
Must have received anti-PD-1 or anti-PD-L1 therapy as part of the most recent regimen (either adjuvant monotherapy or 1L in combination with anti-CTLA-4 or VEGFR-TKI), with no more than 1 prior regimen in the metastatic setting.
a. Patients must have received at least 2 cycles of anti-PD-1 or anti-PD-L1 therapy.
b. For patients who received anti-PD-1 in adjuvant setting, radiographic disease progression must have occurred beyond 6 months of last dose.Karnofsky Performance Score (KPS) ≥ 70%.
At least 1 target lesion measurable by computed tomography/magnetic resonance imaging per RECIST v1.1, not within a field of prior radiation therapy.
Adequate organ and marrow function, as defined by the following laboratory values ≤ 72 hours prior to randomization, except where noted below:
a. Neutrophils: ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within the last 2 weeks).
b. Platelets: ≥ 100 x 103 cells/μL (without thrombopoietic stimulating agents or transfusion within the last 2 weeks).
c. White blood cell (WBC) counts ≥ 2500 cells/μL.
d. Hemoglobin: ≥ 10.0 g/dL (without erythropoietin or erythropoietin-stimulating agents or transfusion within the last 2 weeks).
e. Aspartate aminotransferase (AST): ≤ 2.5 x upper limit of normal (ULN) without hepatic metastasis; ≤ 5 x ULN with hepatic metastasis.
f. Total bilirubin: ≤ 1.5 x ULN, with the exception:
-Patients with known Gilbert disease: total bilirubin ≤ 3 x ULN.
g. Creatinine clearance (CrCl): ≥ 30 mL/min (calculated using the Cockcroft-Gault formula or based on 24-hour urine collection).
h. Albumin ≥ 2.5 g/dL.Acceptable coagulation status as indicated by an international normalized ratio (INR) ≤ 1.5 x ULN obtained ≤ 14 days prior to randomization. Patients on anticoagulation with INR > 1.5 x ULN can be included at the discretion of the investigator.
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test.
Female patients must not be breastfeeding at the time of providing informed consent and throughout the study.
Male and female patients must agree to follow contraception guidelines as detailed in Section TBD.
Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
Unwilling or unable to comply with study procedures and/or study visits, including subsequent treatment data collection for the PFS2 endpoint, safety follow up, and long-term follow-up for survival.
Received prior treatment with a HIF-2α inhibitor.
Received prior treatment with cabozantinib.
Receiving ongoing concomitant treatment with strong CYP3A4 inducers or strong CYP3A4 inhibitors.
History of leptomeningeal disease or spinal cord compression.
History of brain metastases, with the following exception:
a. Patients with treated brain metastases must have no evidence of progression or hemorrhage after therapy for brain metastases (eg, radiation therapy, surgery, radiosurgery); and
b. Patients must not require ongoing treatment with corticosteroids (eg, dexamethasone) or anti-epileptic drugs.Underlying medical or psychiatric conditions that, in the investigator’s or sponsor’s opinion, will make the administration of study-specified therapy hazardous or any of the following:
a. No medical history of severe chronic obstructive pulmonary disease (COPD).
b. Active viral, bacterial, or fungal infections requiring systemic treatment within 14 days of randomization. Note: Prophylactic antibiotic treatment (eg, to prevent a urinary tract infection) is allowed.
c. Clinically significant cardiovascular disease, such as New York Heart Association Class III or greater cardiac disease or cerebrovascular accident within 3 months prior to randomization, unstable angina or new onset angina within 3 months prior to randomization, myocardial infarction within 6 months prior to randomization, or unstable arrhythmia within 3 months prior to randomization.
d. Known mental, psychiatric, or substance abuse disorders that would interfere with cooperation with the requirements of the trial.History of trauma or major surgery within 28 days prior to randomization.
Note: Placement of central venous access catheter (eg, port or similar) or biliary or urinary stent is not considered a major surgical procedure.A pulse oximeter reading < 92% and/or requires intermittent or chronic supplemental oxygen.
QTc ≥ 480 msec using Fredericia’s QT correction formula (based on an average of triplicate recordings).
Other prior malignancy active within the previous year except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer. Also, indolent malignancies, including but not limited to early-stage chronic lymphocytic leukemia and follicular lymphoma or watch-and-wait eligible prostate cancer, that don’t require anticancer treatment could be allowed after discussion with the medical monitor.
Known hypersensitivity to any of the components in the investigational product or cabozantinib formulations.
Inability to swallow study treatment.
Malabsorption condition that would alter the absorption of orally administered medications.
Concomitant treatment with therapeutic doses of anticoagulants such as heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel).
Note: Low-dose aspirin (< 81 mg/daily) and prophylactic low molecular weight heparin (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for at least 1 week before administration of the first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen.Uncontrolled or poorly controlled hypertension, as defined by a sustained blood pressure > 150/90 mm Hg with or without antihypertensive treatment.
Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic even
