CARE1: First-line randomised study platform to optimize treatment in patients with metastatic renal cell carcinoma
Metastatic renal cell carcinoma
ARM A: ICI-ICI Arm (Nivolumab + Ipilimumab): 1. Nivolumab (3 mg/kg IV, every 3 weeks for 4 doses), followed by Ipilimumab (1 mg/kg IV, every 3 weeks for 4 doses). 2. After 4 doses of both, if no major side effects or disease progression, Nivolumab continues as maintenance (240 mg every 2 weeks or 480 mg every 4 weeks) for up to 2 years. 3. Nivolumab is administered first, followed by Ipilimumab with a 30-minute gap. 4. All 4 doses of Nivolumab and Ipilimumab must be completed before Nivolumab monotherapy begins (except in cases of Ipilimumab-induced toxicity). 5. Follow-Up Activity: Every 12 weeks ± 14 days, up to 5 years from randomisation. Long-term survival Follow-Up: Every 12 weeks ± 14 days, up to 8 years from randomisation. ARM B: VEGFR-TKI-ICI Arm (Axitinib + Pembrolizumab): 1. Axitinib (5 mg oral, twice daily) combined with Pembrolizumab (200 mg IV every 3 weeks or 400 mg IV every 6 weeks) for up to 2 years. 2. Pembrolizumab is infused for about 30 minutes. Axitinib should be started on Cycle 1 Day 1 and in subsequent cycles, ideally with Pembrolizumab. 3. Follow-Up Activity: Every 12 weeks ± 14 days, up to 5 years from randomisation. Long-term survival Follow-Up: Every 12 weeks ± 14 days, up to 8 years from randomisation VEGFR-TKI-ICI Arm (Cabozantinib + Nivolumab): 1. Cabozantinib (40 mg oral, once daily, away from meals) with Nivolumab (480 mg IV every 4 weeks or 240 mg every 2 weeks) for up to 2 years. 2. Nivolumab is infused for about 30 minutes (240 mg) or 60 minutes (480 mg). Cabozantinib is started on Cycle 1 Day 1 and in subsequent cycles, alongside the first dose of Nivolumab. 3. Follow-Up Activity: Every 12 weeks ± 14 days, up to 5 years from randomisation. Long-term survival Follow-Up: Every 12 weeks ± 14 days, up to 8 years from randomisation. VEGFR-TKI-ICI Arm (Lenvatinib + Pembrolizumab): 1. Lenvatinib (20 mg oral, once daily) with Pembrolizumab (200 mg IV every 3 weeks or 400 mg IV every 6 weeks) for up to 2 years. 2. Pembrolizumab is in
1. Histologically confirmed metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component. 2. Intermediate- or poor-risk mRCC as defined by IMDC classification. 3. Adult male or female patients (≥ 18 years of age at inclusion). 4. Karnofsky Performance Status (KPS) ≥70%. 5. Adequate organ and marrow function, according to investigator assessment and 5.1. Absolute neutrophil count (ANC) ≥ 1000/μL (≥ 1.5 GI/L) 5.2. Platelets ≥ 100,000/μL (≥ 100 GI/L) 5.3. Hemoglobin ≥ 8 g/dL (≥ 80 g/L) 5.4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN. 5.5. Calculated creatinine clearance ≥ 30 mL/min (≥ 0.67 mL/sec) using the CKD- EPI equation 6. The patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. 7. The patient should be able and willing to comply with study visits and procedures as per protocol 8. Patients must be affiliated with a social security system or beneficiaries of the same 9. Female patients must either be of non-reproductive potential or must have a negative serum pregnancy test within 14 days prior to the administration of the study drug. Childbearing potential women must have agreed to use one barrier method of contraception, such as a condom, plus an additional highly effective method of contraception during treatment on this trial and for up to 5 months after the last dose of study treatment. 10. Fertile men with a female partner of childbearing potential must agree to use one barrier method of contraception, such as a condom, during treatment on this trial and for up to 4 months after the last dose of treatment. Their women of childbearing potential partner must agree to use a highly effective method of contraception during the same period. 11. Female subjects of childbearing potential must not be pregnant at screening.
1. Prior systemic anticancer therapy for mRCC including investigational agents. Note: One prior systemic adjuvant therapy is allowed for completely resected RCC and if recurrence occurred at least 6 months after the last dose of adjuvant therapy. 2. Uncontrolled brain metastases (adequately treated with radiotherapy and/or radiosurgery prior to randomization are eligible). Subjects who are neurologically symptomatic as a result of their CNS metastasis or are receiving systemic corticosteroid treatment (prednisone equivalent > 10 mg/day) at the planned time of randomization are not eligible. 3. Concomitant oral anti-vitamin K anticoagulation. An exception is the use of LMWH or direct oral anticoagulants (DOAC), if considered safe by investigator assessment. 4. The subject has an uncontrolled, significant intercurrent or recent illness such as the following conditions: 4.1. Cardiovascular disorders: 4.1.1. Congestive heart failure (CHF) class III or IV as defined by the New York Heart Association, unstable angina pectoris, myocardial infarction, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes). 4.1.2. Uncontrolled hypertension despite optimal antihypertensive treatment. 4.1.3. Stroke, or other symptomatic ischemic event or severe thromboembolic event (e.g., symptomatic pulmonary embolism [PE], incidental PE is acceptable if deemed safe by the investigator) within 3 months before randomization. 4.2. Active GI bleeding or symptomatic Gastrointestinal (GI) tract obstruction 4.3. Clinically significant bleeding including uncontrolled hematuria, hematemesis, or hemoptysis 4.4. Autoimmune disease that has been symptomatic or required immunosuppressive systemic treatment within the past two years from the date of randomization. Note: Patients with a history of Crohn’s disease or ulcerative colitis are always excluded 4.5. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equi