Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study

Study Details

Primary objective:
To compare the overall survival (OS) in patients with metastatic RCC treated with ipilimumabnivolumab followed by either nivolumab versus cabozantinib-nivolumab.

Secondary objectives:

• To determine PFS of patients treated with nivolumab versus nivolumab-cabozantinib
• To evaluate the 12-month complete response rate in patients treated with ipilimumabnivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab (patients who have CR and relapse before 12 months will not be counted as a CR at 12-months)
• To evaluate the rates of discontinuing therapy at 1 year
• To compare objective response rates (ORR, assessed by RECIST 1.1 and irRECIST criteria) for patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab.
• To document the adverse event profile of ipilimumab-nivolumab followed by cabozantinibnivolumab.

Inclusion Criteria:

1. Histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid features.
2. Any metastatic disease, including visceral, lymph node, other soft tissue and bone, measurable per RECIST 1.1.
3. Measurable disease as defined in the protocol.
4. Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria (1 or more of the following: Karnofsky performance status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN], corrected calcium concentration greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN, platelet count > ULN).
5. Central nervous system (CNS) disease permitted, if stable and not otherwise causing symptoms or needing active treatment.
6. Karnofsky performance status >= 70%.
7. No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting T-cell co-stimulation or checkpoint pathways. The only exception is for prior treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or post-operative trials, as long as > 1 year since completion of systemic therapy.
8. No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above are allowed).
9. No cancer therapy less than 28 days prior to registration; this includes radiation therapy, except for bone lesions less than 14 days prior to registration. There must be a complete recovery and no ongoing complications from radiotherapy.
10. Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
11. Age >= 18 years
12. Absolute neutrophil count (ANC) >= 1,500/mm^3.
13. Platelet count >= 100,000/mm^3.
14. Hemoglobin >= 8 g/dL.
15. Calculated (Calc.) creatinine clearance >= 30 mL/min.
16. Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
17. Total bilirubin =< 1.5 x upper limit of normal (ULN).
18. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present.
19. STEP 2 REGISTRATION ELIGIBILITY CRITERIA
20. Successful completion of at least 1 cycle of ipilimumab/nivolumab.
21. Resolution of any treatment-related adverse events to grade 1 or less per dose modification section (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment-related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed.
22. No more than 70 days from last dose of ipilimumab/nivolumab.