I. To compare the overall survival (OS) in patients with metastatic renal cell cancer (RCC)
treated with ipilimumab-nivolumab followed by either nivolumab versus cabozantinib-nivolumab.
I. To determine PFS of patients treated with nivolumab versus nivolumab-cabozantinib.
II. To evaluate the 12-month complete response rate in patients treated with
ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed
by nivolumab (patients who have complete response [CR] and relapse before 12 months will not
be counted as a CR at 12-months).
III. To evaluate the rates of discontinuing therapy at 1 year. IV. To compare objective
response rates (ORR, assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1
and Immune-Related Response Evaluation Criteria in Solid Tumors [irRECIST] criteria) for
patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus
ipilimumab-nivolumab followed by nivolumab.
V. To document the adverse event profile of ipilimumab-nivolumab followed by
I. To evaluate biomarkers associated with exceptional responses in both arms (exceptional
responses defined as CRs with treatment discontinuation at 12 months or 24 months).
II. To evaluate whether baseline IL-6 is predictive of outcome in patients treated with
QUALITY OF LIFE (QOL) OBJECTIVES:
I. To compare health-related quality of life at 18 months post-registration as assessed by
the Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (FKSI-19) between
patients randomized to nivolumab (nivo) versus (vs) cabozantinib (cabo)/nivo.
II. To compare health-related quality of life as assessed by the FKSI-19 between patients
randomized to nivo vs cabo/nivo at other time points.
III. To compare patient-reported fatigue using Patient-Reported Outcomes Measurement
Information System (PROMIS)-Fatigue between patients randomized to nivo vs cabo/nivo.
IV. To compare quality-adjusted survival (overall survival x utility score assessed by
EuroQol five-dimensional questionnaire [EQ5D-5L]) between patients randomized to nivo vs
INDUCTION: Patients receive nivolumab intravenously (IV) over 30 or 60 minutes and ipilimumab
IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the
absence of disease progression or unacceptable toxicity.
Patients with progression of disease (PD) receive cabozantinib orally (PO) daily on days
1-28. Treatment repeats every 28 days until further disease progression or unacceptable
Patients with CR receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every
28 days in the absence of disease progression or unacceptable toxicity.
Patients with non-CR/non-PD are randomized to 1 of 2 arms.
ARM A: Patients receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every
28 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive nivolumab IV over 30 or 60 minutes on day 1 and cabozantinib PO daily
on days 1-28. Treatment repeats every 28 days in the absence of disease progression or
After completion of study treatment, patients are followed up for 5 years.
- STEP I REGISTRATION CRITERIA
- Histologically documented renal cell carcinoma with clear cell component, including
patients who have sarcomatoid features.
- Any metastatic disease, including visceral, lymph node, other soft tissue and bone,
measurable per RECIST 1.1.
- Measurable disease as defined.
- Intermediate or poor risk patients per International Metastatic Renal Cell Carcinoma
Database (IMDC) criteria will be eligible (1 or more of the following: Karnofsky
performance status (KPS) < 80, < 1 year from diagnosis to systemic treatment,
hemoglobin less than lower limit of normal (LLN), corrected calcium concentration
greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN,
platelet count > ULN).
- Central nervous system (CNS) disease permitted, if stable and not otherwise causing
symptoms or needing active treatment.
- Karnofsky performance status >= 70%.
- No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not
limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab,
tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting
T-cell co-stimulation or checkpoint pathways.
- No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days]
and prior adjuvant sunitinib > 180 days since completion are allowed).
- 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.
- 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.
- None of the following:
- Active autoimmune disease requiring ongoing therapy.
- Ongoing acute toxicity > grade 2 from previous treatment.
- History of severe allergic, anaphylactic or other hypersensitivity reactions to
chimeric or humanized antibodies.
- History of human immunodeficiency virus (HIV) or active hepatitis B/C, or
- Concurrent use of immunosuppressive medication including prednisone above 10 mg
- Uncontrolled adrenal insufficiency.
- Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP
> 90 mmHg).
- Major surgery less than 28 days prior to registration.
- Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to
- Any arterial thrombotic events within 180 days prior to registration.
- Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks
prior to registration.
- Cavitating pulmonary lesions or known endotracheal or endobronchial disease
- Lesions encasing or invading any major blood vessels.
- Moderate of severe hepatic impairment (child-Pugh B or C).
- Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in
the 180 days prior to registration. (Any asymptomatic, treated pulmonary embolism
or asymptomatic, treated deep venous thrombosis > 30 days prior to registration
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
- Unstable cardiac arrhythmia within 6 months prior to registration.
- Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs of
pulmonary hemorrhage =< 90 days prior to registration.
- History of abdominal fistula, gastrointestinal perforation, intra-abdominal
abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior
- Active peptic ulcer disease, inflammatory bowel disease, or malabsorption
syndrome within 28 days prior to registration.
- Untreated hypothyroidism, evidence of pancreatitis, history of organ transplant,
or history of congenital QT syndrome.
- Active treatment with warfarin or any oral factor Xa inhibitors (treatment with
low molecular weight heparin [LMWH] is allowed).
- Absolute neutrophil count (ANC) >= 1,500/mm^3.
- Platelet Count >= 100,000/mm^3.
- Hemoglobin >= 8 g/d.
- Calculated (Calc.) creatinine clearance >= 30 mL/min.
- Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
- Total Bilirubin =< 1.5 x upper limit of normal (ULN).
- Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of
normal (ULN) or < 5 x ULN if hepatic metastases present.
- Creatine kinase MB (CK-MB) and troponin =< upper limit of normal (ULN).
- STEP 2 REGISTRATION ELIGIBILITY CRITERIA
- Successful completion of at least 1 cycle of ipilimumab/nivolumab.
- Resolution of any treatment-related adverse events to grade 1 or less per dose
- No more than 56 days from last dose of ipilimumab/nivolumab.