Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study (A031704)

For a patient to be eligible for participation in this study, all of the following criteria must apply.

• 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 in the protocol.
• 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.
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet Count >= 100,000/mm^3.
• Hemoglobin >= 8 g/dL.
• 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.
• 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 modification section.
• No more than 56 days from last dose of ipilimumab/nivolumab.

A patient may not be eligible for participation in this study if any of the following criteria apply.

• 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 tuberculosis.
• Concurrent use of immunosuppressive medication including prednisone above 10 mg daily.
• 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 registration.
• 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 manifestations.
• 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 allowed).
• 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 to registration.
• 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).
• Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] or non-ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart Association class 3-4 heart failure symptoms

To learn more, visit ClinicalTrials.Gov

Study Type

Phase III

Principal Investigator(s)

Michael Humeniuk, MD

Sponsor(s)

National Cancer Institute (NCI)