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

PD-Inhibitor (Nivolumab) and Ipilimumab Followed by Nivolumab vs. VEGF TKI Cabozantinib With Nivolumab: A Phase III Trial in Metastatic Untreated Renal Cell Cancer [PDIGREE]

This phase III trial compares the usual treatment (treatment with ipilimumab and nivolumab followed by nivolumab alone) to treatment with ipilimumab and nivolumab, followed by nivolumab with cabozantinib in patients with untreated renal cell carcinoma that has spread to other parts of the body. The addition of cabozantinib to the usual treatment may make it work better. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cabozantinib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known how well the combination of cabozantinib and nivolumab after initial treatment with ipilimumab and nivolumab works in treating patients with renal cell cancer that has spread to other parts of the body.

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Genitourinary Cancer

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To learn more, visit ClinicalTrials.Gov or contact Clinical Research at 864-560-6812.

Principal Investigator(s)

Michael Humeniuk, MD

Sponsor(s)

National Cancer Institute (NCI)

Key Trial Criteria

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

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