- 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.
- 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).
- 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. 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.
- 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).
- 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.
- Age >= 18 years
- 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 (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.
- No more than 70 days from last dose of ipilimumab/nivolumab.
- 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 active
tuberculosis (purified protein derivative [PPD] response without active TB is
- 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
- 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
- Cavitating pulmonary lesions or known endotracheal or endobronchial disease
- Lesions encasing or invading any major blood vessels (this does not include tumor
thrombus extending into/through renal vein/inferior vena cava [IVC]). Patients with
tumor thrombus extending into/through renal vein are considered eligible.
- 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
- 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 coumarin agents (e.g., warfarin), direct thrombin inhibitors
(e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g.,
clopidogrel) within 5 days of registration. Allowed anticoagulants include:
prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses of
LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban,
apixaban. Allowed also in patients with known brain metastases who are on a stable
dose of the anticoagulant for at least 1 week prior to registration without clinically
significant hemorrhagic complications from the anticoagulation regimen or the tumor.
- 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