Nivolumab, Ipilimumab, and Cabozantinib for the Treatment of Untreated Renal Cell Carcinoma with Brain Metastases

Inclusion Criteria

• Signed informed consent form (ICF)
• Ability and willingness to comply with the requirements of the study protocol
• Age >= 18 years
• Life expectancy > 12 weeks
• Asymptomatic and off steroids for at least 10 days except patients: who have mild symptoms from intracranial disease that do not affect their performance status
• Prior therapies for extracranial metastatic renal cell carcinoma as long as it did not include anti- CTLA-4 or cabozantinib or MET inhibitors
• Patients with histologically confirmed metastatic renal cell carcinoma and at least one measurable intracranial target lesion for which all of the following criteria are met: * Previously untreated or progressive after previous local therapy (limited to stereotactic radiosurgery [SRS] and surgery) * Immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy * Largest diameter of >= 0.5cm and =< 3cm , as determined by magnetic resonance imaging (MRI) with contrast
• Absolute neutrophil count (ANC) >= 1500 cells/uL (obtained within 14 days prior to the first study treatment [cycle(C)1day(D)1])
• White blood cell (WBC) counts >= 2500/u (obtained within 14 days prior to the first study treatment [C1D1])
• Lymphocyte count >= 500/uL (obtained within 14 days prior to the first study treatment [C1D1])
• Platelet count >= 100,000/uL (obtained within 14 days prior to the first study treatment [C1D1])
• Hemoglobin >= 9.0 g/dL (obtained within 14 days prior to the first study treatment [C1D1])
• Serum albumin >= 2.8 g/dl (obtained within 14 days prior to the first study treatment [C1D1])
• Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled (obtained within 14 days prior to the first study treatment [C1D1])
• Alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) (obtained within 14 days prior to the first study treatment [C1D1])
• Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) (obtained within 14 days prior to the first study treatment [C1D1])
• Alkaline phosphatase =< 5 x ULN in patients with documented bone metastases (obtained within 14 days prior to the first study treatment [C1D1])
• Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 40mL/min (>= 0.675 mL/sec) using the Cockcroft-Gault equation (obtained within 14 days prior to the first study treatment [C1D1])
• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-h urine protein =< 1 g (obtained within 14 days prior to the first study treatment [C1D1])
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for at least 12 months after the last dose of cabozantinib and nivolumab
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN within 7 days prior to study enrollment
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy

Exclusion Criteria

• Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS or whole brain radiation
• Patients who require immediate surgical or radiotherapy interventions for extra-cranial lesions
• Patient has received conventional radiotherapy (to extracranial disease as palliative radiotherapy, or whole brain irradiation) within 7 days prior to study treatment initiation. For stereotactic radiosurgery (SRS), patients are eligible after 2 days of the procedure. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Any condition, other than brain metastases, requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days before first dose of study treatment Note: Inhaled, intranasal, intra-articular, or topical steroids are allowed if minimal systemic absorption. Systemic corticosteroids are allowed for control of infusion reactions or immune-mediated adverse reactions (irAEs) and must be tapered to a dose level =< 10 mg/day of prednisone equivalent before next administration of the IO agent. Prophylactic steroid treatment for subjects with contrast allergies prior to tumor imaging is allowed.
• Patients with leptomeningeal disease
• Any approved anticancer therapy, including chemotherapy and hormonal therapy within 4 weeks prior to initiation of study treatment; however, the following are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)
• Current, recent (within 3 weeks of the first infusion of this study), or planned participation in an experimental drug study
• Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =< 1 except for alopecia
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; > Childes A cirrhosis; fatty liver; and inherited liver disease
• Patients with acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma
• Patients who are pregnant, lactating, or breastfeeding
• Known hypersensitivity to recombinant human antibodies
• Inability to undergo MRI secondary to metal implant and gadolinium contrast allergy
• Inability to comply with study and follow-up procedures
• History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis with the following exception: * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible * Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations * Rash must cover less than 10% of body surface area (BSA), disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) * No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan with the following exception * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic or acute) or hepatitis C infection with the following exception: * Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
• Active tuberculosis
• Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
• Received oral or IV antibiotics within 2 weeks prior to cycle 1, day 1 with the following exception. * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study * Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during the study and at least 5 months after last dose of nivolumab
• Malignancies other than the disease under study within 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score =< 6, and prostate-specific antigen [PSA] =< 10 mg/mL, etc.)
• Life expectancy of less than 12 weeks
• Nivolumab/Ipilimumab Related Exclusion Criteria
• Prior treatment with anti-CTLA-4 therapeutic antibody or pathway-targeting agents
• Patients who have received prior treatment with anti-PD-1/PD-L1 may be enrolled, provided the following requirements are met: * Minimum of 12 weeks from the first dose of anti-PD-1/PD-L1 and > 6 weeks from the last dose. * No history of severe immune-related adverse effects from anti-pd-1/PD-L1 (National Cancer Institute [NCI] CTCAE v5.0 Grade 3 and 4 or grade 2 myasthenia gravis, Guillain-Barre, peripheral neuropathy.)
• Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to cycle 1, day 1
• Treatment with investigational agent within 4 weeks prior to cycle 1, day 1 (or within five half-lives of the investigational product, whichever is longer)
• Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1with following exception * Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to or humanized antibodies or fusion proteins
• Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
• Cabozantinib-Related Exclusion Criteria
• Prior treatment with cabozantinib and MET inhibitors
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. ** Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose of study treatment. Patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) may be deemed eligible if stable on acceptable anti-coagulation or other treatment following discussion and approval by the principal investigator. * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric obstruction within 28 days of enrollment. Patients with these disorders may be deemed eligible following discussion with the principal investigator. ** Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment.
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 4 weeks before first dose of study treatment
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
• Lesions invading or encasing any major blood vessels. Subjects with lesions invading the intrahepatic vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible
• Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 days before first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment. Furthermore, subjects with a history of additional risk factors for torsades de pointes (e.g., long QT syndrome) are also excluded [add reference for Fridericia formula] * Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility
• Inability to swallow tablets or unwillingness or inability to receive IV administration
• Previously identified allergy or hypersensitivity to components of the study treatment formulations. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded
• Other clinically significant disorders that would preclude safe study participation. * Serious non-healing wound/ulcer/bone fracture. * Malabsorption syndrome. * Requirement for hemodialysis or peritoneal dialysis