Nivolumab, Ipilimumab, and Cabozantinib in Stage IIIB-D or Stage IV Unresectable Advanced Melanoma

Inclusion Criteria

• All patients must have unresectable stage IIIb-IIId or IV melanoma by American Joint Committee on Cancer (AJCC) 8th edition
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Measurable disease by Immune-Modified Response Evaluation Criteria in Solid Tumors (imRECIST)
• Baseline tumor specimen available – either archived tumor specimen collection within the past year and no intervening treatment or fresh tumor collection (A waiver may be considered for on treatment biopsy requirement after discussion with study principal investigator)
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4) from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically nonsignificant and/or stable on supportive therapy
• Absolute neutrophil count (ANC) >= 1500/mm^3 (>= 1.5 GI/L) without granulocyte colony-stimulating factor support (within 14 days before first dose of study treatment)
• White blood cell count >= 2500/mm^3 (>= 2.5 GI/L) (within 14 days before first dose of study treatment)
• Platelets >= 100,000/mm^3 (>= 100 GI/L) without transfusion (within 14 days before first dose of study treatment)
• Hemoglobin >= 9 g/dL (>= 90 g/L) (within 14 days before first dose of study treatment)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documented bone metastases (within 14 days before first dose of study treatment)
• Total bilirubin =< 1.5 x ULN (for subjects with Gilbert’s disease =< 3 x ULN) (within 14 days before first dose of study treatment)
• Serum albumin >= 2.8 g/dl (within 14 days before first dose of study treatment)
• Serum creatinine =< 2.0 x ULN or calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault equation: Males: (140 – age) x weight (kg)/(serum creatinine [mg/dL] x 72) Females: [(140 – age) x weight (kg)/(serum creatinine [mg/dL] x 72)] x 0.85 (within 14 days before first dose of study treatment)
• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=<113.2 mg/mmol) (within 14 days before first dose of study treatment)
• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document
• Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
• Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrhoeic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons

Exclusion Criteria

• Prior treatment with anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy or cabozantinib. Prior adjuvant anti-PD-1 and/or anti-CTLA-4 therapy is allowed if relapse is greater than 6 months from last dose
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment
• Radiation therapy for bone metastasis or brain metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
• Known brain metastases that are > 10 mm or cranial epidural disease unless adequately treated with radiosurgery and/or surgery. Patients with treated brain metastases need to be asymptomatic (no neurologic symptoms or stable neurologic deficit) and off corticosteroids prior to start of treatment. If discontinuation of corticosteroids is not feasible due to post-radiation effects, asymptomatic patients on a stable dose of dexamethasone < 2mg daily (or equivalent) for > 1 week prior to start of treatment will be permitted. Patients with active, asymptomatic brain metastases that are < 10 mm and no corticosteroid requirement will be permitted without radiosurgery or surgery based on nivolumab/ipilimumab (nivo/ipi) brain metastasis response data from Checkmate 204. Patients with active untreated brain metastases who are enrolled will require more frequent brain monitoring while on protocol
• History of active autoimmune disorder requiring immunosuppressive agents. Patients with autoimmune disorders considered low risk, such as vitiligo and thyroiditis, will be allowed
• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: * Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted * Low-dose low molecular weight heparins (LMWH) are permitted * Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
• The subject has prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
• 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) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment ** Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before first dose * 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, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ** Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose * 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 12 weeks before first dose * Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation * Lesions invading or encasing any major blood vessels * Other clinically significant disorders that would preclude safe study participation ** Serious non-healing wound/ulcer/bone fracture ** Uncompensated/symptomatic hypothyroidism ** Moderate to severe hepatic impairment (Child-Pugh B or C)
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. 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 28 days before first dose of study treatment. 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
• Pregnant or lactating females
• Inability to swallow tablets
• Previously identified allergy or hypersensitivity to components of the study treatment formulations
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease