Cabozantinib and Nivolumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer, CANOPY Trial

Inclusion Criteria

• Willing and able to provide, or have a legally authorized representative provide, written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed. NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
• Males 18 years of age and above
• Histological or cytological proof of prostate adenocarcinoma
• Eastern Cooperative Oncology Group (ECOG) status of =< 2
• Progressive metastatic castration-resistant prostate cancer (mCRPC) as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND 2) progressive disease as defined by PSA or radiographic progression. Subjects with measurable and non-measurable disease (i.e., bone only metastases) are allowed. NOTE: Enrollment of subjects with non-measurable disease (i.e., bone only metastases) will be capped at 50% of enrollment target (n=25).
• Must have exposure to one prior taxane (or be taxane ineligible or refuse taxane) AND one prior androgen receptor (AR)-targeting agent (for example, abiraterone, enzalutamide, apalutamide, darolutamide). Receipt of taxane or AR-targeting agent may be in the hormone sensitive or castration resistant setting
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically nonsignificant and/or stable on supportive therapy
• White blood cell (WBC) >= 2,500/mcL (within 14 days of treatment start)
• Absolute neutrophil count (ANC) >= 1,500/mcL (within 14 days of treatment start)
• Hemoglobin >= 9 g/dL (transfusions within 7 days of study treatment are permitted) (within 14 days of treatment start)
• Platelet count >= 100,000/mcL (within 14 days of treatment start)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 40 mL/min as defined by Cockcroft-Gault equation (within 14 days of treatment start)
• Total bilirubin =< 1.5 x ULN ( =< 3 x ULN for subjects with documented Gilbert's disease) (within 14 days of treatment start)
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN (within 14 days of treatment start)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (within 14 days of treatment start)
• Alkaline phosphatase (ALP) =< 5 x ULN with documented bone metastases (within 14 days of treatment start)
• Serum albumin >= 2.8 g/dL (within 14 days of treatment start)
• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg ( =< 113.2 mg/mmol), or 24-h urine protein =< 1 g (within 14 days of treatment start)
• Subjects must agree to use a medically acceptable method of birth
• Human immunodeficiency virus (HIV)-positive with negative viral loads on stable antiretroviral regimen will be considered eligible. Subjects must have CD4 count > 350

Exclusion Criteria

• Small cell or neuroendocrine component or histology
• Prior cabozantinib or checkpoint inhibitor
• 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 investigational systemic anti-cancer agent within 4 weeks before first dose of study treatment
• Treatment with abiraterone, apalutamide, or darolutamide within 2 weeks of treatment initiation. Treatment with investigational prostate cancer directed therapy within 4 weeks of treatment initiation. Treatment with enzalutamide within 4 weeks of treatment initiation
• Prior treatment with radium-223
• Receipt of more than 2 lines of therapy for CRPC. Receipt of more than 1 line of chemotherapy (including both hormone sensitive and CRPC). First-generation anti-androgen use (such as bicalutamide) will not be tabulated as a line of therapy
• Administration of a live, attenuated vaccine within 30 days prior to first dose of study treatment
• Active autoimmune disease or condition requiring prednisone >10 mg daily (or equivalent). Physiologic replacement is permitted. Topical, ocular, intra-articular steroids or inhaled corticosteroids are permitted
• Imminent or established spinal cord compression based on clinical and/or imaging findings
• Radiation therapy within 1 week of study treatment start
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Malabsorption syndrome
• Requirement for hemodialysis or peritoneal dialysis
• History of solid organ or allogeneic stem cell transplant
• Active hepatitis B/C or positive tuberculosis (TB) test with active mycobacterial infection requiring systemic treatment
• Active treatment (within 5 days of registration) 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). * Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
• 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 mmHg systolic or > 90 mmHg 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. ** Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or deep venous thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation for at least 1 week before first dose of study treatment * 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 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 12 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 * 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., 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 [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 * Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer or superficial bladder cancer
• Known allergy to any of the compounds under investigation
• Inability to swallow tablets