Overview

This is a multicenter, single-arm, two-stage open-label phase 2 study of the combination of cabozantinib + nivolumab in subjects with advanced castration-resistant prostate cancer (CRPC).

Eligibility

Inclusion Criteria:

        Subjects must meet all of the following applicable inclusion criteria to participate in
        this study:
          -  Willing and able to provide, or have a legally authorized representative provide,
             written informed consent and 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.
          -  ECOG status of ≤ 2
          -  Progressive 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 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 CTCAE v5.0 from toxicities related to any prior
             treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
             therapy.
          -  Normal organ function with acceptable initial laboratory values within 14 days of
             treatment start:
               -  WBC: ≥ 2,500/mcL
               -  ANC: ≥ 1,500/mcL
               -  Hemoglobin: ≥ 9 g/dL (transfusions are permitted)
               -  Platelet count: ≥ 100,000/mcL
               -  Serum creatinine or calculated Creatinine Clearance: Serum creatinine ≤ 1.5 x ULN
                  or calculated CrCl ≥ 30 mL/min as defined by Cockcroft-Gault equation
               -  Total Bilirubin: ≤ 1.5 x ULN (≤ 3 x ULN for subjects with documented Gilbert's
                  disease)
               -  SGOT (AST): ≤ 3 x ULN
               -  SGPT (ALT): ≤ 3 x ULN
               -  Alkaline Phosphatase (ALP): ≤ 5 x ULN with documented bone metastases
               -  Serum Albumin: ≥ 2.8 g/dL
               -  Urine protein/creatinine ratio (UPCR): ≤ 2 mg/mg (≤ 113.2 mg/mmol), or 24-h urine
                  protein ≤ 2 g
          -  Subjects must agree to use a medically acceptable method of birth control as outlined
             in the protocol
          -  HIV-positive with negative viral loads on stable antiretroviral regimen will be
             considered eligible. Subjects must have CD4 count > 350.
        Exclusion Criteria:
        Subjects meeting any of the criteria below may not participate in the study:
          -  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.
          -  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.
          -  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 allogenic stem cell transplant.
          -  Active hepatitis B/C or positive 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 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 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.
                    -  Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6
                       months are allowed if stable, asymptomatic, and treated with a stable dose
                       of permitted anticoagulation (see exclusion criterion above) 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
                  (2.5ml) 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 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 >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.