Cabozantinib in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC)

Exclusion Criteria

• •1. Prior treatment with cabozantinib
• •2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• •3. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) except agents to maintain castrate status within 4 weeks before first dose of study treatment. Antiresportive bone agents are also allowed.
• •4. Subject has received abiraterone acetate or enzalutamide within 2 weeks before enrollment.
• •6. 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 for neurological indications at the time of first dose of study treatment.
• •7. 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).
• •* 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.
• •8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 14 days before the first dose of study treatment.
• •9. 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.
• •* 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. Subjects with lesions invading the intrahepatic vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible.
• •* 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).
• •11. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 28 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.
• •12. Inability to swallow tablets.
• •13. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• •14. 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.
• •Molecular Eligibility
• •To be eligible, a patient's tumor must have evidence of gene amplification, an activating mutation, or overexpression of one of the following genes: MET, KIT, RET, VEGFR-1, VEGFR-2, VEGFR-3, FLT3, AXL, TRKB, or TIE2. Eligibility can be met via the following diagnostic tests:
• •1. DNA sequencing of a metastatic tumor biopsy specimen showing gene amplification or activating mutation using a CLIA-certified assay. Tumor tissue samples must have been collected within 6 months of enrollment.
• •2. Protein overexpression in a metastatic tumor biopsy specimen determined by immunohistochemistry (IHC) showing 2+ or 3+ protein expression using a CLIA-certified assay.These include common in-house KIT and commercial reference labs for panTRK (e.g. NeoGenomics) and cMET (e.g. NeoGenomics, Caris, Mayo Clinic).
• •3. CLIA-certified commercial cell free DNA assay reporting gene amplification or activating mutation within 3 months of enrollment.
• •* For the Guardant360 Liquid Biopsy amplification must be at least (++) or (+++) for to meet eligibility.
• •* For the FoundationOneLiquid assay, amplification will be eligible. Reports that have an "equivocal" or "subclonal" designation will not be eligible.
• •4. Any non-CLIA certified assay such as RNA expression profiling of a metastatic tumor biopsy specimen showing overexpression must be confirmed by a CLIA-certified assay (i.e., immunohistochemistry showing 2+ or 3+ protein expression)
• •Patients who do not meet molecular eligibility criteria will be allowed to enroll if they have liver metastases that meet RECIST criteria for measurable disease. Patients with prostate adenocarcinoma or Neuroendocrine prostate cancer (NEPC) will be allowed to enroll.