Cabozantinib in Men With Castration-Resistant Prostate Cancer

Exclusion Criteria

• •1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment.
• •2. Prior treatment with cabozantinib and other met inhibitors.
• •3. Prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, or before the first dose of study treatment.
• •4. The subject has received radiation therapy:
• •1. to the thoracic cavity or gastrointestinal tract within 3 months of the first dose of study treatment.
• •2. to bone or brain metastasis within 14 days of the first dose of study treatment.
• •3. to any other site(s) within 28 days of the first dose of study treatment.
• •5. The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment.
• •6. The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
• •7. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
• •8. The subject has a primary brain tumor.
• •9. The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain scans are not required to confirm eligibility.)
• •10. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test results at screening ≥ 1.3 x the laboratory ULN.
• •11. The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted.
• •12. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.asp; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• •13. The subject has experienced any of the following:
• •1. clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment.
• •2. hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment.
• •3. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.
• •14. The subject has radiographic evidence of cavitating pulmonary lesion(s).
• •15. The subject has tumor in contact with, invading or encasing major blood vessels.
• •16. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.
• •17. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• •a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening.
• •ii. Concurrent uncontrolled hypertension defined as sustained BP \> 140 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment.
• •iii. Any history of congenital long QT syndrome. iv. Any of the following within 6 months before the first dose of study treatment:
• •* unstable angina pectoris
• •* clinically-significant cardiac arrhythmias
• •* stroke (including TIA, or other ischemic event)
• •* myocardial infarction
• •* intra-abdominal tumor/metastases invading GI mucosa
• •* active peptic ulcer disease
• •* inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
• •* malabsorption syndrome ii. Any of the following within 6 months before the first dose of study treatment:
• •* abdominal fistula
• •* gastrointestinal perforation
• •* bowel obstruction or gastric outlet obstruction
• •* intra-abdominal abscess. Note: Complete resolution of an intraabdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months before the first dose of study treatment.
• •c. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy.
• •d. Other clinically significant disorders such as: i. active infection requiring systemic treatment within 28 days before the first dose of study treatment ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment iii. history of organ transplant iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment v. history of major surgery as follows:
• •* Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications
• •* Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery
• •18. The subject is unable to swallow tablets.
• •19. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) \>500 ms within 28 days before Day 1 of Cycle 1. Note: if initial QTcF is found to be \> 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤500 ms, the subject meets eligibility in this regard.
• •20. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.
• •21. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
• •22. For disease specific studies: The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment.
• •23. The subject has a known allergy to tetracycline.