Cabozantinib for Advanced Urothelial Cancer

Exclusion Criteria

• •The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.
• •Prior treatment with cabozantinib
• •Prior treatment with other small molecule inhibitors of Vascular Endothelial Growth Factor Receptors (VEGFR) within less than or equal to 2 years of study enrollment.
• •The subject has received radiation therapy:
• •to the thoracic cavity or gastrointestinal tract within 3 months before the first dose of study treatment
• •to bone or brain metastasis within 14 days before the first dose of study treatment
• •to any other site(s) within 28 days before the first dose of study treatment
• •The subject has received radionuclide treatment within 6 weeks before the first dose of study treatment
• •The subject has received 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, before the first dose of study treatment.
• •The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
• •The subject has not recovered to baseline or Common Terminology Criteria in Adverse Events (CTCAE). Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
• •The subject has a primary brain tumor
• •The subject has active brain metastases, leptomeningeal 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.)
• •The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test greater than or equal to 1.3 times the laboratory upper limit of normal (ULN) within 7 days before the first dose of study treatment.
• •The subject requires treatment, in therapeutic doses, with oral anticoagulants such as warfarin prior to initiation of protocol therapy. Low dose aspirin (less than or equal to 81 mg/day), lowdose warfarin (less than or equal to 1 mg/day), and low molecular weight heparin (LMWH) are permitted. Subjects will be permitted to use anticoagulation as described if treatment is required while they are enrolled on the protocol.
• •The subject requires chronic concomitant treatment of strong Cytochrome P450 3A4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 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/; 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.
• •The subject has experienced any of the following within 3 months before the first dose of study treatment:
• •clinically-significant hematemesis or gastrointestinal bleeding
• •hemoptysis of greater than or equal to 0.5 teaspoon (greater than or equal to 2.5 mL) of red blood
• •any other signs indicative of pulmonary hemorrhage
• •The subject has tumor invading (or concern for invasion) major blood vessels
• •Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.
• •The subject has evidence of tumor invading the gastrointestinal (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.
• •The subject is unable to swallow tablets
• •The subject has a corrected Q wave, T wave (QT) interval calculated by the Fridericia formula (QTcF) \>500 ms within 28 days before treatment initiation.
• •The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.
• •The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
• •The subject has had within 2 years before the start of study treatment evidence of another malignancy which required systemic treatment
• •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study agents. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.