Cabozantinib-s-malate in Treating Patients with Metastatic or Refractory Solid Tumors and Bone Metastases

Inclusion Criteria

• The participant has a histologic or cytologic diagnosis of a solid tumor (non-prostate, non-breast) that is metastatic and is refractory to or progressed (or relapsed) following standard therapies, or has disease for which no standard therapy exists; presence of metastatic bone lesion(s) is required
• The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support
• Platelets >= 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Bilirubin =< 1.5 X the upper limit of normal (ULN); for participants with known Gilbert’s disease, bilirubin =< 3.0 mg/dL
• Serum albumin >= 2.8 g/dl
• Serum creatinine =< 1.5 X ULN or creatinine clearance >= 50 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 X ULN if no liver involvement, or =< 5 X ULN with liver involvement
• Lipase < 1.5 x the upper limit of normal (except for participants with adenocarcinoma of the pancreas)
• Urine protein/creatinine ratio (UPCR) =< 1
• Serum phosphorus >= lower limit of normal (LLN)
• Calcium (Ca), magnesium (Mg), potassium (K) within normal
• The participant is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Sexually active participants (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all participants of reproductive potential must agree to use both a barrier method and a second method of birth control
• Women of childbearing potential must have a negative pregnancy test at screening; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not post-menopausal; post-menopause is defined as: * Amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, or ovarian suppression or any other reversible reason

Exclusion Criteria

• Prior treatment with cabozantinib
• The participant has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment
• The participant has received radiation therapy: * To the thoracic cavity or gastrointestinal tract within 3 months of the first dose of study treatment * To bone or brain metastasis within 14 days of the first dose of study treatment * To any other site(s) within 28 days of the first dose of study treatment
• The participant has received radionuclide treatment within 6 weeks of the first dose of study treatment
• The participant 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 participant has received any other type of investigational agent within 28 days before the first dose of study treatment
• The participant has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
• The participant has a primary brain tumor
• The participant has active brain metastases or epidural disease (Note: participants 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 participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test results at screening >= 1.3 X the laboratory ULN
• The participant requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa (FXa) inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
• The participant has experienced any of the following within 3 months before the first dose of study treatment: * Clinically-significant hematemesis or lower gastrointestinal bleeding * Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood * Any other signs indicative of pulmonary hemorrhage
• The participant has radiographic evidence of cavitating pulmonary lesion(s) or tumor in contact with, invading or encasing major blood vessels
• The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders including ** Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening) ** Any of the following within 6 months before the first dose of study treatment: *** Unstable angina pectoris *** Clinically-significant cardiac arrhythmias *** Stroke (including transient ischemic attack [TIA], or other ischemic event) *** Myocardial infarction *** Thromboembolic event requiring therapeutic anticoagulation (Note: participants with a venous filter [e.g. vena cava filter] are not eligible for this study) * Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: ** Any of the following at the time of screening *** Intra-abdominal tumor/metastases invading gastrointestinal (GI) mucosa *** Active peptic ulcer disease *** Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis ** Any of the following within 6 months before the first dose of study treatment: *** History of abdominal fistula *** Gastrointestinal perforation *** Bowel obstruction or gastric outlet obstruction *** Intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months ago ** GI surgery (particularly when associated with delayed or incomplete healing) within 28 days; Note: complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more than 28 days ago * Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus * Other clinically significant disorders such as: ** Active infection requiring systemic treatment ** Serious non-healing wound/ulcer/bone fracture ** History of organ transplant ** Concurrent uncompensated hypothyroidism or thyroid dysfunction ** History of major surgery within 4 weeks or minor surgical procedures within 1 week before randomization
• The participant is unable to swallow capsules or tablets
• The patient has a corrected QT interval (corrected QT using Fridericia formula [QTcF]) > 500 ms within 28 days before randomization; if QTcF is >= 500 ms by Bazett formula, this must be confirmed by the Fridericia formula
• The participant is pregnant or breastfeeding
• The participant has a previously identified allergy or hypersensitivity to components of the study treatment formulation
• The participant is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
• The participant has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment