Cabozantinib and Pamiparib for the Treatment of Advanced of Refractory Solid Tumors

Exclusion Criteria

• •Any treatment specifically for systemic tumor control given within 3 weeks before the initiation of the study drugs, within 2 weeks if cytotoxic agents were given weekly, within 4 weeks if cytotoxic agents were given once every 3 to 4 weeks, within 6 weeks for nitrosoureas or mitomycin C, within 5 half-lives for targeted agents with half-lives and pharmacodynamic effects lasting \< 5 days (a minimum of 10 days is required), or failure to recover from toxic effects of any therapy before the initiation of the study drugs
• •Unresolved grade 1 or higher toxicity from prior therapy that is clinically significant
• •Patient has an inability to swallow oral medications. Note: Patient may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN)
• •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 of study treatment.
• •* Note: Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #6) 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.
• •* 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)
• •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 of study treatment
• •No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy \[except for palliative local radiotherapy\]), biological therapy or other novel agent is to be permitted while the patient is receiving study medication. Patients on LHRH analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the Investigator
• •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 at the time of first dose of study treatment. Leptomeningeal or lymphangitic carcinomatosis is not allowed
• •Patient has had prescription or non-prescription drugs or other products known to be moderate to strong inhibitors or inducers of CYP3A which cannot be discontinued at least 5 half-lives if known, or 14 days if unknown prior to day 1 of dosing, and withheld throughout the study until 2 weeks after the last dose of study drug
• •Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients should stop using these herbal medications 5 half-lives if known or 14 days if unknown prior to first dose of study treatment
• •Any known hypersensitivity or contraindication to the components of the study drugs
• •Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment \[QTcf = QT/(RR\^0.33); RR interval = 60/heart rate\], or congenital long QT syndrome.
• •* Note: If a single electrocardiography (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
• •Pregnant or breastfeeding women
• •Serious active infection at the time of study entry, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment
• •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, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
• •Grade 2 or higher peripheral neuropathy
• •Human immunodeficiency virus requiring highly active antiretroviral therapy (HAART) treatment due to unknown drug-drug interactions or has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or C virus (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[quantitative\] is detected) infection: patients who have had active hepatitis B virus \[HBV\] or HCV infections in the past but have evidence of viral clearance as shown by negative viral load, i.e., undetectable HBV DNA or HCV RNA, will be eligible
• •Lesions invading or encasing any major blood vessels. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
• •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
• •Vaccination with live vaccine within 4 weeks of treatment start