Study of Cabozantinib and Nivolumab in Refractory Metastatic Microsatellite Stable (MSS) Colorectal Cancer

Exclusion Criteria

• •1. Known microsatellite-high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer.
• •2. The subject 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;
• •3. Prior treatment with cabozantinib or other small molecule kinase inhibitors;
• •4. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways;
• •6. The subject has received any other type of investigational agent within 28 days before the first dose of study treatment;
• •7. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment;
• •8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment;
• •9. 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:
• •1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• •2. 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;
• •10. 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;
• •11. The subject has radiographic evidence of cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
• •12. The subject has tumor invading or encasing any major blood vessels;
• •13. The subject has evidence of clinically significant bleeding from 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 study treatment;
• •14. 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 blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of 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 transient ischemic attack (TIA), or other ischemic event);
• •* myocardial infarction;
• •* Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #8) for at least 1 week before first dose of study treatment; b. GI disorders particularly those associated with a high risk of perforation or fistula formation including: i. 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 or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization, Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization c. Other clinically significant disorders that would preclude safe study participation: i. Serious non-healing wound/ulcer/bone fracture; ii. Uncompensated/symptomatic hypothyroidism; iii. Moderate to severe hepatic impairment (Child-Pugh B or C);
• •16. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment.
• •a. 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.
• •17. Pregnant or lactating females;
• •18. Inability to swallow intact tablets;
• •19. Previously identified allergy or hypersensitivity to components of the study treatment formulations;
• •20. History of severe hypersensitivity reaction to any monoclonal antibody;
• •21. Diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy;
• •22. Active, known or suspected autoimmune disease (patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted);
• •23. Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of first dose of study treatment. Inhaled or topical steroids and adrenal replacement steroids \>10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. The use of corticosteroids for premedication for patients with documented contrast allergy prior to imaging is permitted;
• •24. Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity;
• •25. Prior stem cell transplant or solid organ transplant;
• •26. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
• •27. Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection, and/or detectable virus;
• •28. Subjects that have received a live/attenuated vaccine within 30 days of first dose of study treatment.