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

• The subject has a histologic or cytologic diagnosis of colorectal adenocarcinoma that is metastatic or unresectable;

‣ The patient either did not tolerate, is refractory to or progressed (or relapsed) following treatment with a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab;

⁃ Prior epidermal growth factor inhibitor therapy is required for patients with left-sided, RAS wild-type tumors;

⁃ Patients must be microsatellite stable (MSS), microsatellite-low (MSI-L) or have proficient mismatch repair (pMMR;

⁃ Prior TAS-102 (Lonsurf) treatment is not required;

⁃ Patients must have known extended RAS and BRAF status as per local standard of practice;

• Measurable disease per RECIST v.1.1 as determined by the investigator;

• The subject has had an assessment of all known disease sites e.g. by computerized tomography (CT) scan and/or magnetic resonance imaging (MRI) within 28 days before the first dose of cabozantinib;

• The subject is ≥ 18 years old on the day of consent;

• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

• Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy;

• Adequate archival tissue available from primary or metastatic site for biomarker analysis (20 unstained FFPE slides and/or tumor block with minimum of 15 slides needed for eligibility). Tissue from the primary site is preferable for analysis, but if unavailable, tissue from a metastatic site may be utilized;

• 1. Subjects enrolled in Part 2 of this study must have a site of disease that is amenable to biopsy and be a candidate for tumor biopsy prior to the first dose of study drug to be considered for this study;

∙ 20 subjects enrolled in Part 2 of the study will be required to undergo mandatory pre- and on-treatment tumor biopsies.

‣ 12 subjects enrolled in Part 2 of the study will not be required to undergo a mandatory tumor biopsy and thus not required to have disease amenable to biopsy;

• The subject has organ and marrow function and laboratory values as follows within 7 days before the first dose of study treatment:

∙ The ANC ≥ 1.5 x 109/L without colony stimulating factor support;

‣ White blood cell count ≥ 2.5 x 109/L;

‣ Platelets ≥ 100 x 109/L without transfusion;

‣ Hemoglobin ≥ 9 g/dL;

‣ Total bilirubin ≤ 1.5 x ULN. For subjects 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 (CrCl) ≥ 40 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:

• i. Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72); ii. Female: Multiply above result by 0.85; h. ALT and AST ≤ 3.0 x ULN in patients without hepatic metastases; ALT and AST ≤ 5.0 x ULN in patients with hepatic metastases; i. Lipase \< 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis; j. UPCR ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1 g; k. Serum phosphorus, calcium, magnesium and potassium ≥ LLN.

⁃ The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document;

⁃ Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 5 months after the last dose of study treatment (i.e., 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo approximately five half-lives);

⁃ Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment (i.e., 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo approximately five half-lives);