Pembrolizumab, Capecitabine, and Bevacizumab for Treating Colorectal Cancer

PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD) of capecitabine when administered with pembrolizumab and bevacizumab. (Safety Lead-In Cohort) II. To evaluate the overall response rate (ORR) to pembrolizumab plus capecitabine and bevacizumab (complete or partial response rate per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) in subjects with metastatic or locally advanced unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal carcinoma (CRC) that is stable or progressing on fluorouracil (5FU)-based therapy. (Phase II Expansion Cohort) SECONDARY OBJECTIVES (Phase II Expansion Cohort): I. To determine the safety and tolerability of pembrolizumab in combination with capecitabine and bevacizumab. II. To evaluate ORR per immune-related RECIST (irRECIST). III. To evaluate duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) per RECIST 1.1 and irRECIST and overall survival (OS). EXPLORATORY OBJECTIVES: I. Correlation of outcomes to line of therapy; stable disease or progression on a prior regimen containing infusional 5-FU or capecitabine; prior exposure to bevacizumab; and primary tumor location. II. To explore baseline immune profiles via PD-L1, and multiplex Immunohistochemistry (IHC) for identification of potentially predictive biomarkers in patients with metastatic or locally advanced, unresectable CRC treated with pembrolizumab-based combination therapy. III. To characterize the change in the populations of tumor-infiltrating immune cells (TIICs) by IHC induced by pembrolizumab-based combination therapy in paired pre- and on-treatment tumor biopsies from patients with metastatic or locally advanced, unresectable MSS / pMMR CRC. IV. To determine the change in T cell repertoire via next generation sequencing (NGS) within blood and tumor biopsy samples induced by pembrolizumab-based combination therapy in patients with metastatic or locally advanced, unresectable MSS/pMMR CRC. V. To establish human immune system (HIS) patient-derived xenograft (PDX) models from pre-treatment biopsies to a) analyze change in immune cell profiles HIS PDX models using the same techniques as described for corresponding patients, above and b) correlate response to pembrolizumab-containing therapy in patients and HIS PDX. OUTLINE: An initial safety lead-in will be performed to define the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 9 weeks until disease progression, start of new anti-cancer therapy, death, or end of the study whichever comes first