Guadecitabine and Nivolumab in Treating Refractory Metastatic Colorectal Cancer

PRIMARY OBJECTIVES: I. To determine the safety, tolerability, maximum tolerated dose (MTD)/recommended phase 2 dose (R2PD) of guadecitabine in combination with nivolumab in patients with refractory CpG island methylator phenotype (CIMP+) metastatic colorectal cancer. (Phase Ib Dose Escalation) II. To assess the overall response rate (ORR) in refractory CIMP+ metastatic colorectal cancer patients treated with guadecitabine and nivolumab. (Phase II Expansion) SECONDARY OBJECTIVES: I. To determine the incidence of adverse events (AEs) and serious adverse events (SAEs) of guadecitabine combined with nivolumab. (Phase Ib Dose Escalation) II. To assess progression-free (PFS) and overall survival (OS) in refractory CIMP+ metastatic colorectal cancer patients treated with guadecitabine and nivolumab. (Phase II Dose Expansion) EXPLORATORY OBJECTIVES: I. Characterize pre and post-treatment morphometric, proteomic and genomic profiles of circulating tumor cells using the high-definition single cell analysis (HD-SCA) platform. II. Determine associations between circulating cell-free tumor deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA) expression, inflammatory T-cell and DNA methylation signatures, with response rate (RR), PFS, OS. III. Determine associations between tumor PD1/PDL1 expression with RR, PFS, OS. OUTLINE: This is a phase Ib, dose-escalation study of guadecitabine followed by a phase II study. Participants receive guadecitabine subcutaneously (SC) on days 1-5 and nivolumab intravenously (IV) over 2 hours on days 8 and 22. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. After completion of study treatment, participants are followed up at 30 days and then every 2 months for 1 year.