Testing the Addition of an Anti-Cancer Drug, Abemaciclib, to the Usual Chemotherapy Treatment (5-Fluorouracil) for Metastatic, Refractory Colorectal Cancer

PRIMARY OBJECTIVE: I. To determine the safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of abemaciclib in combination with 5-fluorouracil (5-FU) in patients with colorectal cancer (CRC). SECONDARY OBJECTIVES: I. To estimate the anti-tumor activity of abemaciclib in combination with 5-FU. II. To determine the pharmacodynamics (PD) of abemaciclib in combination with 5-FU (death receptor 5 \[DR5\] dynamics and apoptosis). III. To identify molecular subpopulations particularly sensitized to abemaciclib and 5-FU. IV. To determine the pharmacokinetics (PK) of abemaciclib and 5-FU. EXPLORATORY OBJECTIVES: I. To explore exposure-response relationships for abemaciclib and 5-FU. II. To evaluate circulating tumor DNA (ctDNA) as a predictor for treatment response to therapy. OUTLINE: This is a dose-escalation study of abemaciclib in combination with 5-FU followed by a dose-expansion study. Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-28 and 5-FU intravenously (IV) over 46 hours on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and radiologic imaging throughout the study and may additionally undergo a tissue biopsy before treatment and on cycle 1 day 16. After completion of study treatment, patients are followed up every 3 months for 6 months.