This phase I trial tests the safety, side effects, and best dose of abemaciclib in combination with 5-fluorouracil and how well it works in treating patients with colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and that has not responded to treatment (refractory). Abemaciclib, a type of cyclin-dependent kinase inhibitor, blocks certain proteins, which may help keep tumor cells from growing. 5-fluorouracil, a type of antimetabolite, stops cells from making deoxyribonucleic acid (DNA) and may kill tumor cells. Giving abemaciclib in combination with 5-fluorouracil may be safe, tolerable, and/or effective in treating patients with metastatic and refractory colorectal cancer.
Patients must have histologically or cytologically confirmed microsatellite stability (MSS) metastatic colorectal cancer where patients have progressed on standard therapies which would have included 5-FU or capecitabine, oxaliplatin, and irinotecan. Patients must have had progression of disease (PD) or intolerance to bevacizumab and anti-EGFR antibodies (cetuximab or panitumumab) in patients who have left-sided and RAS-wildtype CRC
Patients must have measurable disease
Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of abemaciclib in combination with 5-FU in patients < 18 years of age, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia or grade 2 peripheral neuropathy. Patients who are experiencing immune related adverse events (AEs) which are adequately treated with hormone replacement therapy, including diabetes on insulin regimen, hypothyroidism on levothyroxine, and adrenal insufficiency on steroid replacement will also be eligible
Patients who are receiving any other investigational agents. There is to be a washout period of two weeks or five half-lives, whichever is shorter, for all investigational agents prior to treatment initiation on this study. Individual cases can be discussed with the national PI
History of allergic reactions attributed to compounds of similar chemical or biologic composition to abemaciclib or other agents (5-FU) used in study such as a previous intolerance to 5-FU or capecitabine, including patients with known or suspected dihydropyrimidine dehydrogenase deficiency
Patients who have received previous treatment with a CDK4/6 inhibitor
Single group
Abemaciclib
DrugGiven PO
Biopsy Procedure
Procedure/SurgeryUndergo tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Fluorouracil
DrugGiven IV
Radiologic Imaging Procedure
Procedure/SurgeryUndergo radiologic imaging
Dose-limiting toxicity (DLT)
Will be tabulated using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for each dose level.
Maximum tolerated dose (MTD)
MTD will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate.
Incidence of adverse events
Will be evaluated using CTCAE v 5.0 and will be tabulated for each dose level.
Objective response rate (ORR)
ORR will be defined as the addition of complete response and partial response. Response will be assessed based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. The probability of ORR will be estimated with exact 95% binomial confidence intervals.
Clinical benefit rate
Will be assessed using RECIST v 1.1.
Progression free survival (PFS)
PFS will be assessed using the Kaplan-Meier method, along with 95% confidence interval.
Ribonucleic acid sequencing of death receptor 5
Pre-post comparisons will be made within patients being biopsied, using a non-parametric paired test, at a significance level (alpha) of 0.05.
Abemaciclib AUC and trough levels 5-FU AUC
Will be exploratorily correlated with toxicity and response with non-parametric tests at a significance level of 0.05 (PK endpoints in patients with versus without presence of toxicity or response endpoints). Abemaciclib tissue exposure and tissue to plasma ratios will be descriptively reported.
Change in variant allele frequencies (VAF) of tumor mutations in circulating tumor DNA
The detectable VAFs will be assessed and trended during the course of treatment. VAF change will be assessed categorically for each patient (increased or decreased at start of cycle 3 as compared to baseline). The association of VAF change with objective response will be tested using the Fisher's test, where p \< 0.05 will be considered statistically significant.
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