Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

PRIMARY OBJECTIVES: I. Evaluate the proportion of patients who complete 2 cycles of protocol treatment and initiate cycle 3 in arm A (pooled arm A1 and A2) and arm B (pooled arm B1 and B2). SECONDARY OBJECTIVES: I. Evaluate outcome measures for efficacy in each arm including progression-free survival (PFS), time to progression (TTP), and overall survival (OS). II. Compare between arms the cumulative dose and dose intensity received within the first two cycles. III. Evaluate the proportion of patients in each arm that exhibit grade 3 palmar-plantar erythrodysesthesia syndrome (PPES) and/or fatigue, and make comparisons between regorafenib dosing strategies and pre-emptive versus (vs.) reactive strategies to address PPES. IV. Compare quality of life (QOL) between treatment arms (regorafenib dosing strategies and preemptive vs. reactive PPES strategies) as measured by the Hand and Foot Syndrome (HFS)14, Brief Fatigue Inventory (BFI), and Linear Analogue Self-Assessment (LASA) questionnaires. TERTIARY OBJECTIVES: I. Evaluate and compare trough minimum concentration (Cmin) pharmacokinetics (PK) during the first 2 treatment cycles for regorafenib and active metabolites M2, M5 between the low dose (dose escalation) and the standard dose cohorts, and correlate with toxicity profile. II. Evaluate the correlation between PK parameters and tumor response/stable disease after the first two cycles. III. Evaluate the correlation between PK parameters and PFS and OS. IV. Evaluate if trough (Cmin) concentrations are associated with patient-specific factors (such as ? but not limited to ? age and concomitant medications). OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM A1: Patients receive lower-dose regorafenib PO once daily (QD) on days 1-21 and pre-emptive clobetasol propionate given topically twice daily (BID) for 12 weeks, beginning on day 1 of regorafenib. ARM A2: Patients receive lower-dose regorafenib PO as in Arm A1 and reactive clobetasol propionate given topically BID beginning on day 1 per physician discretion upon occurrence of PPES grade \>= 1. ARM B1: Patients receive standard dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate as in Arm A1. ARM B2: Patients receive standard dose regorafenib PO as in Arm B1 and reactive clobetasol propionate as in Arm A2. In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 2-6 months.