A phase 1 study evaluating the pharmacokinetics (PK) and safety of regorafenib (REG) in patients with advanced solid tumors with severe renal impairment (SRI)

Abstract

Background: REG is an oral multikinase inhibitor used for the treatment of metastatic CRC and advanced GIST. This phase 1 study was designed to evaluate the PK and safety of REG in cancer patients with severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 mL/min) vs a control (CTR) group with normal or mildly impaired renal function (CLCR ≥60 mL/min). Methods: This was a phase 1, open‐label, non‐randomized, 2‐parallel group study in patients with advanced solid tumors with severe vs normal/mild renal impairment (NCT01853046). REG 160 mg QD was administered as a single dose on Day 1 with a washout of ≥5 days, then as multiple doses in 28‐day cycles (3 weeks on/1 week off ). Antitumor activity was assessed according to RECIST v1.1 as a secondary endpoint. Blood samples were collected after single and multiple dose administration for PK analysis. Adverse events (AEs) were graded according to NCI CTCAE v4.0. Estimated CLCR was calculated using the Cockcroft‐Gault equation. Results: 24 patients (6 SRI and 18 CTR) were valid for PK and safety analyses and 21 patients for efficacy analysis. Baseline median (range) CLCR was 22.3 mL/min (22‐31 mL/min) in the SRI and 82.6 mL/min (60‐130 mL/min) in the CTR group. After single‐dose REG, geometric mean AUC(0‐tlast) was 76.6 mg × h/L in the SRI and 67.2 mg × h/L in the CTR group, whereas mean terminal half‐lives were 27.9 h and 28.7 h, respectively. Inter‐subject variability of AUC(0‐tlast) was moderate in the 2 groups (CV 50.3% SRI and 45.5% CTR). After repeated dosing, the geometric mean AUC(0‐24) for REG was 55.9 mg.h/L in the SRI and 57.5 mg.h/L in the CTR group. The most common REG‐related treatment‐emergent AEs were hand‐foot skin reaction (54%), diarrhea (46%), fatigue (46%), nausea (42%), decreased appetite (42%), and hypertension (42%). The best response observed was stable disease in 15/21 (71%) patients. Conclusions: The PK of REG 160 mg QD was not affected by severe renal impairment. No safety signal was detected for a potential influence of severe renal impairment on the safety profile of REG. No dose modification is recommended for renal impairment.