Phase I study of regorafenib and sildenafil in advanced solid tumors.

Abstract

3593 Background: Regorafenib (R) is an oral multikinase inhibitor with anti-angiogenic properties approved for use in several solid tumors. Sildenafil (S) is an oral phosphodiesterase-5 (PDE5) inhibitor that interacts synergistically with R in both short-term and colony formation assays to kill multiple cancer cell types. Mechanistic studies identified that PDE5 knockdown enhances R lethality, suggesting a direct target effect for S. Methods: A single-center, open-label, dose-escalation study was conducted in adults with advanced solid tumors. Patients (pts) took R (120 or 160 mg) and S (50 or 100 mg) once daily days 1 through 21 of each 28-day cycle. Pts remained on study treatment until progression or excessive toxicity, with response assessments every 8 wks. The maximum tolerated dose (MTD) was defined as the maximum tested dose with ≤1/6 pts experiencing dose-limiting toxicity (DLT), with Cycle 1 as the DLT observation period. Results: 32 pts were enrolled and 29 treated at 3 dose levels (DLs). Median duration of treatment was 8 (range 2 – 101) wks. One of 6 evaluable pts treated at DL2 (160 mg R + 50 mg S) experienced DLT (grade 4 lipase increase). One of 12 evaluable pts treated at DL3A (160 mg R + 100 mg S, the MTD) experienced DLT (grade 3 rash and grade 3 muscle pain). The toxicity profile was generally consistent with that seen in R monotherapy at FDA-approved doses. 10 pts had a best response of progressive disease (PD). 14 pts had a best response of stable disease (SD), 5 of whom had stable disease duration > 24 wks. 5 treated pts were not evaluable for response. Notably, 2 pts with ovarian cancer and 1 with cervical cancer had stable disease > 24 wks. Analyses of correlative studies to examine pharmacokinetics and drug combination pharmacodynamic effects are underway. Conclusions: The combination was well-tolerated. The recommended phase 2 dose is 160 mg R + 100 mg S. Objective responses were not observed, but prolonged stable disease was seen in a subset of pts. Encouraging disease control was seen in gynecologic cancers. Dosing up to 100 mg S is safe concurrently with standard doses of R, and may be considered as an adjunct to R in future trials. Evaluation of R+S in gynecologic cancers warrants further consideration. Clinical trial information: NCT02466802 . [Table: see text]