Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in Japanese patients with advanced solid tumors

Aim/Background

Ras mutations play an important role in human carcinogenesis. Salirasib is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. This phase I study evaluated the safety, maximum tolerated dose (MTD), antitumor activity, and pharmacokinetics (PK) of salirasib in Japanese patients with advanced solid tumors.

Methods

Salirasib was administered orally twice daily (BID) at doses between 100 and 1000 mg on days 1 to 21 of a 28-day cycle in a “3 + 3” dose escalation design. Adverse event (AE) was evaluated in accordance with CTCAE v4.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Results

Twenty one patients were enrolled in this study. No dose-limiting toxicities (DLTs) were observed. The most common toxicities were diarrhea (Grade 1-3, 81%), abdominal pain (Grade 1, 24%), nausea (Grade 1, 19%), and decreased appetite (Grade 1-2, 19%). Salirasib PK exposure increased dose proportionally up to 800 mg daily, but doses above 800 mg BID did not result in a significant increase in salirasib exposure. 4 patients (including 2 KRAS mutation harboring patients) achieved durable stable disease (SD) ≧ 24 weeks.

Conclusions

Salirasib was well-tolerated at doses up to 1000 mg and showed modest activity in advanced solid tumors. Considering safety profile and PK analysis, the recommended phase 2 dose of salirasib would be 800 mg. SD were observed in three-seventh (43%) of patients with Ras mutations.

Clinical trial identification

JapicCTI-121751

Disclosure

All authors have declared no conflicts of interest.