Phase I first-in-human clinical study of S-trans, trans- farnesylthiosalicylic acid (salirasib) in patients with solid tumors

Purpose: This phase I first-in-human trial evaluated salirasib, an S-prenyl derivative of thiosalicylic acid that competitively blocks RAS signaling. Methods: Patients with advanced cancers received salirasib twice daily for 21 days every 4 weeks. Doses were escalated from 100 to 200, 400, 600, and 800 mg. Results: The most common toxicity was dose-related diarrhea (Grade 1-2, 79% of 24 patients). Other toxicities included abdominal pain, nausea, and vomiting. No Grade 3-4 toxicity was noted. Nineteen (79%) patients had no drug-related toxicity >Grade 1. Dose-limiting toxicity (DLT) was not reached, but all three patients treated with 800 mg experienced Grade 1-2 diarrhea, abrogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib 4 months (range 4-23+). The salirasib pharmacokinetic profile was characterized by slow absorption and a rapid elimination phase following oral administration. Salirasib exposure (C _max; day 1 AUC_inf vs. day 15 AUC_{0-12 h}) was similar between days 1 and 15 (P > 0.05). The T _1/2 (mean ± SD) was 3.6 ± 2.2 h on day 1. Conclusions: Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.