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, brogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥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.
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, brogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥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.
Authors: Jaimeen D Majmudar; Heather B Hodges-Loaiza; Kalub Hahne; James L Donelson; Jiao Song; Liza Shrestha; Marietta L Harrison; Christine A Hrycyna; Richard A Gibbs Journal: Bioorg Med Chem Date: 2011-11-06 Impact factor: 3.641
Authors: Vivek Subbiah; John Slopis; David S Hong; Leena M Ketonen; Jackson Hamilton; Ian E McCutcheon; Razelle Kurzrock Journal: J Clin Oncol Date: 2011-12-27 Impact factor: 44.544
Authors: Daniel Laheru; Preeti Shah; N V Rajeshkumar; Florencia McAllister; Gretchen Taylor; Howard Goldsweig; Dung T Le; Ross Donehower; Antonio Jimeno; Sheila Linden; Ming Zhao; Dongweon Song; Michelle A Rudek; Manuel Hidalgo Journal: Invest New Drugs Date: 2012-05-01 Impact factor: 3.850