Phase I Study of S-Trans, Trans-Farnesylthiosalicylic Acid (Salirasib), a Novel Oral RAS Inhibitor in Patients With Refractory Hematologic Malignancies

Salirasib (Concordia Pharmaceuticals) is an oral rat sarcoma (RAS) inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its membrane-anchoring proteins. A phase I study was conducted to evaluate the safety and efficacy of Salirasib in patients with advanced leukemia. No dose-limiting toxicity was observed, and Grade 1/2 diarrhea was the only frequent nonhematologic toxicity seen. The safety profile of Salirasib and its relevant target makes it ideal to be used in combination therapy. Background: Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with famesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme. Patients and Methods: We report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a 3+3 dose escalation design. Results: Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints. Conclusion: Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy. (C) 2015 Elsevier Inc. All rights reserved.