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

Abstract

Background RAS/RAF/MAPK activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. 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. Salirasib does not inhibit farnesyl transferase enzyme. Methods We report a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1–21 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 dose level of 100, 200, 400, 600 and 800 mg twice daily and 2 pts at dose level of 900 mg twice daily. No dose limiting toxicities were encountered. Grade 1–2 diarrhea has been the only frequent non-hematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral anti-diarrheal. Eight (47%) pts (4 MDS, 2 AML, 1 CMML, and 1 CML) had hematological improvement; 1 in three lineages, 1 in two lineages, and 6 in one lineage. None of the patient achieved complete remission. The responses lasted for a median of 10 weeks (range, 5–115). Study was discontinued for 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 utilized in combination therapy.

An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors

“…Most frequently observed drug-related AEs were gastrointestinal toxicities, such as diarrhea, abdominal pain, and nausea, consistent with the previous phase I/II trials carried out in US patients [11, 12, 15]. In all dose groups, no DLT was observed and no patients discontinued the trial for AEs.…”

“…This mechanism of action may enable treatment of patients with RAS mutations who do not respond to the standard chemotherapies. The previous phase I/II trials in the USA (CCA-FTS-101A/B, 102–105, 201) showed good tolerability, but the efficacy in RAS -mutated patients was not conclusive [11, 12]. The present trial was a phase I trial to investigate the safety, tolerability, and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors.…”

Effect of Piper Nigrum (Linn) on the Toxicity Induced by Ethionamide and Para Amino Salicylic Acid Drugs on Blood Count in Sprague-Dawley Rats

“…In their study they found that oral administration with Isoniazid drug resulted in occurrence of physiological or hypochromic anemia which monitored from the significant decrease in hemoglobin content, RBCs count (erythrocytopenia), hematocrite value, MCH, and MCHC; also, thrombocytopenia (decrease in platelets count) and leucopenia (reduction of TLC) were recorded in compare to control group. Our results are also in accordance with the reports of [21][22][23][24] who reported that chronic application of Isoniazid induces a reduction in the number of platelets, RBCs and leukocytes through the induced oxidative stress, which might affect their life expectancy, induce an apoptosis and thereby ultimately reduce the number of these cells in the blood.…”

How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization

“…Neither drug has been demonstrated to affect K-Ras function in patients [159–161], although a decrease in total K-Ras protein was reported in paired (pre- and post-treatment) tumor biopsies in two patients taking salirasib [161]. In a recent trial on hematological malignancies, salirasib efficacy was modest and did not correlate with Ras mutation status [162]. Although the diseases under study would presumably have made biochemical examination of peripheral blood mononuclear cells relevant, results from such studies were not reported.…”