Phase I Study of S-trans, Trans-farnesylthiosalicylic Acid (FTS), a Novel Oral Ras Inhibitor, in Patients with Refractory Hematologic Malignancies.

Background: Ras activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. Farnesyl transferase inhibitors (FTI) that are thought to alter lipid modification of Ras and thereby alter its membrane targeting, are in clinical trial in hematologic malignancies but their target may not be specific for Ras. Toxicities of FTIs include diarrhea, skin rash and hepatic toxicity. FTS is an oral Ras inhibitor that causes dislocation of Ras from its membrane location by competing directly with farnesylated Ras to bind to its putative membrane binding proteins. FTS does not inhibit farnesyl transferase enzyme.

Methods: We report on an ongoing phase I study of FTS in patients with relapsed/refractory hematologic malignancies in which FTS is administered orally twice daily on days 1–21 of a 28 day cycle in a “3+3” dose escalation design.

Results: To date, 18 patients (pts) have been enrolled, with 17 pts treated (1 cycle=2, 2 cycles=8, 4 cycles=2, 5 cycles=1, 6 cycles=2, 8 cycles=1 and 9 cycles=1). Four pts were enrolled at dose level (DL) of 100 mg, 3 pts at each DL of 200, 400, 600 and 800 mg and 2 pts at DL of 900 mg. One pt enrolled at 100 mg DL was never treated. Median age was 72 years (range, 35 to 85 years), median ECOG status 1 (range 0–2) and median no. of prior therapies 2 (range, 0–7). Diagnoses included: Acute myelogenous leukemia (AML) = 9 pts, myelodysplastic syndrome (MDS) = 5 pts, chronic myelomonocytic leukemia (CMML) = 2 pts, chronic myelogenous leukemia (CML) = 1 pt. and Myeloproliferative Disorder = 1 pt. Preliminary analysis of pharmacokinetic data indicates that both Cmax and AUC increase with dose, but less than dose proportionately. Detailed PK data will be available for presentation at the American Society of Hematology 2007 Annual Meeting. Of 17 pts evaluable for response, 7 pts (41%) (4 MDS, 1 CMML, 1 CML, 1 AML) had hematological improvement (HI) (1 in three lineages, 6 in one lineage) without any complete remission. These responses lasted for a median of 9 weeks (range, 4 to 26 weeks). Currently, 2 patients are continuing on study with improvement in cytopenia and stable disease for over 20 weeks each. Grade 1–2 diarrhea has been the only non-hematologic toxicity seen, observed in 14 of 17 (82%) pts evaluable for toxicity and is completely correctable with oral antidiarrheals.

Conclusion: FTS shows promising activity in refractory hematologic malignancies and to date has minimal toxicity.