Phase I Study of Lonafarnib (SCH66336) in Combination with Imatinib for Patients (Pts) with Chronic Myeloid Leukemia (CML) after Failure to Imatinib.
Authors: Cortes Jorge , O’Brien Susan , Verstovsek Srdan , Daley George , Koller Charles , Ferrajoli Alessandra , Pate Odeal , Faderl Stefan , Ravandi-Kashani Farhad , Talpaz Moshe , Zhu Yali , Statkevich Paul , Sugrue Mary , Kantarjian Hagop 
Published: April 2020

Abstract
Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against Bcr-Abl-positive cell lines and primary human CML cells. Lonafarnib can inhibit proliferation of imatinib mesylate (IM)-resistant cells and increases IM-induced apoptosis in vitro in cells from IM-resistant pts. There is significant in vitro synergy of these agents in IM-resistant cells. We conducted a phase I study of lonafarnib in combination with IM for pts with CML who failed IM. Pts in chronic phase (CP) should not be in hematologic response after 3 months (mo) of IM therapy, or 100% Ph-positive after 6 mo of IM therapy, or ≥35% Ph-positive after 12 mo. Pts in accelerated (AP) or blast (BP) phase were eligible regardless of prior therapy. Starting dose level for CP was IM 400 mg/d + lonafarnib 100mg twice daily (BID); for AP and BP it was 600mg/d and 100 mg BID. Subsequent cohorts escalated the dose of lonafarnib by 25mg/dose to a maximum dose of 200mg BID with no change in IM. 22 pts have been treated: 9 CP, 10 AP, 3 BP. Median age is 59 years (26–79). Prior therapy included imatinib (n=22), IFN-based therapy (n=16), and other agents (n=7), including HHT, DAC, and clofarabine. 4 pts received IM as their first therapy for CML. Median time from diagnosis was 51 months (range 10 to 187). Median WBC at the start of therapy was 9.7 x109/L (range 1.5 to 56) and median %Ph-positive metaphases 100 (range 35 to 100). At the time the combination was started 10 patients were still taking IM at a median dose of 800 (range (400 to 800), and 8 were taking other agents including hydroxyurea (n=7), and anegrelide (n=1). The median duration of treatment with imatinib was 23 months (range 4 to 45). Eight of the 13 (62%) pts in AP or BP had clonal evolution. ABL sequencing was done in 21 pts and mutations were found in 11 (52%). Pts received therapy for a median of 23 weeks (4–45). Among pts in CP, 2 pts had G3 dose-limiting toxicity (DLT) at 400+125mg dose, including diarrhea (n=2), vomiting (n=1) and fatigue (n=1). Among AP/BP DLT was observed 600 + 125mg dose consisting of diarrhea (n=1), vomiting (n=1), and hypokalemia (n=1). Among 6 pts in CP evaluable for hematologic response, 1 pt had a complete hematologic response. One pt (started in CHR) had a partial cytogenetic response. Among patients in AP and BP, 4 had hematologic response: 1 CHR (with mutation F359V), 1 PHR (no mutation), 2 HI (1 pt with lymphoid BP achieved marrow CR - no mutation-, and 1 pt in AP achieved CHR with incomplete platelet recovery - mutation E292V−). To date, pharmacokinetic data from 12 patients suggest no apparent increase in exposure or changes in PK to both lonafarnib and IM when coadministered. We conclude that the combination of lonafarnib and imatinib is well tolerated and the MTD of lonafarnib is 100 mg BID when combined with either Gleevec 400 mg or 600 mg daily. There is early evidence of activity in this refractory population and warrant further clinical evaluation.