Tipifarnib (ZARNESTRA™, R115777) is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor (FTI) with significant anti-tumor activity in several tumor models. FTI have significant anti-leukemia activity in vitro against CML cell lines and patient samples, including some that are IM-resistant, showing synergy between FTI and IM. As a single agent tipifarnib induced minor cytogenetic responses in 4 of 10 pts with CML in CP who failed interferon (

Blood 2003; 101: 1692
). To investigate the tolerability and efficacy of the combination of FTI and IM we designed a phase I study with tipifarnib plus IM in pts with CML in CP who have failed IM. To be eligible pts should not be in hematologic remission after 3 months (mo) of IM therapy, or 100% Ph-positive at 6 mo, or not in major CG remission at 12 mo. Starting dose level was tipifarnib 300 mg twice daily (BID) x14 days every 21 days and imatinib 300 mg daily, with subsequent levels 300 + 400 (+1), 400 + 400 (+2), and 500 + 400 (+3), respectively. Sixteen pts have been treated, 3 at dose levels 0, +1, and +3, and 7 at +2. Median age is 63 years (range, 29 to 79), median time from diagnosis 68 mo (10 to 90). 3 pts had received IM as their first therapy for CML. Median WBC at the start of therapy was 6.8 x109/L (2.7 to 25.6) and median %Ph(+) metaphases 100 (range, 45 to 100). At the time the combination was started 7 pts were still taking IM at a median dose of 400 mg (range, 200 to 800), and 4 were taking other agents (hydroxyurea 1, anagrelide 3). The median duration of treatment with imatinib was 68 mo (range, 10 to 90). All had failed IM, 9 had failed IFN, and 6 had failed other therapies (decitabine 3, BMT 1, ara-C 1, HHT 1). ABL mutations were found in 7 of 14 pts evaluated. Dose limiting toxicity (DLT) was observed at dose level +3 (grade 3 fatigue and esophagitis, 1 each) and the maximally tolerated dose (MTD) is 400 + 400. This cohort is being expanded. Six pts had myelosuppression (1 at level 0, 2 at level 1, 2 at level 2, and 1 at level 3) not meeting definition of DLT (i.e. G3 neutropenia or thrombocytopenia lasting 6 weeks). Seven pts required a dose reduction and 1 pt had a dose increase one dose level for inadequate response with no toxicity. One pt died early (16 days on treatment) of unknown causes, 9 pts have discontinued therapy after a median of 12 3-week cycles (range, 3 to 17), and 6 continue therapy after a median of 11+ cycles (1+ to 21+). 11 pts started with abnormal counts (5 plts >450 x109/L, 3 WBC >10 x109/L, 4 basophils or eosinophils >10%, 1 immature WBC in PB), and 9 had normalization. 4 (25%) pts achieved a cytogenetic response (2 minor, 1 PR, 1 CR), including one pt with a T315I mutation (PR). 2 lost response after 9 months and 2 have ongoing response for >12 months. We conclude that this combination is well tolerated and demonstrates anti-leukemia activity. The MTD is imatinib 400mg daily and tipifarnib 400 mg twice daily.

Topics:
brachial plexus neuritis, imatinib mesylate, leukemia, myelocytic, chronic, tipifarnib, disease remission, leukemia, toxic effect, anagrelide, cytarabine, decitabine

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2005, The American Society of Hematology
2004
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