Farnesyl Transferase Inhibitor (Tipifarnib, Zarnestra; Z) in Combination with Standard Chemotherapy with Idarubicin (Ida) and Cytarabine (ara-C) for Patients (pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS).

Tipifarnib is a non-peptidomimetic farnesyl transferase inhibitor (FTI) with clinical activity in hematologic malignancies, including AML, MDS and CML. Pre-clinical data suggests that tipifarnib may be synergistic with some chemotherapeutic agents. We designed a phase I/II study where pts age 15 to 70 years with previously untreated AML or high-risk MDS (blasts >10%) received induction with Ida 12 mg/m²/d on days 1–3, ara-C 1.5 g/m² IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z with first cohort (6 pts) receiving 200mg orally twice daily (BID), and all others 300 mg BID x 21 days every 28 days. Pts achieving CR received consolidation (5 courses) with Ida 8 mg/m²/d, days 1–2, ara-C 0.75 g/m²/d, days 1–3, and Z 300 mg BID x14 days every 4–6 weeks. Maintenance was with Z 300 mg BID x 21 d every 4–6 wk for 6 months. We have treated 74 pts, median age 50 yrs (17–61 yrs). All pts are evaluable for response. Fifty seven pts (77%) responded: 48 (65%) achieved CR and 9 (12%) CRp. Overall response rate (CR+CRp) in a similar historical population treated with the same chemotherapy regimen (IA) without Z was 68% (p=0.29). Response by cytogenetics was: 26/30 (86%) for diploid, 12/16 (76%) with -5/-7, 1/2 with t(8;21), and 17/25 (68%) with other abnormalities. Response by Flt3 was 11/15 (73%) for unmutated Flt3, 39/46 (85%) for mutated Flt3. Response by age was 26/34 (76%) if ≤50yrs, 9/13 (69%) if >50yrs with diploid karyotype and 13/27 (48%) if >50yrs with abnormal karyotype. With median follow-up of 22 weeks, 34 pts are still on study. Of the 48 pts that achieved CR, 2 died in CR of unrelated causes and 9 pts have relapsed after 5, 11 13, 14, 16, 26, 29, 34, and 39 weeks, respectively. The most common grade 3 adverse events include diarrhea in 31 (42%) and hyperbilirrubinemia in 10 (14%), both transient. Thirty nine (53%) pts have required treatment interruptions/dose reductions during induction, 17 (16%), and 2 (7%) during consolidation and maintenance respectively. We conclude that Z combined with Ida and ara-C induces a high rate of CR in AML, with increased incidence of diarrhea and hyperbilirrrubinemia. Direct comparison with chemotherapy alone is warranted in a randomized trial.