A Randomized Phase 3 Study of Tipifarnib Compared to Best Supportive Care (Including Hydroxyurea) in the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) in Patients 70 Years or Older.

Tipifarnib (R115777, ZARNESTRA®) treatment resulted in complete remission among patients (pts) with AML in phase 1–2 studies. Results are reported for the multicenter, open-label study comparing tipifarnib to best supportive care (BSC), including hydroxyurea, as first line therapy in elderly pts (≥70 years) with newly diagnosed, de novo or secondary AML. Methods: A total of 457 pts who were not medically fit for or did not wish to be treated with combination chemotherapy were randomized, with stratification for age (<75 vs. ≥75 years) and Eastern Cooperative Oncology Group performance status (PS 0–1 vs. 2). Overall, 24% of pts were ≥80 year old, 28% had PS 2, 32% had unfavorable cytogenetics and 36% had AML with myelodysplasia. Tipifarnib was administered at 600 mg p.o. BID for the first 21 consecutive days, in 28-day cycles. Pts on BSC were permitted to receive hydroxyurea if clinically indicated. The primary endpoint was to compare overall survival (OS) between treatment groups, both overall and for pts with AML with myelodysplasia. Pts were treated until disease progression, intolerable toxicity, death, or withdrawal of consent. Pts were followed after treatment termination for subsequent therapy and survival. A total of 394 events (deaths) were required to detect a hazard ratio of 0.75 for OS, with 80% power given a 2-sided significance level of 0.043 (α1). Results: At the time of this analysis, 201 (88%) of 228 pts on the tipifarnib arm and 195 (85%) of 229 pts on the BSC arm had died. With median follow-up of 539 days, the median survival was 107 days (95% CI: 85, 129 days) for the tipifarnib arm and 109 days (95% CI: 93, 136 days) for the BSC arm. The hazard ratio (tipifarnib vs. BSC) for OS was 1.02 (95% CI: 0.84, 1.24). The p-value from the stratified log-rank test on OS was 0.843. The complete response (CR) rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. In the tipifarnib arm, OS was not negatively affected by the rate of early deaths (21% for tipifarnib and 17% for BSC) or total drug-related deaths (4 pts, 2%). The most frequent grade 3 or 4 adverse events were cytopenias. The rate of grade 3 or 4 infections was slightly higher on the tipifarnib arm (39% vs. 33%), as was the incidence of febrile neutropenia (16% vs. 10%). The incidence of other drug-related non-hematological grade 3–4 adverse events was low. The median duration of hospitalization was 19 days for BSC and 22 days for tipifarnib-treated pts. The rate of hospitalization for infections was not increased: 28% vs. 29% respectively. Conclusions: In this randomized study, treatment with tipifarnib did not result in an overall increased survival when compared to BSC including hydroxyurea. There was a low incidence of drug-related deaths, and severe infections or febrile neutropenia were only slightly increased.