Phase II Studies of Different Schedules and Doses of the Farnesyl Transferase Inhibitor Tipifarnib (R115777, Zarnestra, NSC-702818) for Patients of Age 70 or Older with Previously Untreated Acute Myeloid Leukemia (AML): A North American Intergroup Study (S0432).
Authors: Erba Harry P. , Kopecky Kenneth J. , Kirschbaum Mark H. , Tallman Martin S. , Larson Richard A. , Willman Cheryl L. , Slovak Marilyn L. , Gundacker Holly M. , Appelbaum Frederick R. 
Published: October 2019

The prognosis of older adults with acute myeloid leukemia (AML) has not improved over the last three decades, despite the improvement in the outcome of younger adults during this same time due to the use of hematopoietic stem cell transplantation and intensive cytarabine consolidation. Older adults can not tolerate intensive therapy due to poor performance status, impaired organ function, and comorbid illnesses. Tipifarnib is an oral farnesyl transferase inhibitor with activity in the treatment of myelodysplastic syndrome (MDS) and high-risk AML patients. The primary objective of study S0432 was to test whether any of four different regimens of tipifarnib is sufficiently effective and tolerable therapy for previously untreated AML in patients of age 70 or over to warrant phase III study. Patients could not be considered candidates for, or must have declined, conventional induction chemotherapy. Patients had to have adequate renal and hepatic function, and the white blood cell (WBC) count had to be less than 30,000/cmm at the time of registration. Eligible patients could have a history of MDS, but could not have received AML induction chemotherapy or stem cell transplantation. Patients were randomized to receive either 600 mg or 300 mg of tipifarnib twice daily for either 21 consecutive days or 7 days every other week. Cycles were repeated every 28 days until disease progression or unacceptable toxicity. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) were to receive three additional cycles and then discontinue therapy. Patients achieving partial remission (PR) or with stable disease could continue treatment until progression of AML. If none of the first 15 patients on an arm achieved CR, CRi or PR, then accrual to that arm would be closed. However, all 4 treatment arms continued to full accrual. Three hundred forty-eight patients were registered between September 15, 2004 and February 15, 2006. Eighteen patients were excluded from analysis due to diagnosis other than AML, WBC above 30,000/cmm, no protocol therapy, and incorrect regimen administered. The median age in each arm was 78 years. The following are the treatment regimens: arm 1, 600 mg twice daily for 21 days; arm 2, 600 mg twice daily for 7 days every other week; arm 3, 300 mg twice daily for 21 days; arm 4, 300 mg twice daily for 7 days every other week.

Responses were seen in each of the treatment arms with acceptable toxicities. The most common grade 3 or 4 adverse events were fatigue, febrile neutropenia, and infection in each treatment arm. However, the CR + CRi rates were less than 20% in each treatment arm, suggesting that further investigation of any of these regimens of tipifarnib is not warranted. Identification of predictors of response to tipifarnib, to further define the population of elderly AML patients most likely to benefit from this agent, should be investigated.

Arm 1 Arm 2 Arm 3 Arm 4 CR 8% 4% 11% 1% CRi 5% 6% 4% 5% Fatal toxicity 8% 4% 2% 0% One year survival 14% 25% 28% 14%