R115777 Induces Reductions in Bone Marrow Blasts

NANTES, France—The farnesyl transferase inhibitor R115777 (tipifarnib, also known as Zarnestra) is well-tolerated and effective even in relapsed, refractory acute myelogenous leukemia (AML), according to interim results of a phase II study (ASCO abstract 1056). "In this multicenter trial, we have treated relapsed and refractory patients including those who never had a complete response," lead author Jean-Luc Harousseau, MD, professor and head of the hematology department at University Hospital (hotel Dieu) in Nantes, France, told Oncology News International. "Disappearance of blasts and complete response is very encouraging for the future of Zarnestra in AML."

Because current treatment for patients with refractory or relapsed AML is unsatisfactory, the focus of research has shifted to farnesyl transferase inhibitors (FTIs), which disrupt multiple signal transduction pathways. In preclinical models, FTIs arrest growth and inhibit angiogenesis.

R115777 is an orally bioavailable and specific FTI which showed in vivo biologic activity and dose-related accumulation in bone marrow. In an earlier phase I dose-escalation trial, R115777 produced clinical responses in 8 of 25 adults (32%) with refractory, relapsed, or high-risk AML, and led to complete remission in 2 patients.

Confirmatory Trials

To confirm the activity of R115777 in patients with relapsed and refractory AML, Dr. Harousseau and colleagues are conducting a multicenter, open-label phase II trial, which thus far has enrolled 151 patients. The starting dose (cycles 1-3) is 600 mg twice daily × 21 days every 4 weeks.

Of study subjects with relapsed AML, 70% are male, 46% are over age 59, 31% had a second relapse, 11% did not have a complete response after first induction, 63% had abnormal cytogenetics, and 9% had an abnormal chromosome 5, 7, or 11.

Of 50 evaluable patients (median age 56 years) with relapsed AML, seven (14%) had reductions in bone marrow leukemic blasts to less than 5% after R115777 treatment. Prior therapy in these seven patients included cytarabine, daunorubicin (daunomycin, Cerubidine) mitoxantrone (Novantrone), and etoposide. Three of these seven patients tolerated R115777 without dose reductions. At least a 50% decrease in blasts from baseline occurred in 31 patients (62%).

Of study subjects with refractory AML, 62% are male, 59% are over age 59, 74% did not have a complete response after first induction, 67% never had a complete response, 63% had abnormal cytogenetics, and 18% had an abnormal chromosome 5, 7, or 11.

Of 40 evaluable patients with refractory AML, 8% had less than 5% blasts and 60% had at least a 50% decrease in blasts after R115777 treatment.

Median survival in treated patients was 2.3 months for patients with relapsed AML and 2.1 months for patients with refractory AML.

Accrual Is Ongoing

"The drug induces significant reductions in bone marrow leukemic blasts in patients with relapsed AML," Dr. Harousseau said. "The drug is given orally, and has a very low incidence of nonhematologic side effects."

The most frequent grade 3/4 drug-related adverse events among the evaluable relapsed patients were hypokalemia, rash, and hyperbilirubinemia, each reported in two patients. Other nonhematologic toxicities thought to be drug-related were fever (4%), fatigue (6%), and asthenia (5%). Grade 3/4 hematologic toxicities thought to be drug-related were anemia (16%), thrombocytopenia (26%), granulocytopenia (21%), leukopenia (14%) and pancytopenia (4%).

Accrual is ongoing to confirm these encouraging results and to assess the potential of R115777 to induce sustained clinical responses in AML patients.

"Since this drug is effective and well-tolerated, it could be tested in earlier stages of the disease, and should also be tested as maintenance therapy," Dr. Harousseau said. "We are planning a study in elderly patients in complete remission in combination with other cytotoxic agents."