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R115777 Induces Reductions in Bone Marrow Blasts

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%).

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