SAN FRANCISCOThe investigational farnesyl transferase inhibitor (FTI), R115777 (tipifarmib, Zarnestra) causes robust clinical responses in some patients with myelodysplastic syndrome (MDS), but these responses are not correlated with the drug’s ability to inhibit farnesyl transferase, according to a study presented at the 93rd Annual Meeting of the American Association for Cancer Research (abstract 4959).
The hypothesis-driven clinical trial was a collaboration between M.D. Anderson Cancer Center, where the patients were accrued, and the H. Lee Moffitt Cancer Center and Research Institute, Tampa, where the biochemical correlative work was carried out.
"In every patient, the molecular target was hit, but only 30% responded," said researcher Said M. Sebti, PhD, professor of oncology, biochemistry and molecular biology, Moffitt Cancer Center. "Our study tells us that inhibition of farnesyl transferation is critical for response, but, by itself, it does not correlate with response." Dr. Sebti is also director of Moffitt’s Drug Discovery Program.
In the study, 6 of 20 evaluable myelodysplastic syndrome patients achieved a hematologic partial or complete response to R115777, said lead researcher Razelle Kurzrock, MD, professor of medicine, M.D. Anderson Cancer Center. Some of the responses have been quite durable, lasting up to 15 months. Responses were seen at all dose levels, and did not correspond with the ability of the drug to hit its molecular target and inhibit farnesyl transferase.
The study suggests that the six patients who responded must have a molecular signaturea blueprintthat requires farnesyl transferase for tumor survival. "That’s why we see responses in these patients," Dr. Sebti said.
Eligible patients had received less than two prior therapies and had adequate renal and hepatic function. Myelodysplastic syndrome patients of all subtypes were included in the trial.
The patients received R115777 orally twice a day for 3 weeks of a 4-week cycle. Dosing started at 300 mg twice daily and increased up to 900 mg/d until patients showed toxicity or no longer benefited from therapy. Three patients responded at 600 mg/d, two at 800 mg/d, and one at 900 mg/d. "There was more than 80% farnesyl transferase inhibition with every patient," Dr. Sebti said. The enzyme did not come back to basal level even 1 week after stopping the drug.