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Executive Summary

Parke-Davis' Oncopent was unanimously recommended for approval on July 2 by FDA's Oncologic Drugs Advisory Committee for the treatment of hairy cell leukemia patients who are refractory to alfa interferon. Observing that the extent and rapidity of response seen with Oncopent (pentostatin) was "clearly impressive," committee member Sandra Horning, MD, Stanford University Medical Center, said that she "heartily endorse(BRACKET)s] the approval of pentostatin for refractory hairy cell leukemia." Warner-Lambert's Parke-Davis unit submitted the NDA (No. 20- 122) for pentostatin in February. An orphan drug, pentostatin has been available under a Group C/Treatment IND protocol since July 1988. There are 500-600 new cases of hairy cell leukemia diagnosed in the U.S. each year. Alfa interferon treatment (Schering's Intron A and Hoffmann-La Roche's Roferon-A) has produced complete responses in 5%-30% of patients in clinical studies. The approval recommendation was based on data from Phase II trials conducted by the M.D. Anderson Cancer Center and several multicenter groups. Results from the studies in 133 alfa interferon-refractory hairy cell leukemia patients were presented by Parke-Davis Senior Director of Oncology Charles Kowal, MD. Resistance to interferon was defined as relapse three months after interferon treatment or the development of neutralizing antibodies to interferon. Patients received 4 mg/m pentostatin once a week for three weeks or every other week. Pentostatin treatment led to a 64% complete response rate and a 16% partial response rate, yielding an 80% overall response rate in patients. At M.D. Anderson and in the National Cancer Institute of Canada study, the response rates were highest: 93% and 100%, respectively. The duration of complete responses has averaged 30 months to date, and 85% of the patients are still alive with a median follow-up of nine months. Oncopent also significantly increased patients neutrophil counts, hemoglobin and platelets in complete and partial responders. Nonresponders also had peripheral blood improvements, although not as great as in the responders. Infection rates of 60% for responders and 40% for nonresponders in the first three months were reduced by pentostatin treatment to 20% at nine months. Transfusion requirements were also decreased, from 19% in the first three months of therapy to 1% after six months. The committee agreed that pentostatin "exhibited a trend toward reduction in red blood cell and platelet transfusions," but not a "marked reduction" as proposed by Parke-Davis in labeling. In addition, evidence was not sufficient to include a claim that pentostatin decreases infectious episodes and fever, the committee concluded. While there appeared to be a trend toward a reduction in infections, Horning commented that "if [we are] talking about a labeling indication, I don't think we have data to support it." Pentostatin's effect on hemoglobin levels, platelet counts and neutrophil counts, a majority of the committee agreed, improves the quality of life of hairy cell leukemia patients. Two committee members dissented in that opinion. The committee uniformly agreed that pentostatin caused no improvement in performance status, probably because most patients who entered into the trials were still in the early stages of disease. The committee suggested that studies be conducted to determine dosing for patients with moderately severe renal impairment. However, the panel did not make approval contingent on the studies. Instead it recommended that the studies be done post- approval in a Phase IV trial. The major adverse events observed in patients treated with pentostatin were leukopenia in 60%, nausea and vomiting in 58%, rash in 31%, and anemia in 32%. Fever, which occurred in 48% of patients, infection, occuring in 47%, and thrombocytopenia, occurring in 35%, were thought to be more related to the disease than drug therapy. Five of the 18 deaths in the studies were considered to be drug-related compared to 13 deaths attributable to disease. Twelve percent of patients withdrew from treatment due to hematologic toxicity. A head-to-head comparison of pentostatin and alfa interferon for use as a first-line therapy in hairy cell leukemia recently has been completed by the Southwest Oncology Group (SWOG). The data from that study are currently being analyzed. NCI is investigating pentostatin's utility in the treatment of mycosis fungoides, an often lethal skin malignancy, and chronic lymphocytic leukemia. In addition, a draft protocol is under consideration to use a colony stimulating factor to counteract pentostatin's depression of neutrophil levels in the first three weeks of therapy. Parke- Davis said it has not yet determined which of the CSFs, G-CSF or GM-CSF, will be used in the study.

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