Ceplene® Phase III Clinical Trial.
In September 2000, EpiCept completed enrollment of the MP-MA-0201 Phase III AML clinical trial. This was an international, multi-center, randomized, open-label, Phase III trial that commenced in November 1997. The trial was designed to evaluate whether Ceplene in conjunction with low dose interleukin-2, or IL-2, given as a remission therapy can prolong leukemia-free survival and prevent relapse in AML patients in first or subsequent remission compared to the current standard of care, which is no therapy during remission. Accordingly, Ceplene is intended to complement rather than supplant induction chemotherapy.
Prior to enrollment for remission therapy, patients were treated with induction and consolidation therapy according to institutional practices. Upon enrollment, patients were randomized to one of two treatment groups, either the Ceplene plus IL-2 group or the control group (standard of care, no treatment). Randomization was stratified by country and complete remission status. Complete remission status was divided into two groups; those in their first complete remission (CR1) and those in their second or later complete remission (CR>1). Altogether 320 patients were entered into this study; 160 were randomized to active treatment and 160 were randomized to standard of care (no treatment).
Patients on the active treatment arm received Ceplene plus IL-2 during ten 3-week treatment periods. After each of the first three treatment periods, there was a 3-week rest period, whereas each of the remaining cycles was followed by a 6-week rest period. Treatment duration was approximately 18 months. IL-2 was administered subcutaneously, or sc, 1 µg/kg body weight twice daily, or BID, during treatment periods. Ceplene was administered sc 0.5 mg BID after IL-2. After the patient became comfortable with self-injection under the investigator’s supervision, both drugs could be administered at home. Patients were followed for relapse and survival until at least three years from randomization of the last patient enrolled.
Safety was assessed throughout the study by clinical symptoms, physical examinations, vital signs, and clinical laboratory tests. In addition, patients were monitored for safety for 28 days following removal from treatment for any reason. Additional assessments included bone marrow biopsies as clinically indicated and quality of life.
The two treatment groups were well balanced regarding baseline characteristics and prognostic factors. With a minimum follow-up of three years, a stratified log-rank test (stratified by country and first complete remission vs. second or later complete remission) of the Kaplan-Meier, or KM, estimate of leukemia free survival of all randomized patients showed a statistically significant advantage for the treatment group (p =0.0096). At three years after randomization, 24% of control patients were alive and free of leukemia, compared with 34% of patients treated with Ceplene plus IL-2, stratified by log-rank.
The improvement in leukemia free survival was most striking in patients in their first complete remission (CR1). These patients experienced nearly a six month increase in survival, or a 55 percent improvement over the control group. The application for approval with the EMEA is a proposed indication for use in CR1 patients.
Phase II Clinical Trial
A Phase II investigator trial was conducted in Sweden in which 39 AML patients in complete remission were treated with various combinations of Ceplene and low-dose IL-2. The objective of the study was to determine a Ceplene plus IL-2 treatment regimen that would have the least negative impact on normal living for patients in remission, and to determine the feasibility of using that regimen in a larger study of AML patients in complete remission in a long-term, at-home, self-administration clinical trial. Some patients were treated with chemotherapy as well as Ceplene and IL-2 therapy.
Results of the first 29 patients enrolled from this investigator trial were encouraging: of the 18 patients in their first complete remission 67% remained in complete remission (median 23 months follow-up), and of the 11 patients in their second or later complete remission, 36% remained in complete remission (median 32 months follow-up). The trial results also demonstrated that the regimen of Ceplene 0.5 mg and IL-2 1 µg/kg administered subcutaneously at home was safe and well tolerated by most subjects. The results of this study led to the development of the Phase III protocol MP-MMA-0201.