CTNI-29 - A phase 2 study to evaluate efficacy and safety of ACT001 and temozolomide combination treatment in patients with recurrent glioblastoma multiforme

Background: Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence.

Results: 7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study.

Conclusions: ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.