A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM).

Abstract

2046 Background: Several plant-derived cannabinoids have shown efficacy in animal models of GBM, particularly when co-administered with temozolomide, a commonly-used treatment in both primary and recurrent disease. Methods: We conducted a two-part study in patients with recurrent GBM following standard chemo-radiotherapy treatment as described by Stupp et al. In Part 1 of the study, 6 patients were treated to an MTD of 1:1 CBD:THC oro-mucosal spray, as an adjunct to dose-intense temozolomide (DIT), to assess the safety of the combination. Part 2 was a double blind, randomized, placebo-controlled study in a planned 20 patients receiving either their individualized dose of 1:1 CBD:THC or placebo plus DIT. The primary endpoint was tolerability of 1:1 CBD:THC plus temozolomide. Results: There were no Grade 3 or 4 toxicities in Part 1 of the study. In Part 2, 12 patients were randomized to CBD:THC and 9 to placebo. Mean age was 58 years in both treatment groups, but there were more males in the placebo group (5 of 12 and 8 of 9, respectively). Baseline median Karnofsky score was 90 in both groups and median time from diagnosis of recurrence to start of treatment (day 1) was similar (3.6 and 3.0 weeks in the CBD:THC and placebo group, respectively). The median number of days of dosing with CBD:THC or placebo was similar (155 days [range: 50-356] and 134 days [range: 13-359]). Median survival in the placebo group was 369 days, and > 550 days in the CBD:THC treatment group (NS) and 1 year survival was 83% and 56% in the CBD:THC and placebo groups, respectively (p = 0.042). PFS6 was 42% in the CBD:THC group and 33% in the placebo group (NS). Overall, the commonest treatment related toxicities were dizziness (in 11/18 patients) and nausea (in 7/18 patients). Results of biomarker analyses are awaited. Conclusions: This randomized study provides preliminary evidence that 1:1 CBD:THC offers some efficacy in patients with recurrent GBM when used as an adjunct to dose-intense temozolomide and confirms the safety and feasibility of individualized dosing. Clinical trial information: NCT01812603.