A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

Chris Twelves,Bola Tayo,Susan C Short,Maria Jove,Lucy Brazil,Sharon Miller,Michael Sabel,Daniel Checketts

doi:10.1038/s41416-021-01259-3

Abstract

BackgroundPreclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM.MethodsPart 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored.ResultsThe most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.ConclusionsWith personalised dosing, nabiximols had acceptable safety and tolerability with no drug–drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.Clinical trial registrationClinicalTrials.gov: Part 1– NCT01812603; Part 2– NCT01812616.

Highlights

Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM)
We investigate the safety and tolerability of nabiximols oromucosal spray in combination with dose-intense TMZ (DIT) in patients with recurrent GBM, as reflected by the frequency and severity of treatment-emergent adverse events (TEAEs: adverse events with onset or worsening after administration of the first dose of study drug, irrespective of relatedness to treatment)
Three patients (50.0%) came off study due to Grade 1 and 2 TEAEs, and three (50.0%) because of disease progression after an overall mean of 4.13 months for the six patients that came off study (Fig. 2a)

Summary

Introduction

Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM. METHODS: Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/ day with DIT for up to 12 months. GBM is incurable, but current optimal therapy involves maximal debulking surgery followed by local high-dose radiotherapy and temozolomide (TMZ) chemotherapy.[2] With this treatment median overall survival (OS) is. Median survival falls to 1.0–10.8 months,[4,5] and there is no current standard of care for such patients.[6]. Subgroups of GBM patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation have been shown to have a better prognosis and benefit from more aggressive initial therapy with TMZ and lomustine.[10,11,12] As such, while recent advances in molecular pathology may allow for more individualised treatment in some patients, many patients with GBM do not benefit, and new treatments are urgently required

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