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

Br J Cancer. 2021 Apr;124(8):1379-1387. doi: 10.1038/s41416-021-01259-3. Epub 2021 Feb 24.

Abstract

Background: 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. 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.

Results: The 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.

Conclusions: With 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 registration: ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Brain Neoplasms / drug therapy*
  • Cannabidiol / administration & dosage*
  • Cannabidiol / adverse effects
  • Cannabidiol / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Dronabinol / administration & dosage*
  • Dronabinol / adverse effects
  • Dronabinol / pharmacokinetics
  • Drug Combinations
  • Glioblastoma / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Oral Sprays
  • Precision Medicine
  • Survival Analysis
  • Temozolomide / administration & dosage*
  • Temozolomide / adverse effects
  • Temozolomide / pharmacokinetics
  • Treatment Outcome

Substances

  • Drug Combinations
  • Oral Sprays
  • Cannabidiol
  • Dronabinol
  • nabiximols
  • Temozolomide

Associated data

  • ClinicalTrials.gov/NCT01812603
  • ClinicalTrials.gov/NCT01812616