ARISTOCRAT: Blinded Trial of Temozolomide +/- Cannabinoids

Inclusion Criteria:

• Histological diagnosis of MGMT promoter methylated, IDH wild type (WT) GBM withconsistent local molecular pathology (repeat biopsy at recurrence is NOT required).

• First recurrence of GBM planned for systemic treatment as determined by localMultidisciplinary Team (MDT), including agreement of a Consultant Neuro-Radiologistthat imaging changes are most in keeping with recurrence and not pseudo-progressionand patient is planned for systemic treatment. Patients with a prior recurrencetreated by surgical resection alone are eligible at time of first recurrence plannedfor systemic treatment.

• Patients must have received initial first-line treatment with standard doseconventionally fractionated radiotherapy (i.e. 40 Gy in 15 fractions or 54-60 Gy in 28-33 fractions; other regimes may be considered in consultation with the ARISTOCRATTrial Office) with concomitant and adjuvant TMZ.

• A minimum of 3 cycles of adjuvant TMZ must have been received.

• A minimum of SD (or PR/CR) at the end of first-line treatment.

• ≥3 months since day 28 of the last cycle of TMZ.

• Karnofsky Performance Status ≥60.

• Adequate hematologic, renal, and hepatic function within 14 days prior torandomisation:

• Absolute neutrophil count (ANC) ≥1.5 x 109/L

• Platelet count ≥100 x 109/L

• Serum creatinine clearance (measured or calculated (using local standardpractice)) >30ml/min

• Total serum bilirubin ≤1.5 x upper limit of normal (ULN)

• Liver transaminases <2.5 x ULN

• If surgery has been performed for first recurrence then the wound must be adequatelyhealed and there must be residual enhancing disease on MRI within 21 days of surgeryor new enhancement at later follow up deemed suitable for systemic treatment.

• Recovered from previous treatment side-effects ≤ Grade 2.

• If on systemic steroids, must be on stable (≥7 days) or decreasing dose of steroids.

• Willing and able to provide trial-specific informed consent.

• Willing and able to comply with trial requirements.

• Age ≥16.

• Able to start treatment within 28 days of randomisation.

Exclusion Criteria:

• Pathology inconsistent with IDH WT GBM (e.g. patients with molecular features of PXAor BRAF mutation (on original pathology) will be excluded).

• Prior invasive malignancy (except non-melanoma skin cancer), unless disease free fora minimum of one year.

• Prior treatment with stereotactic radiotherapy, brachytherapy or Convection EnhancedDelivery (CED) of any agent.

• Prior treatment, apart from debulking surgery, for first recurrence of GBM.

• Any active co-morbidity making patient unsuitable for trial treatment in the view ofthe Investigator.

• Personal history of schizophrenia, other psychotic illness, severe personalitydisorder or other significant psychiatric diagnosis other than depression associatedwith their underlying glioma condition.

• Prior allergic reaction or significant toxicity (≥Grade 3 CTCAE) related to TMZtreatment.

• Current or recent cannabis or cannabinoid-based medications within 30 days ofrandomisation and/or unwilling to abstain for the duration of the trial.

• Women who are pregnant, breastfeeding or a woman of childbearing potential who isunwilling to use effective contraceptive methods during trial treatment and for 6months after completion of trial treatment. o Women of childbearing age must have a negative pregnancy test within 7 days priorto randomisation.

• Men who are sexually active and unwilling/unable to use medically acceptable formsof contraception during trial treatment or for 6 months after completion of trialtreatment.

• Contra-indication to MRI or gadolinium.

• Hereditary galactose intolerance, total lactase deficiency or glucose-galactosemalabsorption.

• Known hypersensitivity to cannabinoids or excipients of the IMP.

• Known history of current or prior alcohol or drug dependence.

• Known Hepatitis B (HBV), Cytomegalovirus (CMV) or opportunistic infection.

• Has received a live vaccine within 28 days prior to randomisation.

• Unable to administer oromucosal medication due to mucosal lesions or other issues.

• Participation in another therapeutic clinical trial whilst taking part in thistrial.

• Any psychological, familial, sociological or geographical condition hamperingprotocol compliance.