ARISTOCRAT: Blinded Trial of Temozolomide +/- Cannabinoids

Prior treatment

• Prior treatment with stereotactic radiotherapy, brachytherapy or Convection Enhanced Delivery (CED) of any agent.
• Prior treatment, apart from debulking surgery, for first recurrence of GBM.
• Prior allergic reaction or significant toxicity (≥Grade 3 CTCAE) related to TMZ treatment.
• Current or recent cannabis or cannabinoid-based medications within 28 days of randomisation and/or unwilling to abstain for the duration of the trial.
• Women who are pregnant, breastfeeding or a woman of childbearing potential who is unwilling to use effective contraceptive methods during trial treatment and for 6 months after completion of trial treatment.
  • o Women of childbearing age must have a negative pregnancy test within 7 days prior to randomisation.
• Known history of current or prior alcohol or drug dependence.
• Has received a live vaccine within 28 days prior to randomisation.
• Unable to administer oromucosal medication due to mucosal lesions or other issues.

Other illness

• Prior invasive malignancy (except non-melanoma skin cancer), unless disease free for a minimum of one year.
• Personal history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric diagnosis other than depression associated with their underlying glioma condition.
• Known hypersensitivity to cannabinoids or excipients of the IMP.
• Known Hepatitis B (HBV), Cytomegalovirus (CMV) or opportunistic infection.
• Any psychological, familial, sociological or geographical condition hampering protocol compliance.

Lab values

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

Other

• Pathology inconsistent with IDH WT GBM (e.g. patients with molecular features of PXA or BRAF mutation will be excluded).
• Any active co-morbidity making patient unsuitable for trial treatment in the view of the Investigator.
• Men who are sexually active and unwilling/unable to use medically acceptable forms of contraception during trial treatment or for 6 months after completion of trial treatment.
• Contra-indication to MRI or gadolinium.
• Participation in another therapeutic clinical trial whilst taking part in this trial.

• Histological diagnosis of MGMT promoter methylated, IDH wild type (WT) GBM with consistent local molecular pathology (repeat biopsy at recurrence is NOT required).
• First recurrence of GBM planned for systemic treatment as determined by local Multidisciplinary Team (MDT), including agreement of a Consultant Neuro-Radiologist that imaging changes are most in keeping with recurrence and not pseudo-progression. Patients with a prior recurrence treated by surgical resection alone are eligible at time of first recurrence planned for systemic treatment.
• Patients must have received initial first-line treatment with standard dose conventionally 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 ARISTOCRAT Trial Office) with concomitant and adjuvant TMZ.
  • A minimum of 3 cycles of adjuvant TMZ must have been received.
  • A minimum of Stable Disease (SD) (or Partial Response (PR)/Complete Response (CR)) at the end of first-line treatment (measured by Response Assessment for Neuro-Oncology (RANO) criteria).
• ≥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 to randomisation:
  • Absolute neutrophil count (ANC) ≥1.5 x 109/L
  • Platelet count ≥100 x 109/L
  • Serum creatinine clearance (measured or calculated (using local standard practice)) \>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 adequately healed and there must be residual enhancing disease on MRI within 21 days of surgery or 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.