Table 1 Key eligibility criteria for ARISTOCRAT

Inclusion criteria

Age ≥ 16

Karnofsky Performance Status ≥ 60

Histological diagnosis of MGMT promoter methylated, IDH wild type GBM with consistent local molecular pathology

First recurrence of GBM planned for systemic treatment are most in keeping with recurrence and not pseudo-progression and patient is 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 54-54-60 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 SD (or PR/CR) at the end of first-line treatment

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

Adequate hematologic, renal, and hepatic function within 14 days prior to randomisation

Exclusion criteria

Pathology inconsistent with IDH wild type GBM

Prior invasive malignancy (except non-melanoma skin cancer), unless disease free for a minimum of one year

Prior treatment with stereotactic radiotherapy, brachytherapy, or convection enhanced delivery of any agent

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

Personal history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric diagnosis other than depression associated with their underlying glioma condition

Prior allergic reaction or significant toxicity (≥ Grade 3 CTCAE) related to TMZ treatment

Current or recent cannabis or cannabinoid-based medications within 30 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

• Women of childbearing age must have a negative pregnancy test within 7 days prior to randomisation

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

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

Known history of current or prior alcohol or drug dependence

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