Phase III trial of lomustine/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT promoter methylated glioblastoma (IDHwt) patients +/- tumor treating fields (Optune)

Prior treatment

• Patients with reproductive potential who do not accept to use contraception during chemotherapy and 6 months thereafter
• Treatment in another clinical trial with oncological therapeutic intervention or use of any other investigational agent within 30 days before enrolment
• Prior systemic chemotherapy with DNA-damaging agents for any cancer
• Prior RT to the brain
• Concurrent administration of any other antitumor therapy not described in the protocol
• Concurrent administration of complementary or alternative drugs

Other illness

• Any active infection (at the discretion of the investigator)
• Any psychological, cognitive, familial, social or geographical condition potentially hampering compliance with the study protocol and follow-up scheduled visits (at the discretion of investigator)
• Allergy or intolerability of temozolomide, dacarbazine, lomustine or other nitrosourea derivatives including celiac disease and wheat allergy
• Past medical history of diseases with poor prognosis, e.g. severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)

Age

• Prior malignancy (except adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer), unless the prior malignancy was diagnosed and curatively treated ≥3 years previously with no subsquent evidence of recurrence

Other

• Female patients that are breastfeeding and not willing to refrain
• Unable to perform MRI
• Severly reduced lung function (at the discretion of the investigator)

• Written informed consent
• Adequate organ function as described in the protocol
• Patients on anticoagulation can be included at the discretion of the investigator, but oral anticoagulants, including NOAC/DOAC are recommended to be switched to Low-molecular-weight heparin (LMWH) during the treatment phase and until platelets are >50 or according to local guidelines.
• Patient capable of understanding the rationale and necessity of study therapy and procedures.
• Newly diagnosed histologically proven GBM, giant-cell GBM or gliosarcoma WHO Grad 4, histology confirmed by the local neuropathologist as IDHwt. Histology obtained by complete resection, partial resection, open biopsy or stereotactic biopsy.
• Methylated MGMT promoter in the tumor as determined according to local routine. For centers using the same method/kit the same cut-off for mMGMT will be used.
• Males or females 18-75 years of age, estimated life expectancy of at least 12 weeks
• WHO Performance Score 0-2
• Patient compliance and geographic proximity that allow adequate follow up
• Male and female patients with reproductive potential must use an approved contraceptive method (intrauterine device, birth control pills, or barrier device) during and for 6 months after end of chemotherapy (Pearl index <1%)
• Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained within 14 days prior to treatment start