The MAYA2 trial

Prior treatment

• Previous treatment with temozolomide.
• Concurrent secondary active malignancy.
• Patients with either homozygosity or compound heterozygosity for multiple gene variants of dihydropyrimidine dehydrogenase (DPD), leading to a significant reduction in 5-FU metabolism do not meet eligibility criteria. However, those with decreased DPD activity who have previously tolerated 5-FU treatment can participate with capecitabine dosed according to the latest tolerated dose of capecitabine or 5FU.

Other illness

• Any condition requiring a daily dose of more than 10 mg prednisolone (or any other corticosteroid of equivalent strength), or any other immunosupressant, e.g. but not limited to mycophenolate and anti-TNF agents.
• Clinically significant cardiovascular disease, such as recent cerebrovascular accidents or myocardial infarction within 6 months of study enrollment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or higher congestive heart failure, or severe uncontrolled cardiac arrhythmia.
• Any other condition or therapy, which in the investigators opinion may pose a risk to the patient or interfere with the study objectives.
• History of autoimmune disease. Exceptions are adequately controlled autoimmune induced hypothyroidism, type 1 diabetes. Psoriasis or vitiligo are allowed as long as no systemic treatment is required.
• Patients with known hypersensitivity to any of the study drugs or their excipients.
• Malabsorption, significant bowel resection, or any other disease that would significantly inhibit bowel absorption.

Other

• Symptomatic brain metastases, or radiographic evidence of progression of known brain metastases within 8 weeks of entry in the study.
• Pregnancy or breastfeeding
• Significant co-morbidity that the investigator considers inadequately controlled, or that would make the patient unable to tolerate study treatment.
• Inability to swallow tablets.

• Signed written informed consent according to ethics committee requirements
• Age ≥18 years
• Metastatic or non-resectable adenocarcinoma of the colon or rectum
• MSS or pMMR confirmed locally by PCR or IHC, respectively
• MGMT promoter methylation confirmed by PCR and IHC in solid tumor tissue
• Prior therapy with oxaliplatin, irinotecan and fluoropyrimidin based chemotherapy (or intolerance to these). Prior cetuximab, panitumumab, bevacizumab, aflibercept, regorafenib or trifluridine/tipiracil is allowed but not mandatory.
• ECOG performance status 0-1
• Woman of childbearing potential must have been tested negative in a serum pregnancy test within 5 days prior to randomization. Fertile patients must agree to use a highly effective method of birth control (see appendix 2 – highly effective methods of contraception) during the study and for six months after the discontinuation of study medication.
• Adequate bone marrow function and organ function: a. Absolute neutrophil count (ANC) > 1.5 x 109/l and platelets (pl) > 100 x 109/l b. Serum bilirubin < 1.5 × upper limit of normal (ULN); and AST/ALT < 2.5 × ULN (or < 5 × ULN in patients with liver metastases). c. Estimated (eGFR) or measured glomerular filtration rate (GFR) > 50 ml/min