Pan-tumor Neoadjuvant Basket Study of Immune Check-point Inhibition and Novel Immuno-oncology Combinations

Inclusion Criteria:

1. Signed written informed consent
2. Patients at least 18 years of age
3. Non-metastatic, newly diagnosed dMMR and pMMR cancers either fitting within a specific basket or in the "other" cohort (e.g. sarcoma, head and neck cancers, anal cancer, esophageal SCC)
4. In case of pMMR tumors: no indication for neoadjuvant therapy according to standard of care, unless adjuvant treatment is considered a standard of care alternative;
5. Eligible for study biopsy
6. World health organization (WHO) performance status of 0 or 1
7. Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: White blood cell count (WBC \> 2.0 x 10\^9/L, Absolute neutrophil count (ANC) \> 1.5x10\^9/L, platelets \> 100 x 10\^9/L, Hemoglobin \> 5.0mmol/L. Transfusion is allowed to obtain an adequate hemoglobin level. Liver function tests: total bilirubin \< 1.5 upper limit of normal (ULN) (except for subjects with Gilbert syndrome, who can have total bilirubin \<3.0 mg/dL); alkaline phosphatase \<1.5 ULN; transaminases (ASAT/ALAT) \<3 x ULN; Lactate dehydrogenase (LDH) \< 1.5x ULN; Creatinine clearance (Cockcroft-Gault) of \>45 ml/min, Albumin \> 3.0 g/dL
8. Women of childbearing potential (WOCBP)\* must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 20 weeks after the last dose of investigational drug, Non-childbearing potential is defined as:

   1. Postmenopausal: ≥ 50 years of age and has not had menses for greater than 1 year.
   2. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and a follicle- stimulating hormone value in the postmenopausal range upon pre-study(screening) evaluation.
   3. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.
9. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of cycle 1 day 1
10. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving the study treatment and who are sexually active with WOCBP (excluding azoospermic men) will be instructed to adhere to contraception for a period of 28 weeks after the last dose of investigational drug and are not allowed to donate sperm during that timeframe.

Exclusion Criteria:

1. Signs of distant metastases on imaging and physical examination
2. Clinical obstruction
3. Clinical symptoms or radiological suspicion of perforation
4. Previous treatment with immune checkpoint inhibitors including but not limited to anti-CTLA4 or anti-PD1
5. Prior chemotherapy for any cancer
6. Radiotherapy prior to or planned post-surgery radiotherapy for disease under study
7. Active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. \<10% in 5 years)
8. Allergies and Adverse Drug Reaction:

   1. History of allergy to study drug components
   2. History of severe hypersensitivity reaction to any monoclonal antibody
9. Intercurrent illnesses, including but not limited to infections, unstable angina pectoris
10. Underlying medical conditions that, in the investigator's opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events
11. Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
12. History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
13. Active autoimmune disease or a documented history of autoimmune disease, or other medical conditions requiring systemic steroid or immunosuppressive medications, except for subjects with vitiligo, diabetes mellitus type 1, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis or resolved childhood asthma/atopy not requiring systemic treatment
14. Conditions requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
15. Live vaccines in the 4 weeks prior to inclusion
16. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
17. Current pregnancy or breastfeeding

Specific for pMMR GEA cohort:

Known DPD deficiency; refer local clinical guidance, for DPD status recommendation prior to starting treatment.