Overview

The purpose of this investigator-initiated, multicenter phase II trial is to evaluate the efficacy and tolerability of nivolumab and ipilimumab in patients with stage 1-3 MSI/dMMR rectal cancer.

The primary objective is:

Number of patients with complete clinical response after one or two cycles of immunotherapy.

Patients will be treated with 1 or 2 cycles of combination immunotherapy:

Cycle 1: Nivolumab 3 mg/kg days 1 and 15 \& ipilimumab 1 mg/kg day 1 Cycle 2: Nivolumab 3 mg/kg days 50 and 65 \& ipilimumab 1 mg/kg day 50

Eligibility

Inclusion Criteria:

• Age ≥ 18 years.
• Histologically verified non-metastatic rectal cancer stage 1-3.
• No indication for local therapy like TEM.
• Histologically verified dMMR or MSI.
• Performance status (WHO) of 0-1.
• No previous chemotherapy, radiotherapy or immunotherapy for colorectal cancer
• Adequate haematological function defined as neutrophils ≥ 1.5 x 109/l and platelets ≥ 100 x 109/l.
• Adequate organ function (bilirubin ≤ 1.5 x UNL (upper normal limit), GFR (may be calculated) \> 30 ml/min.
• Women of childbearing potential must have been tested negative in a serum pregnancy test within five days prior to registration. Fertile patients must agree to use a highly effective method of birth control. (i.e., pregnancy rate of less than 1 % per year) (Appendix 1) during the study and for six months after the discontinuation of study medication.
• Has provided written informed consent prior to performance of any study procedure.
• Written informed consent must be obtained according to the local Ethics Committee requirements.

Exclusion Criteria:

• Any other condition or therapy, which in the investigator's opinion may pose a risk to the patient or interfere with the study objectives.
• Concomitant use of systemic glucocorticoids more than the equivalent dose to tablet prednisolone 10 mg/day. Treatment with systemic glucocorticoids must end no later than two weeks before inclusion.
• Subjects with active, known, or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
• Known allergy or intolerance to any of the drugs used (nivolumab and ipilimumab).