RecruitingPhase 2NCT05732389

Immunotherapy in Patients With Early dMMR Rectal Cancer

Sponsor

Odense University Hospital

Enrollment

39 participants

Start Date

Feb 1, 2023

Study Type

INTERVENTIONAL

Conditions

Cancer of Rectum

Summary

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

Min Age: 18 Years

Inclusion Criteria11

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 Criteria4

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).

Interventions

DRUGNivolumab

Nivolumab is a highly selective fully humanized, IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1) (17). PD-1 is an inhibitory receptor expressed on the surface of T-cells, B cells, macrophages, and NK cells. Endogenous binding of PD-1 with one of its two ligands PD-L1 and PD-L2 results in production of an inhibitory signal which results in reduction of T-cell proliferation, cytokine production, and cytotoxic activity. This results in significant dampening of the immune response. Nivolumab acts to selectively block the receptor activation of PD-L1 and PD-L2, resulting in a release of PD-1 mediated inhibition of the immune response.

DRUGIpilimumab

Ipilimumab is a fully humanized monoclonal anti-CTLA-4 antibody that acts as an antineoplastic ICI by selectively binding to cytotoxic T-lymphocyte-associated antigen 4, a molecule located on the surface of cytotoxic T-cells, suppressing the immune response (17). Ipilimumab blocks CTLA-4, leading to a continuously active immune response in malignant cells.