Immunotherapy in Patients With Early dMMR Rectal Cancer

Study Overview
=================
Brief Summary
-----------------
Colorectal cancer (CRC) is the third most common cancer (1.8 million cases) and the third most common cause of cancer-related death (0.8 million deaths) worldwide in 2018, and rectal cancer accounts for roughly one-third of CRC. The main curative treatment modality for patients with rectal cancer is surgery, often combined with chemotherapy and/or radiotherapy (RT). The global recognition of total mesorectal excision (TME), that decreased locoregional recurrence (LRR) by itself, questioned the need for radiotherapy (RT) before or after surgery. Several randomized trials have demonstrated the importance of preoperative RT (short course RT or long course chemo-radiotherapy (CRT)) in reducing LRR, in patients with high-risk rectal cancer. However, RT or CRT does not improve overall survival, and in addition neoadjuvant RT/CRT followed by TME is associated with perioperative morbidity and the risk is increasing with age. Therefore, ongoing trials are testing other strategies, such as the omission of (C)RT or even avoidance of surgery. In May 2022, a presentation with simultaneous NEJM publication showed that 14/14 patients with dMMR rectal cancer obtained complete response after six months (9 cycles every 3 weeks) of immunotherapy (dostarlimab). Thus, the investigators have now become confident that immunotherapy without surgery will be the new standard, and the investigators will recommend a W&W strategy in patients with rectal cancer obtaining major tumor shrinkage and these patients will be followed carefully with clinical and molecular evaluation (which was not part of the NEJM paper). No patient in the NEJM paper had progressive disease and therefore the investigators recommend a second cycle of immunotherapy (instead of resection in unclear cases) and re-evaluation. The investigators are confident that 1 or 2 cycles of immunotherapy will result in complete radiological, pathological, and molecular response in a substantial number of patients and this short duration of therapy will reduce toxicity and especially drug costs. In conclusion, immunotherapy in patients with dMMR CRC tumors may completely eradicate the primary cancer and regional lymph nodes leading to a possibility for organ-sparing medical treatments, and the investigators are confident that this new strategy of 1 or 2 cycles of immunotherapy will be the future standard of care, and in Denmark the investigators have the chance to monitor these patients closely with clinical and high-level molecular follow-up.

Official Title
-----------------
Immunotherapy in Patients With Early dMMR Rectal Cancer

Conditions
-----------------
Cancer of Rectum

Intervention / Treatment
-----------------
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nivolumab + ipilimumab<br>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 | Drug: Nivolumab<br>* 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.<br>Drug: Ipilimumab<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete clinical response | Proportion of patients with clinical complete response | Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with complete biological response |  | Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks) | 
| Proportion of patients without any sign of recurrence after 12 months. |  | after 12 months | 
| Response rate according to mrTRG. |  | after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks) | 
| Adverse events |  | after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks) | 
| Correlation between bio-markers (ctDNA and CEA) and outcome. |  | after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks) | 
| Change in Quality of life (EORCT QLQ-C30) |  | after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks) | 
| Change in Quality of life (EORCT QLQ-CR29) |  | after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks) |