Cancer of Rectum
Conditions
Brief 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
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.
Sponsors
Rigshospitalet, Denmark
Zealand University Hospital
Aalborg University Hospital
Aarhus University Hospital
Bispebjerg Hospital
Herlev and Gentofte Hospital
Vejle Hospital
Odense University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete clinical response | Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks) | Proportion of patients with complete clinical response Complete clinical response will be defined as no visible or palpable tumor examined by rectal exploration (if low tumors), endoscopy and MR-scan. Patients with definite but less than complete regression BUT with a representative biopsy without viable tumor cells will also be classified as cCR in this trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete biological response | Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks) | Proportion of patients with complete biological response |
| 12 months recurrence | after 12 months | Proportion of patients without any sign of recurrence after 12 months. |
| Respons rate | after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks) | Response rate according to mrTRG. |
| 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) | Change in Quality of life (EORCT QLQ-CR29) |
| Bio-marker predictive models for treatment response and survival. | after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks) | Correlation between bio-markers (ctDNA and CEA) and outcome. |
| 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-C30) |
| Adverse events | after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks) | Adverse events assessed by the investigator according to the definitions in NCI-CTC, version 5.0 |
Countries
Denmark
Contacts
Primary ContactJulie Bach
Backup ContactChristian P Olsen, Phd
Outcome results
None listed