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Immunotherapy in Patients With Early dMMR Rectal Cancer (RESET-R)

Primary Purpose

Cancer of Rectum

Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Nivolumab
Ipilimumab
Sponsored by
Odense University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cancer of Rectum

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Department of Oncology, Odense University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

nivolumab + ipilimumab

Arm Description

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

Outcomes

Primary Outcome Measures

Complete clinical response
Proportion of patients with clinical complete response

Secondary Outcome Measures

Proportion of patients with complete biological response
Proportion of patients without any sign of recurrence after 12 months.
Response rate according to mrTRG.
Adverse events
Correlation between bio-markers (ctDNA and CEA) and outcome.
Change in Quality of life (EORCT QLQ-C30)
Change in Quality of life (EORCT QLQ-CR29)

Full Information

First Posted
January 17, 2023
Last Updated
August 9, 2023
Sponsor
Odense University Hospital
Collaborators
Rigshospitalet, Denmark, Zealand University Hospital, Aalborg University Hospital, Aarhus University Hospital, Bispebjerg Hospital, Herlev and Gentofte Hospital, Vejle Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05732389
Brief Title
Immunotherapy in Patients With Early dMMR Rectal Cancer
Acronym
RESET-R
Official Title
Immunotherapy in Patients With Early dMMR Rectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 1, 2023 (Actual)
Primary Completion Date
February 2025 (Anticipated)
Study Completion Date
February 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Odense University Hospital
Collaborators
Rigshospitalet, Denmark, Zealand University Hospital, Aalborg University Hospital, Aarhus University Hospital, Bispebjerg Hospital, Herlev and Gentofte Hospital, Vejle Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer of Rectum

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
nivolumab + ipilimumab
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Intervention Description
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.
Primary Outcome Measure Information:
Title
Complete clinical response
Description
Proportion of patients with clinical complete response
Time Frame
Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks)
Secondary Outcome Measure Information:
Title
Proportion of patients with complete biological response
Time Frame
Evaluated at day 93 (+/- 7 days) after one or two cycles of immunotherapy. (Each cycle is 7 weeks)
Title
Proportion of patients without any sign of recurrence after 12 months.
Time Frame
after 12 months
Title
Response rate according to mrTRG.
Time Frame
after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks)
Title
Adverse events
Time Frame
after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)
Title
Correlation between bio-markers (ctDNA and CEA) and outcome.
Time Frame
after 1 or 2 cycles of immunotherapy. (Each cycle is 7 weeks)
Title
Change in Quality of life (EORCT QLQ-C30)
Time Frame
after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)
Title
Change in Quality of life (EORCT QLQ-CR29)
Time Frame
after 1 or 2 cycles of immunotherapy and months 4, 10, 16, and 24. (Each cycle is 7 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christian P Olsen, Phd
Phone
24342488
Email
Christian.pilely.olsen@rsyd.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Line S Tarpgaard, MD, Phd
Organizational Affiliation
Department of Oncology, Odense University Hospital, Denmark
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Oncology, Odense University Hospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Line S Tarpgarrd, MD
Phone
+45 6541 2921
Email
line.tarpgaard@rsyd.dk
First Name & Middle Initial & Last Name & Degree
Line S Tarpgarrd, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Immunotherapy in Patients With Early dMMR Rectal Cancer

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