Combination Immunotherapy in Colorectal Cancer

Study Overview
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Brief Summary
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This is a pilot study to see whether a combination of two investigational drugs that target the immune system can be given to people with colorectal cancer before surgically removing the tumor. This study is also being done to see what side effects this combination of drugs has and what effect they have on colorectal cancer. The two monoclonal antibodies are balstilimab, a programmed cell death protein 1 (PD-1) inhibitor, and botensilimab, a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor. Participants will receive a dose of balstilimab and botensilimab, both given intravenously (IV), followed by a second dose of balstilimab approximately 2 weeks after the first dose. Both doses of balstilimab and the single dose of botensilimab will be given during an 8 weeks period before surgery.

Detailed Description
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This is a pilot study to assess the feasibility, safety, and efficacy of using a combination of a programmed cell death protein 1 (PD-1) inhibitor (balstilimab) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor (botensilimab) in the neoadjuvant setting in patients with colorectal cancer, prior to resection. This is a single-center, single-arm, open-label, pilot study in which patients will receive 2 doses of intravenous (IV) balstilimab (each dose approximately 2 weeks apart), and a single dose of botensilimab IV, within 8 weeks prior to resection in patients with colon cancer. Following surgical resection, participants will return to the clinic for 2 follow-up visits. Follow-up visit 1 will occur 1-3 weeks post-op (+/- 7 days), and follow-up visit 2 (+/- 7 days) will occur 4-6 weeks post-op.

Official Title
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Novel Exploratory Study to Test Combination of Botensilimab and Balstilimab Immunotherapy in Resectable Colorectal Cancer Patients

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Botensilimab
* Drug: Balstilimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Stage 1-3 adenocarcinoma of the colon with plans to have a surgical resection If capable of becoming pregnant, or getting someone else pregnant, must be willing to use highly effective contraception from Screening period through 90 days following the last dose of study drug Exclusion Criteria: Metastatic cancer (cancer that has spread to other parts of the body) Previous treatment with immune checkpoint inhibitors targeting CTLA-4, PD-1 or PD-L1 Currently participating in another study and receiving a study drug History of severe allergic reactions to immunotherapies Pregnant or breastfeeding Active infection requiring treatment On immunosuppressive medications Active cardiovascular disease, such as stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure, or serious uncontrolled cardiac arrhythmia requiring medication that may prevent surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Botensilimab and balstilimab (bot/bal)<br>Botensilimab and balstilimab are both monoclonal antibodies that are administered intravenously. A single dose of botensilimab (75 mg IV), and two doses of balstilimab (240 mg IV), will be administered on the same day. A second dose of balstilimab (240 mg IV) will be administered 14 days later (-2 +5 days). Surgical resection will occur 1-6 weeks following the second dose of balstilimab. | Drug: Botensilimab<br>* Botensilimab, a CTLA-4 inhibitor, will be administered prior to surgical resection as described in the arm description.<br>Drug: Balstilimab<br>* Balstilimab, a PD-1 inhibitor, will be administered prior to surgical resection as described in the arm description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological overall response (pOR) rate determined by analysis of tissue resected during surgery | Resected tumors will be examined in their entirety, and regression of resected tumors was assessed by estimating the percentage of residual viable tumor of the macroscopically identifiable tumor bed, as identified on routine hematoxylin and eosin (H&E) staining. In addition, regression will be classified using the Mandard tumor regression grading system. Major pathologic response (MPR) will be defined as ≤10% of residual viable tumor cells (or ≥ 90% response), corresponding to Mandard tumor regression grade 1 (CR) or 2 (near-CR). PR will be defined as at least 50% tumor regression. However, considering the lack of consensus on the definition of PR after immunotherapy, tumors with >50% and <90% residual viable tumor will be labeled accordingly as '10-50% tumor regression', as per the NICHE study (Chalabi et. al., 2020). When analyzing pMMR responders versus pMMR nonresponders, this subgroup will be included in the group of nonresponders. | Day 30 | 
| Number of Adverse Events | Safety will be assessed by evaluation of the number of AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at 90 days post-the last dose of study drug | Day 105 | 
| Number of Serious Adverse Events | Safety will be assessed by evaluation of the number of SAEs according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at 90 days post-the last dose of study drug | Day 105 | 
| Number of complications leading to delays of 12 weeks or more in surgery after initiation of treatment | Any AEs or SAEs that lead to a delay in surgery greater than 12 weeks from treatment initiation (Day 0) will be recorded. If there are ≥ 2 patients out of the first 6 patients, or ≥ 4 patients out of the full 12 participants (≥33%), with AEs/SAEs that lead to a delay in surgery beyond 12 weeks from treatment initiation, with the exception of COVID-related procedural delays, then this combination of botensilimab and balstilimab, at these dosages will not be considered feasible in this population. | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Minimal Residual Disease assessed using ctDNA pre- and post-surgical resection | Summary statistics including mean, standard deviation, median, and range will be provided for ctDNA levels obtained at various time points. Linear mixed-effects models will be used to model longitudinal biomarker values. Simultaneous testing of general linear hypotheses will be used to evaluate contrasts of interest. | Baseline, Day 0, Day 14, Day 45, Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Colorectal Cancer, PD-1, CTLA-4