Combination Immunotherapy in Colorectal Cancer

Phase 2Active Not RecruitingNCT05571293

Weill Medical College of Cornell University26 enrolled

Overview

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. This study has 3 cohorts. Participants in Cohort A will receive a total of 2 doses of balstilimab and a single dose of botensilimab, both given intravenously (IV), before surgery. Participants in Cohort B and C will receive a total of 4 doses of balstilimab and a single dose of botensilimab, both given intravenously (IV), before surgery. Participants in Cohort C must have dMMR/MSI-High colorectal cancer.

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, open-label, pilot study in which patients will receive 2 or 4 doses of intravenous (IV) balstilimab (each dose approximately 2 weeks apart), and a single dose of botensilimab IV, prior to resection in patients with colon cancer. Following surgical resection, participants will return to the clinic for 1-2 post-op follow-up visits.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 18 years of age or older * Histologically, cytologically, or clinically confirmed adenocarcinoma of the colon or rectal cancer as long as there is no plans for neoadjuvant radiation for the patients with rectal cancer. Note: patients can enroll in cohort B while awaiting mismatch repair testing results. If noted to be dMMR/MSI-High, they would be still considered evaluable and moved to cohort C. * 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 Participants in Cohort C must be dMMR/MSI-High.

Outcomes

Primary Outcomes

Cohort A and B: Pathological Overall Response (pOR) Rate Determined by Analysis of Tissue Resected During Surgery Reported by Cohort

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.

Time frame: Immediately following surgical resection of the primary tumor

Cohort A: Number of Participants Who Experience Potentially Treatment-related SAEs According to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at 90 Days Following the Last Treatment With Balstilimab or Botensilimab

Safety will be assessed by evaluation of the number of participants experiencing SAEs according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at 90 days post-the last dose of study drug. Grade 3 or 4 adverse event possibly, probably or definitely attributed to bot/bal. Patients from cohorts B and C were not included in the analysis of this outcome measure per study protocol.

Time frame: From date of last dose of study drug up to 90 days after

Cohort A: Number of Participants Who Experience Treatment-related Complications Leading to Delays of 12 Weeks or More in Surgery After Treatment Initiation (Day 0)

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.

Time frame: 12 weeks after treatment initiation date (Day 0)

Cohort C: Composite Rate of Clinical Complete Response or Major Pathological Response at 6 Months

The joint patient-surgeon decision to defer surgery for a watch and wait (Watch-\&-Wait W\&W) approach is allowed as long as the patient is demonstrating sustained response as determined by clinical, radiographic, endoscopic, and/or blood-based biomarkers. For participants who elect to undergo surgery, pathological response will be determined as described above. The key endpoint here will be "Major pathological response (MPR; CR + near-CR). Patients who opt for non-operative management based on clinical response will be considered to have CR. Complete response will be determined by the treating physician and surgeon based on composite subjective and objective assessments of clinical, radiographic, endoscopic, blood-based biomarker assessments, and/or the absence of clinical and radiographic progression.

Time frame: 6 months

Secondary Outcomes

All Cohorts: Changes in Minimal Residual Disease Assessed Using ctDNA Pre- and 30 Days Post-surgical Resection

Summary statistics including mean, standard deviation 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.

Time frame: Immediately prior to initiation of therapy and 30 days following surgical resection