Platform Study of Immunotherapy Combinations in Colorectal Cancer Liver Metastases

The goal of this clinical trial is to to learn about different combinations of immunotherapy in patients with colorectal cancer whose cancer has spread to their liver and are planning to have surgery to remove tumor metastases from their liver. The main questions it aims to answer are:

• whether these combinations of immunotherapy change the tumor microenvironment in the liver
• whether these combinations of immunotherapy are safe and effective when used in colorectal cancer with liver metastases

Participants will be randomly assigned to one of the following:

• Botensilimab and balstilimab
• Botensilimab, balstilimab, and AGEN1423
• Botensilimab, balstilimab, and radiation

Participants will be asked to come in to receive drug infusions (and radiation, if applicable) before and after their surgical resection. Participants will be followed for up to 2 years.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Colorectal Cancer Metastatic; Liver Metastases
• Intervention / Treatment: Drug: Botensilimab; Drug: Balstilimab; Drug: AGEN1423; Radiation: Radiation

Detailed Description

This is a single-center, 3-arm, randomized, open-label, phase II, screening study to assess the initial immunological changes in the tumor microenvironment in response to treatment with combination immunotherapy (Botensilimab/ Balstilimab), with or without radiation and/or additional TGFβ-CD73 trap, in patients with colorectal cancer liver metastases.

Participants who meet eligibility criteria will be randomized to receive one of 3 investigational treatment: botensilimab + balstilimab (Arm 1); botensilimab + balstilimab + AGEN1423 (Arm 2); or botensilimab + balstilimab + radiation (Arm 3). The study arms are not directly or formally compared with each other. It is established that the tumor infiltrating lymphocytes have been predictive of patient survival following resection of colorectal cancer liver metastases. Immunotherapy combinations with an increase in the ratio of CD8+ T cells: Tregs will be considered for further investigation.

All participants will have a total of four treatment visits to receive immunotherapy infusions. Two visits will occur prior to surgery, each approximately 3 weeks apart. Surgery will be scheduled between day 28-42. After surgery, you will return for two more treatment visits. After the last dose of immunotherapy, participants will come to the clinic approximately 3 weeks and 3 months later for follow-up visits. Participants will be followed remotely for up to two years.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Myriam Elizaire-Williams; Email: mye4001@med.cornell.edu
• Study Contact Backup: Name: Casey Owens; Phone Number: 646-962-6046; Email: cdo4001@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medicine/NewYork-Presbyterian Hospital
      • Contact: Myriam Elizaire-Williams; Email: mye4001@med.cornell.edu
      • Contact: Casey Owens; Phone Number: 646-962-6046; Email: cdo4001@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of metastatic colorectal adenocarcinoma with liver metastases
• Participant must be planning to undergo a surgical resection of their liver metastases.
• Tumor is non-MSI-H/dMMR
• Presence of measurable disease
• Participants must be willing to consent to additional molecular analyses of tumor samples removed during surgery for research purposes
• Women of childbearing potential (WOCBP), or anyone with a uterus, must not be pregnant or breastfeeding. All participants of childbearing potential must agree to use highly effective contraception during this study
• Participants may not receive chemotherapy, growth factor support, transfusions, or albumin administration within 14 days of start of study treatment.

Exclusion Criteria:

• Not eligible for surgery
• Any medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
• Previous allogeneic tissue/organ transplant
• Previously received PD-1, PD-L1, or CTLA-4 therapy including experimental immunologic agents
• Participants must not have any contraindications to immune checkpoint inhibitors
• Participants must not have active autoimmune disease that has required systemic treatment within 2 years prior to registration. Some exceptions are allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Botensilimab and Balstilimab; Two balstilimab infusions will be given prior to surgery and two infusions will be given after surgery, for a total of four doses. Each infusion will be scheduled approximately 3 weeks apart. On the same day as the first and third balstilimab infusions, botensilimab will also be given, for a total of two doses, one before and one after surgery.	Drug: Botensilimab; 75 mg IV Q6W; Other Names: AGEN1181; Drug: Balstilimab; 450 mg IV Q3W; Other Names: AGEN2034
Experimental: Botensilimab, Balstilimab, and AGEN1423; Two balstilimab infusions will be given prior to surgery and two infusions will be given after surgery, for a total of four doses. On the same day as each balstilimab infusion, participants will also receive AGEN1423 infusions, for a total of four doses. Each infusion will be scheduled approximately 3 weeks apart. On the same day as the first and third balstilimab + AGEN1423 infusions, botensilimab will also be given, for a total of two doses, one before and one after surgery.	Drug: Botensilimab; 75 mg IV Q6W; Other Names: AGEN1181; Drug: Balstilimab; 450 mg IV Q3W; Other Names: AGEN2034; Drug: AGEN1423; 30 mg/kg IV Q3W
Experimental: Botensilimab, Balstilimab, and Radiation; Participants will receive 3 doses of radiation prior to surgery. Additionally, two balstilimab infusions will be given prior to surgery and two infusions will be given after surgery, for a total of four doses. Each infusion will be scheduled approximately 3 weeks apart. On the same day as the first and third balstilimab infusions, botensilimab will also be given, for a total of two doses, one before and one after surgery.	Drug: Botensilimab; 75 mg IV Q6W; Other Names: AGEN1181; Drug: Balstilimab; 450 mg IV Q3W; Other Names: AGEN2034; Radiation: Radiation; 8Gy x 3 between Day 0 - 18; Allowed techniques for radiation are 3D conformal, intensity modulated radiotherapy (IMRT), or SBRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean CD8:Treg ratio, as determined by flow cytometry of tumor tissue, at time of surgical resection in each treatment arm	Preliminary immunological response to treatment will be assessed by comparison of the CD8:Treg ratios in tumor tissue obtained during standard of care surgical resection between treatment arms. CD8:Treg ratio will be assessed by flow cytometry	At surgical resection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Response Rate Per Arm	Resected tumors from the liver 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). PR will be defined as at least 50% tumor regression. Pathological response rate will be reported as the number of patients with MPR or PR.	At surgical resection
Radiographic Response Rate Per Arm	Radiographic response will be evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Radiographic response rate will be reported as the number of patients with CR or PR.	90 days following the last dose of study drug
Number of Participants Per Arm with ctDNA Clearance	Circulating tumor DNA (ctDNA) will be assessed at 90 days following the last dose of study drug	90 days following the last dose of study drug
Number of Treatment-Related Adverse Events (TRAEs) as assessed by CTCAE v5.0 per treatment arm	Potentially treatment-related AEs include any AEs that are assessed as possibly, probably, or definitely related to one of the study interventions. AEs will be reported by CTCAE v5.0 term.	90 days following the last dose of study drug

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Agenus Inc.
• Investigators: Principal Investigator: Manish Shah, M.D., Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 29, 2024
• First Submitted That Met QC Criteria: February 29, 2024
• First Posted (Actual): March 8, 2024

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Balstilimab; Botensilimab
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Physical Phenomena; Radiation; balstilimab
• Other Study ID Numbers: 23-06026214

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No