Platform Study of Immunotherapy Combinations in Colorectal Cancer Liver Metastases
- Conditions
- Liver MetastasesColorectal CancerColorectal Cancer Metastatic
- Interventions
- Registration Number
- NCT06300463
- Lead Sponsor
- Weill Medical College of Cornell University
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 24
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Botensilimab and Balstilimab 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. Botensilimab, Balstilimab, and Radiation 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. Botensilimab, Balstilimab, and AGEN1423 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. Botensilimab and Balstilimab Botensilimab 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. Botensilimab, Balstilimab, and AGEN1423 Botensilimab 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. Botensilimab, Balstilimab, and Radiation Botensilimab 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. Botensilimab, Balstilimab, and AGEN1423 Balstilimab 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. Botensilimab, Balstilimab, and Radiation Balstilimab 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.
- Primary Outcome Measures
Name Time Method Mean CD8:Treg ratio, as determined by flow cytometry of tumor tissue, at time of surgical resection in each treatment arm At surgical resection 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
- Secondary Outcome Measures
Name Time Method Radiographic Response Rate Per Arm 90 days following the last dose of study drug 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.
Number of Treatment-Related Adverse Events (TRAEs) as assessed by CTCAE v5.0 per treatment arm 90 days following the last dose of study drug 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.
Pathological Response Rate Per Arm At surgical resection 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.
Number of Participants Per Arm with ctDNA Clearance 90 days following the last dose of study drug Circulating tumor DNA (ctDNA) will be assessed at 90 days following the last dose of study drug
Trial Locations
- Locations (1)
Weill Cornell Medicine/NewYork-Presbyterian Hospital
🇺🇸New York, New York, United States