Overview
The goal of this clinical trial is to learn whether the combination of balstilimab, botensilimab, and agenT-797 is safe and effective in treating adults with previously treated metastatic colorectal cancer that is microsatellite stable (pMMR) and has spread to the liver.
The main questions it aims to answer are:
- What proportion of participants experience tumor shrinkage (objective response rate) based on imaging assessments?
- What side effects occur with this combination treatment, including immune-related and cytokine-related reactions?
All participants in this study will receive the combination treatment. There is no comparison group.
Participants will:
- Receive balstilimab, botensilimab, and agenT-797 in repeating 42-day treatment cycles
- Undergo imaging scans (such as CT or MRI) to assess tumor response
- Have blood samples collected to monitor safety and evaluate biomarkers
- Provide tumor tissue samples for research
- Be monitored for side effects throughout the study
- Participate in follow-up visits to assess survival after treatment completion
Description
This is a Phase II, single-arm, investigator-sponsored clinical trial evaluating the safety and efficacy of the combination of balstilimab (anti-PD-1), botensilimab (Fc-enhanced anti-CTLA-4), and agenT-797 (allogeneic invariant natural killer T \[iNKT\] cell therapy) in patients with previously treated microsatellite stable (pMMR) metastatic colorectal cancer with liver metastases.
Patients with pMMR/MSS metastatic colorectal cancer derive limited benefit from currently available immunotherapy approaches. The liver tumor microenvironment is associated with immune tolerance and resistance to checkpoint blockade. This study is designed to evaluate whether combining dual checkpoint inhibition with cellular therapy can enhance anti-tumor immune responses and improve clinical outcomes in this population.
The primary objective of the study is to evaluate the objective response rate (ORR) as assessed by RECIST v1.1. Secondary objectives include evaluation of safety and tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives include assessment of biomarkers such as circulating tumor DNA (ctDNA), tumor markers, and immune-related correlates.
Participants will receive combination treatment in 42-day cycles for up to nine cycles or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. Balstilimab and botensilimab will be administered in combination with agenT-797 according to the study protocol.
Tumor assessments will be performed using CT or MRI at regular intervals to evaluate response per RECIST v1.1. Safety will be monitored throughout the study through assessment of adverse events, laboratory evaluations, and clinical examinations, with particular attention to immune-mediated and cytokine-related toxicities.
Blood samples will be collected for safety monitoring and exploratory biomarker analyses, including ctDNA and immune profiling. Archival tumor tissue will be collected when available, and on-study biopsies may be obtained to support correlative research.
Following completion of study treatment, participants will undergo a safety follow-up period and will be followed for survival at regular intervals.
Eligibility
Inclusion Criteria:
- Adults ≥18 years of age with histologically confirmed metastatic colorectal cancer with liver metastases, including evidence of active liver disease if previously treated locally
- At least one measurable lesion per RECIST v1.1, with ≥1 target lesion in the liver
- Tumor confirmed as microsatellite stable (MSS)/proficient mismatch repair (pMMR) per a FDA-approved assay (Caris MI Cancer Seek®, FoundationOne® CDx, or Tempus xT CDx).
- Received ≥1 prior line of systemic therapy including fluorouracil, oxaliplatin, and irinotecan (not necessarily in combination), and prior EGFR inhibitor or bevacizumab if eligible, unless contraindicated
- ECOG performance status 0-1 and life expectancy ≥12 weeks
- Adequate organ and marrow function:
- ANC ≥1.5 × 10⁹/L
- Platelets ≥100 × 10⁹/L
- Hemoglobin ≥ 9 g/dL
- AST/ALT ≤2.5 × ULN
- Total bilirubin ≤1.5 × ULN
- Creatinine clearance ≥ 40 mL/min, as measured or calculated per local institutional standards.
- Albumin ≥3 g/dL
- PT/PTT ≤1.5 × ULN
- Willing and able to provide written informed consent
- Negative pregnancy test for women of childbearing potential
- Agreement to use effective contraception during study participation
Exclusion Criteria:
- Tumor is dMMR/MSI-high
- Prior treatment with PD-1, PD-L1, CTLA-4 inhibitors, or other immunotherapy agents
- Evidence of bowel obstruction, impending obstruction, or recent obstruction (within 3 months)
- Refractory ascites requiring frequent paracentesis or recent escalation of diuretics
- Clinically significant cardiovascular disease (e.g., recent myocardial infarction or stroke, unstable angina, NYHA class ≥III heart failure, uncontrolled arrhythmias) or QTc \>480 ms
- Active or untreated brain metastases or leptomeningeal disease
- Concurrent malignancy requiring treatment or active within 2 years (with protocol-specified exceptions)
- Receipt of prior anti-cancer therapy within protocol-defined washout periods, including:
- Cytotoxic, targeted therapy or other investigational therapy within 3 weeks.
- Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar therapy, within 4 weeks, or 5 half-lives, whichever is shorter.
- Small molecules/tyrosine kinase inhibitors within 2 weeks or less than 5 circulating half-lives of investigational drug.
- Known hypersensitivity to study drugs or excipients
- History of or active interstitial lung disease or pneumonitis requiring systemic steroids
- Prior allogeneic transplant (organ, stem cell, or bone marrow)
- Active or recent autoimmune disease requiring systemic treatment
- Requirement for systemic corticosteroids (\>10 mg prednisone equivalent) or other immunosuppressive therapy within defined windows
- Active infection, including HIV, HTLV, HBV, HCV, or other infections requiring systemic therapy
- Recent SARS-CoV-2 infection within protocol-defined timeframe
- Uncontrolled hypertension, significant proteinuria (UPCR ≥1 g/g), or other clinically significant uncontrolled medical conditions
- Non-healing wounds, active bleeding, or uncontrolled thyroid dysfunction
- Psychiatric or substance use disorders that may interfere with study participation
- Receipt of live or attenuated vaccines within 30 days prior to treatment and while participating in the study
- Pregnant or breastfeeding women, or those planning pregnancy during the study
