Testing the Combination of Anti-Cancer Drugs, Botensilimab (AGEN1181) and Balstilimab (AGEN2034), After Standard Treatment for Colorectal Cancer, Combat Trial

A Phase 2 Study of Microsatellite Stable Colorectal Cancer (Stage 2 or 3) With Radiographic Occult Molecular Residual Disease Treated With Botensilimab (AGEN1181; Bot) Plus Balstilimab (AGEN2034, Bal) After Established Definitive Therapy (COMBAT Study)

This phase II trial tests the effect of the botensilimab in combination with balstilimab in treating patients with stage II/III colorectal adenocarcinoma with detectable circulating tumor (ct) deoxyribonucleic acid (DNA) in the blood. Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving botensilimab and balstilimab may be an effective combination to remove any remaining microscopic cancer cells in the bloodstream in patients with stage II/III colorectal adenocarcinoma. In addition, clearing the ctDNA from the blood may serve as an early indicator of treatment response.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Adenocarcinoma; Stage III Colorectal Cancer AJCC v8; Stage II Colorectal Cancer AJCC v8
• Intervention / Treatment: Biological: Balstilimab; Biological: Botensilimab; Procedure: Biospecimen Collection; Procedure: Biopsy Procedure; Procedure: Radiographic Examination

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the 6-month circulating tumor DNA (ctDNA) clearance rate following 6 months of therapy with botensilimab (AGEN1181) and balstilimab (AGEN2034) regimen in patients with colorectal cancer (CRC) who present with radiographic occult molecular residual disease (MRD) after completing definitive standard-of-care (SOC) therapy.

SECONDARY OBJECTIVES:

I. To determine the 3-month ctDNA clearance rate following botensilimab (AGEN1181) and balstilimab (AGEN2034) treatment.

II. To determine recurrence-free survival (RFS) at 1-year following 6 months of botensilimab (AGEN1181) and balstilimab (AGEN2034) treatment.

III. To determine overall survival (OS) at 1-year following 6 months of botensilimab (AGEN1181) and balstilimab (AGEN2034) treatment.

IV. To determine the safety and tolerability of botensilimab (AGEN1181) and balstilimab (AGEN2034).

V. To determine if Cancer Immunotherapy Response Classifier (CIRCLE) in archival tumor (using whole exome sequencing [WES]) may predict clinical benefit of botensilimab (AGEN1181) plus balstilimab (AGEN2034) in MRD CRC.

EXPLORATORY OBJECTIVES:

I. To determine changes in profiles of ctDNA (including time to ctDNA negative status, duration of ctDNA negative status, overall ctDNA negative rate, lead time from ctDNA detection to radiographic detection) during and following treatment with botensilimab (AGEN1181) and balstilimab (AGEN2034).

II. To determine baseline characteristics in archival tumor and/or plasma that may predict clinical benefit or lack thereof.

OUTLINE:

Patients receive balstilimab intravenously (IV) over 30 minutes on days 1 and 22 of cycles 1-4 and botensilimab IV over 30 minutes on days 1 of cycles 1 and 2. Treatment repeats every 42 days for up to 4 cycles (6 months) in the absence of disease progression or unacceptable toxicity. Patients also undergo urine and blood sample collection and imaging throughout the study. Additionally, patients may undergo optional tumor tissue biopsy on study.

After completion of study treatment, patients are followed for up to 90 days, every 3 months during the first year, every 4 months during the second year, then every 6 months during the third year unless recurrence of tumor or death occurs.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Recruiting
      • Ochsner Medical Center Jefferson
      • Principal Investigator: Lingling Du
      • Contact: Site Public Contact; Phone Number: 504-842-8084; Email: Elisemarie.curry@ochsner.org
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas MD Anderson Cancer Center LAO
      • Principal Investigator: Kanwal P. Raghav
      • Contact: Kanwal P. Raghav; Email: kpraghav@mdanderson.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of botensilimab (AGEN1181) in combination with balstilimab (AGEN2034) in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (or Karnofsky ≥ 60%)
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 100,000/mcL

• Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN)

  • Patients with documented Gilbert's syndrome may be included if total bilirubin is ≤ 3 x ULN
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN

• Creatinine clearance ≥ 40 mL/min

  • Creatinine clearance (Clcr) can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation
• Histological confirmation of colorectal cancer (adenocarcinoma) (CRC)
• Post-R0 resection of stages II and III CRC and all planned adjuvant therapies have been completed. Patients with rectal cancer who have completed total neoadjuvant therapy and have complete clinical response (cCR) and are on wait-and-watch approach will be permitted as long as they have no radiographic and endoscopic evidence of disease recurrence at the time of enrollment
• No evidence of radiographic disease within 28 days (before or after) of a positive ctDNA assay
• Evident MRD as defined by positive ctDNA (Signatera™ MRD) assay. MRD status will be confirmed with the Signatera™ assay prior to initiation of study therapy. MRD positivity is defined based on testing performed after completion of planned standard treatment (e.g., surgery or chemotherapy), provided assessments occur at least 3 weeks post-surgery (if no adjuvant therapy is planned) and at least 3 weeks after last chemotherapy (if adjuvant therapy is given) to avoid transient false positives. The window from MRD positivity to first dose should be no more than 90 days
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• The effects of botensilimab (AGEN1181) and balstilimab (AGEN2034) on the developing human fetus are unknown. Women of child-bearing potential [refer to MD Anderson (MDA) Policy CLN 1114] must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 4 months after the last dose. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

  • Postmenopausal (no menses in greater than or equal to 12 consecutive months)
  • History of hysterectomy or bilateral salpingo-oophorectomy
  • Ovarian failure (follicle stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy)
  • History of bilateral tubal ligation or another surgical sterilization procedure.)
  • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of administration. In addition, women of childbearing age should not donate egg(s) and men should not donate sperm for the duration of study participation and 6 months after completion of the last dose of botensilimab (AGEN1181) and balstilimab (AGEN2034).
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to botensilimab (AGEN1181) and balstilimab (AGEN2034)
• Patients that are pregnant, breast feeding, or planning to become pregnant while enrolled in the study, up to the end of treatment (EOT) visit, are excluded from this study because botensilimab (AGEN1181) and balstilimab (AGEN2034) are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with botensilimab (AGEN1181) and balstilimab (AGEN2034), breastfeeding should be discontinued if the mother is treated with botensilimab (AGEN1181) and balstilimab (AGEN2034)
• Patients with microsatellite instability (MSI-high) or deficient mismatch repair (dMMR) CRC (MMR/MSI testing is required prior to enrollment)
• Concurrent treatment with a drug with which the interactions are considered clinically significant by the investigator. Major surgical procedure or significant traumatic injury within 21 days before start of study medication * Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Systemic therapy with immunosuppressive agents within 7 days or use of any investigational drug within 28 days before the start of trial treatment
• Prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy for metastatic (m)CRC
• Receipt of any organ transplantation, including allogeneic stem cell transplantation (exception: transplants that do not require immunosuppression, such as hair transplant)
• Patients with active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
• Patients with known severe hypersensitivity reactions to monoclonal antibodies (grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
• Patients with corrected QT interval (QTc) > 470 ms on electrocardiogram (EKG) at screening
• Patients with clinically relevant diseases (for example, inflammatory bowel disease) and / or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair the subject's tolerance or ability to participate in the trial. Stable, well-controlled conditions such as vitiligo, type 1 diabetes, or hypothyroidism on replacement can be allowed
• Failure to recover from any toxicity related to previous anticancer treatment to ≤ grade 1 for toxicities that may overlap with botensilimab (AGEN1181) and balstilimab (AGEN2034) (e.g., diarrhea, cutaneous toxicity) and to ≤ grade 2 for all other toxicities
• Receipt of a live-virus vaccine within 30 days prior to first dose of study drug (seasonal flu vaccines that do not contain live virus are permitted)
• Evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of study drug
• Patients with a history of (non-infectious) pneumonitis that required steroids, ongoing pneumonitis, or history of interstitial lung disease
• Patients with grade >= 3 proteinuria (> 3.5 g/24 hours)
• Patients with grade >= 3 hypertension (systolic blood pressure > 160 or diastolic blood pressure > 100)
• Active autoimmune disease requiring systemic treatment in the past 2 years (e.g., steroids > 10 mg prednisone equivalent, biologics, other immunosuppressants)
• Active or prior inflammatory bowel disease (Crohn's, ulcerative colitis, microscopic colitis). This is especially critical in colon cancer patients where you might otherwise capture inflammatory bowel disease (IBD)-associated CRC

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (balstilimab, botensilimab); Patients receive balstilimab IV over 30 minutes on days 1 and 22 of cycles 1-4 and botensilimab IV over 30 minutes on days 1 of cycles 1 and 2. Treatment repeats every 42 days for up to 4 cycles (6 months) in the absence of disease progression or unacceptable toxicity. Patients also undergo urine and blood sample collection and imaging throughout the study. Additionally, patients may undergo optional tumor tissue biopsy on study.

Biological: Balstilimab; Given IV; Other Names: AGEN2034; AGEN 2034; AGEN-2034; Biological: Botensilimab; Given IV; Other Names: AGEN1181; AGEN 1181; AGEN-1181; Anti-CTLA-4 Monoclonal Antibody AGEN1181; Procedure: Biospecimen Collection; Undergo urine and blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Biopsy Procedure; Undergo tumor tissue biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Procedure: Radiographic Examination; Undergo imaging; Other Names: Radiography; Radiographic Exam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating tumor deoxyribonucleic acid (ctDNA) clearance	Will be defined as clearance of ctDNA and no radiographic evidence of disease. Will estimate clearance rate and its 95% confidence interval.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ctDNA clearance rate	Will evaluate the proportion of all included patients whose ctDNA converts from positive to negative. The proportion is presented together with 90% exact intervals.	At 3 months
Recurrence-free survival (RFS)	Median RFS and 95% confidence intervals will be estimated using the Kaplan-Meier method.	From the start of botensilimab (AGEN1181) and balstilimab (AGEN2034) to recurrence of tumor or death, whichever occurred first, assessed up to 3 years
Overall survival (OS)	Will use Kaplan-Meier methods to evaluate time to event endpoints and will report median OS and its 95% confidence interval.	From the first dose of study treatment to the date of death from any cause, assessed up to 3 years
Incidence and severity of adverse events (AEs)	Severity of AEs will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. toxicity grading scale. Safety will be assessed by descriptive statistics and summarized in tabular format.	Up to 90 days after last dose of study treatment
Determination if Cancer Immunotherapy Response Classifier may predict benefit	Whole exome sequencing data from archival tumor will be acquired and analyzed.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to ctDNA negative status	Summary statistics for biomarkers and their corresponding changes (or percent changes) from baseline will be tabulated by planned study. The time-course of biomarker measures will be investigated graphically. If an indication of meaningful pattern over time under treatment of botensilimab (AGEN1181) and balstilimab (AGEN2034) is observed, further analyses (e.g., by linear mixed model) may be performed to characterize the relationship.	At baseline, during and following treatment, assessed up to 3 years
Duration of ctDNA negative status	Summary statistics for biomarkers and their corresponding changes (or percent changes) from baseline will be tabulated by planned study. The time-course of biomarker measures will be investigated graphically. If an indication of meaningful pattern over time under treatment of botensilimab (AGEN1181) and balstilimab (AGEN2034) is observed, further analyses (e.g., by linear mixed model) may be performed to characterize the relationship.	During and following treatment, assessed up to 3 years
Overall ctDNA negative rate	Summary statistics for biomarkers and their corresponding changes (or percent changes) from baseline will be tabulated by planned study. The time-course of biomarker measures will be investigated graphically. If an indication of meaningful pattern over time under treatment of botensilimab (AGEN1181) and balstilimab (AGEN2034) is observed, further analyses (e.g., by linear mixed model) may be performed to characterize the relationship.	During and following treatment, assessed up to 3 years
Lead time from ctDNA detection to radiographic detection	Summary statistics for biomarkers and their corresponding changes (or percent changes) from baseline will be tabulated by planned study. The time-course of biomarker measures will be investigated graphically. If an indication of meaningful pattern over time under treatment of botensilimab (AGEN1181) and balstilimab (AGEN2034) is observed, further analyses (e.g., by linear mixed model) may be performed to characterize the relationship.	During and following treatment, assessed up to 3 years
Baseline characteristics that may predict clinical benefit or lack thereof	Methods such as, but not limited to, Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards model will be used to explore possible associations between biomarker measures and clinical outcomes.	At baseline

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Kanwal P Raghav, University of Texas MD Anderson Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Estimated): May 25, 2027
• Primary Completion (Estimated): August 28, 2029
• Study Completion (Estimated): August 28, 2029

Study Registration Dates

• First Submitted: April 24, 2026
• First Submitted That Met QC Criteria: April 24, 2026
• First Posted (Actual): April 27, 2026

Study Record Updates

• Last Update Posted (Actual): September 18, 2026
• Last Update Submitted That Met QC Criteria: September 17, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• 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; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Physical Phenomena; Diagnostic Techniques, Surgical; Electromagnetic Phenomena; Magnetic Phenomena; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Biopsy; Specimen Handling; X-Rays; balstilimab
• Other Study ID Numbers: NCI-2026-02784 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186688 (U.S. NIH Grant/Contract); 10741 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No