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)

Official Summary

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.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 20 participants

Study Arms

• Treatment (balstilimab, botensilimab) (EXPERIMENTAL)
  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.

Interventions

• BIOLOGICAL: Balstilimab — Given IV
• PROCEDURE: Biopsy Procedure — Undergo tumor tissue biopsy
• PROCEDURE: Biospecimen Collection — Undergo urine and blood sample collection
• BIOLOGICAL: Botensilimab — Given IV
• PROCEDURE: Radiographic Examination — Undergo imaging

Primary Outcomes

• Circulating tumor deoxyribonucleic acid (ctDNA) clearance (Up to 6 months)

Secondary Outcomes

• ctDNA clearance rate (At 3 months)
• Recurrence-free survival (RFS) (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) (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) (Up to 90 days after last dose of study treatment)
• Determination if Cancer Immunotherapy Response Classifier may predict benefit (Up to 3 years)

Eligibility Criteria

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
* 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 therapy. The MRD status should be assessed at least 4 weeks post-surgery and at least 3 weeks after last chemo 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 Officials

• Kanwal P Raghav — PRINCIPAL_INVESTIGATOR
  University of Texas MD Anderson Cancer Center LAO

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