Botensilimab and Balstilimab for the Treatment of Colorectal Cancer in Patients with Persistent Circulating Tumor Deoxyribonucleic Acid following Surgery and Chemotherapy
This phase II trial studies how well botensilimab with balstilimab followed by balstilimab alone works in treating patients with colorectal cancer and persistent circulating tumor deoxyribonucleic acid (ctDNA) following surgery and chemotherapy. Botensilimab is a type of drug called a CTLA-4 inhibitor and balstilimab is a type of drug called a programmed cell death protein 1 (PD-1) inhibitor. The CTLA-4 and PD-1 proteins act as a “brake” on the immune system. Blocking these proteins is like releasing the brakes, so the immune system can target tumor cells and destroy them. Botensilimab and balstilimab treatment is a type of treatment called immunotherapy (treatment that boosts the body’s natural defenses to fight cancer). Because botensilimab and balstilimab treatment blocks 2 proteins, it may work better than treatment with other CTLA-4 or PD-1 inhibitors that target only one. Giving botensilimab with balstilimab followed by balstilimab alone may be more effective in treating patients with colorectal cancer and persistent ctDNA following surgery and chemotherapy.
Inclusion Criteria
- Subject or legally authorized representative, is willing and able to provide written informed consent
- Histologically- or cytologically- confirmed colorectal cancer
- ≥ 18 years of age on day of signing informed consent
- Consent for use of archival tissue and blood draws for research purposes
- Performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
- Known non-MSI-H/pMMR by immunohistochemistry (IHC), polymerase chain reaction (PCR) or next generation sequencing (NGS) testing. Memorial Sloan Kettering Cancer Center (MSKCC) confirmation of non-MSI-H/pMMR status is not mandatory prior to enrollment and treatment on the study. For patients with outside testing, if sufficient tissue is available testing may be repeated at MSKCC and will not impact initial eligibility
- Consent to undergo Memorial Sloan Kettering (MSK) IMPACT or NGS, if not previously done
- Disease specific criteria: * Cohorts 1a and 2a: Undergone a complete surgical resection (R0) for stage III colon cancer, followed by adjuvant chemotherapy with fluorouracil, leucovorin calcium, oxaliplatin (FOLFOX) or capecitabine, oxaliplatin (CAPEOX) * Cohorts 1b and 2b: Undergone a complete surgical resection (R0) for liver metastasis (ablation or stereotactic body radiation therapy [SBRT], but not yttrium Y-90 [Y-90], is permitted) and completed standard peri-operative chemotherapy. Peri-operative chemotherapy not required if received previous oxaliplatin-based therapy. Prior floxuridine via hepatic arterial infusion pump is permitted. Completed definitive treatment for the primary tumor including (R0) resection, or total neoadjuvant therapy for rectal cancer with complete clinical and radiographic response
- Positive ctDNA following completion of appropriate standard of care therapy. Note, if ctDNA has a negative result, ctDNA can be re-tested within 6 months of completion of standard therapy
- Patients must sign informed consent within 4 weeks of positive ctDNA result. The 4 weeks is considered from the date that the ctDNA is resulted, and not the date it is drawn
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 75,000/mm^3
- Hemoglobin ≥ 9.0 g/dL
- Creatinine clearance (CrCl) ≥ 60 mL/min
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)
- Bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN
- Subjects of childbearing potential (or with partners of childbearing potential) must use effective contraception for the course of the study starting with the screening visit through at least 5 months after the last dose of study treatment. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom)
Exclusion Criteria
- Presence of metastatic or recurrent disease
- Known deoxyribonucleic acid (DNA) polymerase epsilon (POLE) or DNA polymerase delta (POLD) activating mutation
- R1 (microscopic residual tumor) or R2 resection (macroscopic residual tumor at resection margin)
- Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment * Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., dexamethasone containing antiemetic regimen or steroids as CT scan contrast premedication) may be enrolled * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- Hypersensitivity to botensilimab or balstilimab or any of its excipients
- Chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- History of, or any evidence of active, non-infectious pneumonitis
- Active infection requiring systemic therapy
- Current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 90 days after the last dose of trial treatment
- Prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 agent
- Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs). The following are exceptions: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
- Known active TB (Bacillus tuberculosis)
- Uncontrolled infection with human immunodeficiency virus (HIV). Patients on stable highly active antiretroviral therapy with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required
- Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Patients who are receiving or who have received anti-HBV therapy and have undetectable HBV DNA prior to study entry are eligible. Serological testing for HBV at screening is not required
- Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for HCV at screening is not required
- Received a live vaccine within 30 days of planned start of study therapy
Additional locations may be listed on ClinicalTrials.gov for NCT07227636.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
PRIMARY OBJECTIVES:
I. To determine the rate of ctDNA clearance at 6 months in patients with non-microsatellite instability-high (MSI-H)/mismatch repair protein proficient (pMMR) stage III colon cancer after surgery and chemotherapy with minimal residual disease (MRD), following treatment with botensilimab and balstilimab. (Part 1 Cohort 1a)
II. To determine the rate of ctDNA clearance at 6 months in patients with non-MSI-H/pMMR colorectal liver metastases (CRLM) after surgery and peri-operative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1b)
III. To compare recurrence-free survival (RFS) in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab versus placebo. (Part 2 Cohort 2a)
IV. To compare RFS in patients with non-MSI-H/pMMR CRLM after surgery and perioperative chemotherapy with MRD, following treatment with botensilimab and balstilimab versus placebo. (Part 2 Cohort 2b)
SECONDARY OBJECTIVES:
I. To assess median RFS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1a)
II. To assess 2-year RFS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1a)
III. To assess 3-year RFS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and peri-operative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1a)\
IV. To assess median overall survival (OS) in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1a)
V. To assess safety and tolerability of botensilimab plus balstilimab. (Part 1 Cohort 1a)
VI. To assess median RFS in patients with non-MSI-H/pMMR CRLM after surgery and peri-operative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1b)
VII. To assess 2-year RFS in patients with non-MSI-H/pMMR CRLM after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1b)
VIII. To assess 3-year RFS in patients with non-MSI-H/pMMR CRLM after surgery and perioperative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1b)
IX. To assess median OS in patients with non-MSI-H/pMMR CRLM after surgery and perioperative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 Cohort 1b)
X. To assess safety and tolerability of botensilimab plus balstilimab. (Part 1 Cohort 1b)
XI. To compare the rate of ctDNA clearance at 6 months in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab versus placebo. (Part 2 Cohort 2a)
XII. To assess median RFS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab compared to placebo. (Part 2 Cohort 2a)
XIII. To assess 2-year RFS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 2 Cohort 2a)
XIV. To assess 3-year RFS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and peri-operative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 2 Cohort 2a)
XV. To assess median OS in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab compared to placebo. (Part 2 Cohort 2a)
XVI. To assess safety and tolerability of botensilimab plus balstilimab. (Part 2 Cohort 2a)
XVII. To compare the rate of ctDNA clearance at 6 months in patients with non-MSI-H/pMMR CRLM after surgery and peri-operative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 2 Cohort 2b)
XVIII. To assess median RFS in patients with non-MSI-H/pMMR CRLM after surgery and peri-operative chemotherapy with MRD, following treatment with botensilimab and balstilimab compared to placebo. (Part 2 Cohort 2b)
XIX. To assess 2-year RFS in patients with non-MSI-H/pMMR CRLM after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 2 Cohort 2b)
XX. To assess 3-year RFS in patients with non-MSI-H/pMMR CRLM after surgery and perioperative chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 2 Cohort 2b)
XXI. To assess median OS in patients with non-MSI-H/pMMR CRLM after surgery and perioperative chemotherapy with MRD, following treatment with botensilimab and balstilimab compared to placebo. (Part 2 Cohort 2b)
XXII. To assess safety and tolerability of botensilimab plus balstilimab. (Part 2 Cohort 2b)
EXPLORATORY OBJECTIVES:
I. To correlate tumor and genomics characteristics, and immune cell repertoire status with ctDNA clearance in patients with non-MSI-H/pMMR stage III colon cancer after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 and Part 2)
II. To correlate baseline tumor characteristic and immune cell repertoire status with ctDNA clearance in patients with non-MSI-H/pMMR CRLM after surgery and chemotherapy with MRD, following treatment with botensilimab and balstilimab. (Part 1 and Part 2)
OUTLINE: Patients are assigned to 1 of 2 parts.
PART 1 COHORTS 1A AND 1B: Patients receive botensilimab intravenously (IV) over 30 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to an additional 4 cycles in the absence of disease progression of unacceptable toxicity.
PART 2 COHORTS 2A AND 2B: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive botensilimab and balstilimab treatment followed by balstilimab treatment alone as in Part 1 in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive botensilimab placebo IV over 30 minutes on day 1 of each cycle and balstilimab placebo IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive balstilimab placebo IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to an additional 4 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, all patients undergo blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo colonoscopy during follow up.
After completion of study treatment, patients are followed up at 7, 30, and 90 days and then every 3 months for up to 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorNeil Howard Segal
- Primary ID25-132
- Secondary IDsNCI-2025-08584
- ClinicalTrials.gov IDNCT07227636