BAL/BOT/agenT-797 in pMMR CRC With Liver Metastases

Официальное название

A Single-Arm, Phase II Study Evaluating Combination Balstilimab Plus Botensilimab With AgenT-797 in Previously Treated Patients With pMMR Metastatic CRC With Liver Metastases

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат Balstilimab (BAL)
  Administered at a fixed dose of 240mg intravenously (IV) on Days 1, 15, 29 of each 42-day cycle, for up to 9 cycles.
• Препарат Botensilimab (BOT)
  Administered at a fixed dose of 75mg IV on Day 1 of Cycles 1 through 4. In the event of protocol-defined toxicity, the dose may be reduced to 50mg IV per protocol defined criteria.
• Препарат agenT-797
  Administered at a dose of 1.4 x 107 cells/kg IV on Day 1 of Cycle 1 and Day 15 of Cycle 2.

Первичные конечные точки

• Overall Response Rate (ORR) [Срок оценки: From enrollment until first documented disease progression or end of study treatment (up to approximately 12 months).]

Вторичные конечные точки (7)

• Overall response rate in liver metastasis (ORLM) [Срок оценки: From enrollment until first documented disease progression or end of study treatment (up to approximately 12 months).]
• Progression free survival (PFS) at 6 months (PFS6) [Срок оценки: At 6 months from enrollment]
• Progression Free Survival (PFS) at 12 months (PFS12) [Срок оценки: At 12 months from enrollment]
• Overall Survival (OS) [Срок оценки: From enrollment until death from any cause]
• Time to Tumor Response (TTR) [Срок оценки: From enrollment until first documented complete (CR) or partial response (CR) per RECIST v1.1 (up to approximately 12 months).]
• Duration of Response (DOR) [Срок оценки: From date of first documented CR or PR per RECIST v1.1 to date of disease progression or death from any cause, whichever occurs first (up to approximately 12 months).]
• Biochemical response (CEA and/or CA 19-9) [Срок оценки: From enrollment until completion of biomarker assessments (up to approximately 12 months).]

Критерии участия

Критерии включения

• 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)
• 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 ≥8 g/dL
• AST/ALT ≤2.5 × ULN
• Total bilirubin ≤1.5 × ULN
• Creatinine clearance ≥30 mL/min
• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Scripps Clinic Torrey Pines — La Jolla

Публикации

• Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Kaer LV. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol. 2009 Mar 1;182(5):2816-26. doi: 10.4049/jimmunol.0803648. PMID 19234176
• Andre T, Elez E, Lenz HJ, Jensen LH, Touchefeu Y, Van Cutsem E, Garcia-Carbonero R, Tougeron D, Mendez GA, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Manzano Mozo JL, Dahan L, Tortora G, Chalabi M, Goekkurt E, Braghiroli MI, Joshi R, Cil T, Aubin F, Cela E, Chen T, Lei M, Jin L, Blum SI, Lonardi S. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high meta PMID 39874977
• Liu Y, Wang G, Chai D, Dang Y, Zheng J, Li H. iNKT: A new avenue for CAR-based cancer immunotherapy. Transl Oncol. 2022 Mar;17:101342. doi: 10.1016/j.tranon.2022.101342. Epub 2022 Jan 18. PMID 35063813
• Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol. 2023 Feb 10;14:1133308. doi: 10.3389/fimmu.2023.1133308. eCollection 2023. PMID 36845131
• Bullock AJ, Schlechter BL, Fakih MG, Tsimberidou AM, Grossman JE, Gordon MS, Wilky BA, Pimentel A, Mahadevan D, Balmanoukian AS, Sanborn RE, Schwartz GK, Abou-Alfa GK, Segal NH, Bockorny B, Moser JC, Sharma S, Patel JM, Wu W, Chand D, Rosenthal K, Mednick G, Delepine C, Curiel TJ, Stebbing J, Lenz HJ, O'Day SJ, El-Khoueiry AB. Botensilimab plus balstilimab in relapsed/refractory microsatellite sta PMID 38871975
• Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20) PMID 25970050
• Overman MJ, Lonardi S, Leone F, et al. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142. Journal of Clinical Oncology. 2017;35(4_suppl):519-519. doi:10.1200/JCO.2017.35.4_suppl.519
• Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardo PMID 28596308

Идентификаторы

NCT: NCT07550088 · SC-CRC-IST-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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