NCT07277322招募中1 期
Master Protocol for A Phase 1b/2 Study of Neoadjuvant Immunotherapy in Microsatellite Stable (MSS) Colorectal Cancer (CRC) Subjects With Resectable Liver Metastases
Dan Feng1 个研究点 分布在 1 个国家目标入组 24 人开始时间: 2026年9月1日最近更新:
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Number of dose limiting toxicities (DLTs)
研究概览
简要总结
This Phase 1b/2 trial will evaluate the safety and efficacy of neoadjuvant immunotherapy in microsatellite stable (MSS) colorectal cancer (CRC) subjects with resectable liver metastases.
详细描述
This is a Phase 1b/2 study of neoadjuvant dupilumab and toripalimab in MSS CRC subjects with resectable liver metastases. The primary objective of Phase 1b is to determine the safety of neoadjuvant immunotherapy in MSS CRC subjects with resectable liver metastases. The primary objective of Phase 2 is to determine the efficacy of immunotherapy in MSS CRC subjects with resectable liver metastases as measured by the percentage of subjects achieving a major pathological response (MPR). Eligible subjects will receive dupilumab (600mg on Day 1 and 300mg on D15 ±2 days) and toripalimab 240mg on Day 1 before planned surgery. Dupilumab is administered as a subcutaneous injection. Toripalimab is administered intravenously over 60 minutes or longer. Based on clinical signal in the current cohort and new findings in animal models, additional cohorts will be added to test different immunotherapy combinations in the same patient population with the same endpoints and statistical method in the future.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological diagnosis of non-MSI-H/pMMR CRC
- •Subjects who have biology-proven non-MSI-H/pMMR CRC and with radiographic findings suggestive of liver metastases may be eligible.
- •Resectable liver metastases including:
- •synchronous liver metastases (present at the time of diagnosis of MSS CRC) and treatment-naïve
- •metachronous liver metastasis (developed after resection of the primary tumor) without prior adjuvant chemotherapy
- •metachronous liver metastasis (developed after resection of the primary tumor) with adjuvant chemotherapy completed greater than 3 months from the time of consent.
- •Surgical candidate for resection
- •Age ≥ 18 years. Rationale: Because no dosing or adverse event data are currently available on the use of dupilumab in combination with toripalimab in subjects <18 years of age, children are excluded from this study.
- •ECOG Performance Status 0-1 (Karnofsky ≥60%,)
- •Subjects with performance status >1 carrying long-term disability (such as cerebral palsy) where the disability is not acute nor progressive, and unlikely to significantly affect their response to therapy may be enrolled at the investigator's discretion
- •Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception upon study entry, for the duration of study participation, and for 3 months following completion of therapy.
- •A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
- •Has not undergone a hysterectomy or bilateral oophorectomy; or
- •Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
- •Ability to understand and the willingness to sign a written informed consent. Legally authorized representatives may sign and give informed consent on behalf of study participants.
- •Adequate organ and marrow function as defined:
- •Hematologic
- •o Absolute neutrophil count (ANC) ≥1,000 /mcL
- •Platelets ≥75,000 /mcL
- •Hemoglobin ≥8 g/dL
- •Renal* o Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated (Creatinine clearance should be calculated per institutional standard) creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥45 mL/min for subjects with creatinine levels > 1.5 X institutional ULN
- •Hepatic* o Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN; ≤ 3 X ULN for subjects with liver metastases o AST ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
- •ALT ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
- •Albumin >2.5 mg/dL
- •Coagulation*
- •International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants
- •Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants * If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert's syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to HAART therapy, elevated INR due to anticoagulation) then the lab values will not be used to exclude subject from this trial. This determination will be made by PI.
排除标准
- •History of autoimmune disorder with the following exceptions:
- •Vitiligo, alopecia, psoriasis or any chronic skin condition that does not require systemic therapy
- •Hypothyroidism (e.g. following autoimmune thyroiditis) stable on thyroid replacement
- •Celiac disease controlled by diet alone
- •Treatment, for any reason, with an immunomodulatory drug, within 8 weeks from time of consent.
- •Prior treatment with dupilumab within the last 8 weeks.
- •Prior treatment with chemotherapy for MSS CRC or locoregional therapy to the target lesion (that will be biopsied and subsequently resected) within 3 months prior to entering the study.
- •Previous therapy for a different cancer (a different primary) is acceptable.
- •Use of investigational agents for treatment of cancer.
- •Subjects with extrahepatic metastases that are not amendable to resectable or locoregional therapy, for whom the intent of surgery would not be curative.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (exception is a brief (≤10 days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements, as determined the treating investigator.
- •Pregnant or nursing women due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
- •Breastfeeding should be discontinued prior to study enrollment.
- •Has a diagnosis of primary 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.
- •Chronic steroids equivalent to ≤ 10mg prednisone are permitted.
- •Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- •Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.
- •Has a known additional malignancy that is progressing and requires active treatment.
- •Exceptions include: basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical or anal cancer, prostate cancer on stable dose of hormonal therapy without rising PSA, and breast cancer treated with curative intent now on hormonal therapy.
- •Has a history or 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.
- •HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with <200 CD4+ T cells/microliter in the peripheral blood. HIV testing is mandatory for patients with no known history of HIV. For such patients, HIV testing will be considered SOC.
- •Has known active Hepatitis B (e.g., HBV detected by PCR (>200 IU/ml) or known active Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- •Subjects who started antiviral therapy >/=14days from baseline are permitted.
- •History of allogeneic hematopoietic cell transplantation or solid organ transplantation.
- •Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps) Principle investigator believes that for one or multiple reasons the subject will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the subject.
研究组 & 干预措施
Dupilumab and toripalimab
Experimental
Participants will receive the combination of Dupilumab and Toripalimab
干预措施: Dupilumab (Drug)
Dupilumab and toripalimab
Experimental
Participants will receive the combination of Dupilumab and Toripalimab
干预措施: Toripalimab (Drug)
结局指标
主要结局
Number of dose limiting toxicities (DLTs)
时间窗: up to 30 days post last administration of study drug dupilumab
Phase 2: Safety of treatment, defined as the frequency and percentage of DLTs, from start of treatment up to 30 days post the last administration of study drug (dupilumab).
次要结局
- Event free survival (EFS)(Initial treatment to progression of disease, recurrence of tumor following surgery, up to 8 weeks, whichever comes first after first dose of dupilumab,)
- Major pathological response (MPR)(Day of Surgery (day 16-22))
- Time to surgery(up to 22 days)
- Percentage of participants with adverse event(within 90 days following the final dose of dupilumab)
- Overall survival (OS)(From treatment initiation until death from any cause, up to 2 years, whichever comes first)
研究者
Dan Feng
Assistant Professor
Icahn School of Medicine at Mount Sinai
研究点 (1)
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