Toripalimab Plus Celecoxib With Response-adapted Non-operative Management for Mismatch Repair-deficient or Microsatellite Instability-high Locally Advanced Colorectal Cancer (PICC-3): a Multicenter, Single-arm, Phase 2 Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- Event-free survival (EFS)
研究概览
简要总结
The PICC-3 study is a multicentre, single-arm, phase II trial evaluating toripalimab plus celecoxib in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer. The trial uses a response-adapted treatment strategy, whereby patients with clinical complete response (cCR) after therapy may enter a non-operative management pathway, while patients without cCR proceed to surgery. Response assessment is based on imaging, endoscopy, biopsy evaluation, and ctDNA analysis.
详细描述
Patients with dMMR/MSI-H locally advanced colorectal cancer have shown high sensitivity to neoadjuvant immune checkpoint inhibitor. Several phase II studies have demonstrated high rates of clinical complete response (cCR) and pathological complete response (pCR), supporting the feasibility and safety of immunotherapy in localized dMMR/MSI-H colorectal cancer.
Radical surgery for locally advanced colorectal cancer is associated with substantial perioperative morbidity and long-term functional consequences. In particular, total mesorectal excision for rectal cancer may result in bowel, urinary, and sexual dysfunction, and some patients may require temporary or permanent stoma formation. Therefore, organ preservation and non-operative management have become important treatment goals for selected patients with colorectal cancer who achieve complete clinical response after neoadjuvant therapy.
Previous studies have demonstrated the feasibility and safety of non-operative management after immune checkpoint inhibitor in patients with dMMR/MSI-H rectal cancer, while emerging evidence suggests that this strategy may also be feasible in selected patients with colon cancer following immunotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open Label
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
- •Signed informed consent and willingness/compliance with study procedures.
- •Age ≥18 years.
- •Histologically confirmed colorectal adenocarcinoma.
- •ECOG performance status 0-
- •Locally advanced primary tumor (T3/T4 and/or N+) confirmed by CT/MRI (pelvic MRI for rectal cancer).
- •dMMR (IHC) or MSI-H (PCR) status.
- •No prior anti-cancer therapy for colonrectal cancer (surgery/chemotherapy/targeted therapy/radiation).
- •Adequate organ function
- •For women of childbearing potential: negative pregnancy test and contraception use during and for 3 months post-treatment. Male participants with fertile partners must use contraception.
- •Willingness to adhere to study requirements.
排除标准
- •Presence of distant metastases (M1) confirmed by CT/MRI or PET-CT (at least covering the chest, abdomen, and pelvis).
- •Complete intestinal obstruction, active bleeding, or perforation requiring emergency surgery.
- •Inability to achieve complete resection of the primary colorectal tumor.
- •History or concurrent active malignancy (except malignancies cured ≥5 years ago or adequately treated carcinoma in situ).
- •Prior treatment with anti-PD-1/PD-L1 antibodies, anti-CTLA-4 antibodies, or other drugs/antibodies targeting T-cell co-stimulation or checkpoint pathways.
- •Major surgery (e.g., laparotomy, thoracotomy, organ resection via laparoscopy) or severe trauma within 4 weeks before enrollment (surgical incision must be fully healed).
- •Thromboembolic events (e.g., cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis) within 12 months before enrollment.
- •Active coronary artery disease, severe/unstable angina, or newly diagnosed angina/myocardial infarction within 12 months before enrollment.
- •New York Heart Association (NYHA) Class II or higher congestive heart failure (see Appendix 3).
- •HIV infection, AIDS, or untreated active hepatitis (HBV-DNA ≥500 IU/mL; HCV-RNA above detection limit).
- •Active inflammatory bowel disease or other colorectal disorders causing chronic diarrhea.
- •Active, known, or suspected autoimmune disease (exceptions: stable conditions like type 1 diabetes, hypothyroidism on hormone replacement, or skin disorders without systemic treatment, e.g., vitiligo, psoriasis, alopecia).
- •Interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases (e.g., diabetes, hypertension, pulmonary fibrosis, acute pneumonia).
- •Residual toxicity ≥Grade 2 (per CTCAE v5.0) from prior therapies (except anemia, alopecia, skin pigmentation).
- •Known or suspected hypersensitivity to any study-related drugs.
- •Pregnancy or lactation.
- •Women of childbearing potential (last menstruation <2 years ago) or fertile men unwilling to use effective non-hormonal contraception.
- •Any unstable medical condition compromising safety or protocol compliance.
研究组 & 干预措施
Toripalimab plus celecoxib
Toripalimab is administered intravenously at 3 mg/kg over 30 minutes once every 2 weeks for a total of 12 doses. Celecoxib is administered orally at 200 mg twice daily for 6 months. Patients achieving clinical complete response (cCR) are recommended for non-operative management, whereas patients without cCR are recommended to undergo curative-intent surgery.
干预措施: Toripalimab plus celecoxib (Drug)
Toripalimab plus celecoxib
Toripalimab is administered intravenously at 3 mg/kg over 30 minutes once every 2 weeks for a total of 12 doses. Celecoxib is administered orally at 200 mg twice daily for 6 months. Patients achieving clinical complete response (cCR) are recommended for non-operative management, whereas patients without cCR are recommended to undergo curative-intent surgery.
干预措施: Non-operative management (Procedure)
Toripalimab plus celecoxib
Toripalimab is administered intravenously at 3 mg/kg over 30 minutes once every 2 weeks for a total of 12 doses. Celecoxib is administered orally at 200 mg twice daily for 6 months. Patients achieving clinical complete response (cCR) are recommended for non-operative management, whereas patients without cCR are recommended to undergo curative-intent surgery.
干预措施: Curative-intent surgery (Procedure)
结局指标
主要结局
Event-free survival (EFS)
时间窗: 3 years
the time from the first dose of study treatment to the occurrence of one of the following events: locally progressive disease of the primary tumour precluding curative-intent surgery, R2 resection, local recurrence after R0 or R1 resection, unsalvageable local regrowth during non-operative management, distant metastasis, a second primary colorectal cancer, or death from any cause, whichever occurs first.
次要结局
- Pathological complete response (pCR) rate(3 years)
- Clinical complete response (cCR) rate(3 years)
- Complete response (CR) rate(3 years)
- Overall survival (OS)(5 years)
- Incidence of treatment-related adverse events(3 years)
研究者
Yanhong Deng
Professor
Sixth Affiliated Hospital, Sun Yat-sen University