Clinical trial NCT06903858: Neoadjuvant Toripalimab Plus Celecoxib for dMMR/MSI-H Locally Advanced Colorectal Cancer
Official title: Neoadjuvant Toripalimab Plus Celecoxib in Mismatch-repair Deficient or Microsatellite Instability-high Locally Advanced Colorectal Cancer (PICC-3): a Multicenter, Single-arm, Phase 2 Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Colorectal Cancer (CRC)
PD-1 Inhibitor
Neoadjuvant Immunotherapy
Celecoxib
Watch &Amp; Wait
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2025-04-01
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Prospective, Multicenter, Single-arm, Phase II
Primary purpose: TREATMENT

Brief summary: Several Phase II studies have demonstrated the feasibility, effectiveness, and good tolerability of neoadjuvant immune checkpoint inhibitor (ICI) treatment for localized dMMR colorectal and rectal cancers. The significant clinical and pathological complete response rates offer the possibility of avoiding surgical resection. dMMR colorectal cancers are generally larger and more advanced than pMMR tumors, often requiring more extensive surgery with associated risks such as anastomotic leakage, ureteral injury, and infection. If oncological outcomes are not affected (requiring long-term follow-up), non-surgical treatment becomes an attractive option for localized dMMR colorectal cancer. Moreover, pelvic radiotherapy, the standard for locally advanced rectal cancer, causes both short-term and long-term adverse effects (e.g., bowel and bladder dysfunction, fistula, infertility), significantly impacting quality of life. Total mesorectal excision also carries risks of complications and sexual dysfunction, often requiring a stoma, making organ preservation a more urgent need for rectal cancer patients.

Phase II trials and the international "watch-and-wait" database have confirmed the feasibility and safety of organ preservation for pMMR locally advanced rectal cancer. Therefore, the high clinical and pathological complete response rates achieved by neoadjuvant immunotherapy for dMMR/MSI-H rectal cancer offer promising prospects for non-surgical treatment.


Eligibility criteria: Inclusion Criteria:

1. Signed informed consent and willingness/compliance with study procedures.
2. Age ≥18 years.
3. Histologically confirmed colorectal adenocarcinoma.
4. ECOG performance status 0-1.
5. Locally advanced primary tumor (T3/T4 and/or N+) confirmed by CT/MRI (pelvic MRI for rectal cancer).
6. dMMR (IHC) or MSI-H (PCR) status.
7. No prior anti-cancer therapy for colonrectal cancer (surgery/chemotherapy/targeted therapy/radiation).
8. Adequate organ function
9. 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.
10. Willingness to adhere to study requirements.

Exclusion Criteria:

1. Presence of distant metastases (M1) confirmed by CT/MRI or PET-CT (at least covering the chest, abdomen, and pelvis).
2. Complete intestinal obstruction, active bleeding, or perforation requiring emergency surgery.
3. Inability to achieve complete resection of the primary colorectal tumor.
4. History or concurrent active malignancy (except malignancies cured ≥5 years ago or adequately treated carcinoma in situ).
5. 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.
6. Major surgery (e.g., laparotomy, thoracotomy, organ resection via laparoscopy) or severe trauma within 4 weeks before enrollment (surgical incision must be fully healed).
7. Thromboembolic events (e.g., cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis) within 12 months before enrollment.
8. Active coronary artery disease, severe/unstable angina, or newly diagnosed angina/myocardial infarction within 12 months before enrollment.
9. New York Heart Association (NYHA) Class II or higher congestive heart failure (see Appendix 3).
10. HIV infection, AIDS, or untreated active hepatitis (HBV-DNA ≥500 IU/mL; HCV-RNA above detection limit).
11. Active inflammatory bowel disease or other colorectal disorders causing chronic diarrhea.
12. 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).
13. Interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases (e.g., diabetes, hypertension, pulmonary fibrosis, acute pneumonia).
14. Residual toxicity ≥Grade 2 (per CTCAE v5.0) from prior therapies (except anemia, alopecia, skin pigmentation).
15. Known or suspected hypersensitivity to any study-related drugs.
16. Pregnancy or lactation.
17. Women of childbearing potential (last menstruation \<2 years ago) or fertile men unwilling to use effective non-hormonal contraception.
18. Any unstable medical condition compromising safety or protocol compliance.

Primary outcomes:
measure: Event-free survival (EFS)
timeFrame: 3 years
Secondary outcomes:
measure: Pathologic complete response (pCR) rate
timeFrame: 3 years
measure: Overall survival (OS)
timeFrame: 3 years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The Sixth Affiliated Hospital, Sun Yat-sen University
state: Guangdong
Study officials:
References: