Neoadjuvant Toripalimab With or Without Celecoxib in dMMR/MSI-H Colorectal Cancer

NCT03926338 | Recruiting Phase 2

• 1 other identifier: GIHSYSU-14
• Study Type: interventional
• Target: 270
• Locations: 1 country
• Sites: 1

Brief Summary

Colorectal cancer of Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) accounts for approximately 15% of all colorectal cancer patients, with a higher proportion in right colon cancer. Previous studies have found that colon cancer patients with dMMR/MSI-H cannot benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and the prognosis is significantly worse than that of mismatch repair-proficient (pMMR)/microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in 《N Engl J Med》 showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy. Anti-PD-1 neoadjuvant therapy has proven to be safe and feasible in lung cancer, bladder cancer and malignant melanoma, and can achieve more than 40% of major pathological response. However, there are no reports of anti-PD-1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colorectal cancer patient with the dMMR/MSI-H phenotype and to explore whether cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could further improve efficacy.

Conditions

Colorectal Cancer; Mismatch Repair-deficient (dMMR); Microsatellite Instability-high (MSI-H); Neoadjuvant Therapy

Outcome Measures

Primary Outcomes (2)

• Pathological complete response (pCR) rates (PICC-1 and PICC-2 cohorts)

  The proportion of patients who achieved a pCR, which was defined as the absence of residual viable tumor cells in the primary tumor and all sampled lymph nodes at surgery.

  1 year

• Event-free survival (EFS) (PICC-3 cohort)

  Defined as the time from randomization until the date of one of the following events (whichever occurred first): disease progression that precluded surgery, local R2 resection, local recurrence after an R0/1 resection, distant metastases, a new primary colorectal cancer, or death from any cause.

  3 years

Secondary Outcomes (4)

• Overall survival (OS)

  5 years

• R0 resection rates

  1 years

• Surgical and perioperative treatment safety

  1 years

• Surgery feasibility

  30 days after surgery

Study Arms (3)

PICC-1 exploratory cohort

EXPERIMENTAL

Neoadjuvant toripalimab with or without celecoxib for 6 cycles

Drug: Neoadjuvant toripalimab plus celecoxib for 6 cycles; Drug: Neoadjuvant toripalimab monotherapy for 6 cycles

PICC-2 cohort

EXPERIMENTAL

Neoadjuvant toripalimab with or without celecoxib for 12 cycles

Drug: Neoadjuvant toripalimab plus celecoxib for 12 cycles; Drug: Neoadjuvant toripalimab monotherapy for 12 cycles

PICC-3 cohort

EXPERIMENTAL

Toripalimab plus celecoxib as neoadjuvant or definitive therapy

Drug: Toripalimab plus celecoxib as neoadjuvant or definitive therapy

Interventions

Neoadjuvant toripalimab plus celecoxib for 6 cycles DRUG

Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 6 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery.

Also known as: Toripalimab, Celecoxib

PICC-1 exploratory cohort

Neoadjuvant toripalimab monotherapy for 6 cycles DRUG

Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 6 cycles, followed by surgery.

Also known as: Toripalimab

PICC-1 exploratory cohort

Neoadjuvant toripalimab plus celecoxib for 12 cycles DRUG

Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery.

Also known as: Toripalimab, Celecoxib

PICC-2 cohort

Neoadjuvant toripalimab monotherapy for 12 cycles DRUG

Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, followed by surgery.

Also known as: Toripalimab

PICC-2 cohort

Toripalimab plus celecoxib as neoadjuvant or definitive therapy DRUG

Toripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery or non-operative management based on restaging (non-operative management was recommended for patients with a complete clinical response).

Also known as: Toripalimab, Celecoxib

PICC-3 cohort

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent.
• Histological or cytological documentation of adenocarcinoma of the colon or rectum.
• Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).
• Male or female subjects aged 18 to 75 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Determined CT or MRI scans (done within 14 days of registration) of the chest, abdomen and pelvis: locally advanced (cT3-4 or cN1-2 \[with the definition of a clinically positive lymph node being any node ≥ 1.0 cm\]).
• Non complicated primary tumor (obstruction, perforation, bleeding).
• No previous any systemic anticancer therapy for colorectal cancer disease.
• Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.

You may not qualify if:

• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization.
• Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.
• Heart failure grade III/IV (NYHA-classification).
• Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure.
• Subjects with known allergy to the study drugs or to any of its excipients.
• Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
• Breast- feeding or pregnant women
• Lack of effective contraception.
• Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody or other drug/antibody that acts on T cell costimulation or checkpoint pathways.
• With any distant metastasis.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

The Sixth Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, 510655, China

RECRUITING

Related Publications (3)

• Cao W, Hu H, Li J, Wu Q, Shi L, Li B, Zhou J, Wang X, Chen J, Wang C, Wang H, Deng W, Huang Y, Deng Y. China special issue on gastrointestinal tumors-Radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial. Int J Cancer. 2023 Dec 1;153(11):1894-1903. doi: 10.1002/ijc.34647. Epub 2023 Jul 6.

  PMID: 37409565 DERIVED

• Hu H, Kang L, Zhang J, Wu Z, Wang H, Huang M, Lan P, Wu X, Wang C, Cao W, Hu J, Huang Y, Huang L, Wang H, Shi L, Cai Y, Shen C, Ling J, Xie X, Cai Y, He X, Dou R, Zhou J, Ma T, Zhang X, Luo S, Deng W, Ling L, Liu H, Deng Y. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2022 Jan;7(1):38-48. doi: 10.1016/S2468-1253(21)00348-4. Epub 2021 Oct 22.

  PMID: 34688374 DERIVED

• Wang D, Cabalag CS, Clemons NJ, DuBois RN. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer. Gastroenterology. 2021 Dec;161(6):1813-1829. doi: 10.1053/j.gastro.2021.09.059. Epub 2021 Oct 2.

  PMID: 34606846 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Turcot syndrome

Interventions

Celecoxib; toripalimab; Neoadjuvant Therapy

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Combined Modality Therapy; Therapeutics

Study Officials

• Yanhong Deng, M.D.

  Sixth Affiliated Hospital, Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yanhong Deng, M.D.

CONTACT

86-13925106525; dengyanh@mail.sysu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Patients and treating physicians are not masked to the study treatment. Investigators who assess radiological, endoscopic, and pathological responses are masked to the treatment allocation and to all other study data.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Medical Oncology, Clinical Professor

Model Details: The PICC trial is an investigator-initiated, multi-cohort platform trial designed to evaluate the efficacy and safety of neoadjuvant toripalimab, with or without celecoxib, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer. Each cohort within the PICC platform was independently conducted and analyzed according to prespecified objectives.

Study Record Dates

• First Submitted: April 20, 2019
• First Posted: April 24, 2019
• Study Start: May 10, 2019
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2030
• Last Updated: November 20, 2025

Record last verified: 2025-11

Locations

CN (1)