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Toripalimab With or Without Celecoxib as Neoadjuvant Therapy in Resectable dMMR/MSI-H Colorectal Cancer (PICC)

Primary Purpose

Colorectal Cancer, Mismatch Repair-deficient (dMMR), Microsatellite Instability-high (MSI-H)

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor

Neoadjuvant therapy with PD-1 inhibitor

About this trial

This is an interventional treatment trial for Colorectal Cancer

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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 ≧ 18 years ≦ 75 of age.
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 or radiologic evaluation of tumor regression < 20% or unacceptable toxic effects during neoadjuvant chemotherapy.
Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.

Exclusion Criteria:

Previous or concurrent cancer that is distinct in primary site or histology from colon 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.

Sites / Locations

The Sixth Affiliated Hospital of Sun Yat-sen UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

PD-1 inhibitor plus COX inhibitor

PD-1 inhibitor

Arm Description

Neoadjuvant therapy with PD-1 inhibitor (Toripalimab) plus COX inhibitor (Celecoxib)

Neoadjuvant therapy with PD-1 inhibitor (Toripalimab)

Outcomes

Primary Outcome Measures

Disease-free survival (DFS)

Defined as the time from randomization to relapse, metastasis or death from any cause.

Pathological complete response (pCR) rates

Proportion of patients experiencing a pCR to perioperative PD-1 antibody in each group

Secondary Outcome Measures

Overall survival (OS)

Defined as the time from randomization to death from any cause.

R0 resection rates

The proportion of patients achieved a complete resection with negative margin.

Surgical and perioperative treatment safety

Assessed by evaluation of treatment-related adverse events

Surgery feasibility

Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose

Full Information

NCT ID

NCT03926338

First Posted

April 20, 2019

Last Updated

February 26, 2023

Sponsor

Sun Yat-sen University

1. Study Identification

Unique Protocol Identification Number

NCT03926338

Brief Title

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

Acronym

PICC

Official Title

A Pilot Study of Toripalimab With or Without Celecoxib as Neoadjuvant Therapy in Resectable Non-metastatic Colorectal Cancer Patients With Mismatch Repair-deficient or Microsatellite Instability-high

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

May 10, 2019 (Actual)

Primary Completion Date

May 1, 2023 (Anticipated)

Study Completion Date

May 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Sun Yat-sen University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

69 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

PD-1 inhibitor plus COX inhibitor

Arm Type

Experimental

Arm Description

Neoadjuvant therapy with PD-1 inhibitor (Toripalimab) plus COX inhibitor (Celecoxib)

Arm Title

PD-1 inhibitor

Arm Type

Experimental

Arm Description

Neoadjuvant therapy with PD-1 inhibitor (Toripalimab)

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor

Other Intervention Name(s)

Toripalimab, Celecoxib

Intervention Description

Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 3 months or 6 months) and Celecoxib (oral 200mg twice daily for 3 months or 6 months) followed by colectomy. The choice of treatment duration of 3 months or 6 months was made by the treating physician and patient before randomization.

Intervention Type

Drug

Intervention Name(s)

Neoadjuvant therapy with PD-1 inhibitor

Other Intervention Name(s)

Toripalimab

Intervention Description

Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 3 months or 6 months) followed by colectomy. The choice of treatment duration of 3 months or 6 months was made by the treating physician and patient before randomization.

Primary Outcome Measure Information:

Title

Disease-free survival (DFS)

Description

Defined as the time from randomization to relapse, metastasis or death from any cause.

Time Frame

3 years

Title

Pathological complete response (pCR) rates

Description

Proportion of patients experiencing a pCR to perioperative PD-1 antibody in each group

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Overall survival (OS)

Description

Defined as the time from randomization to death from any cause.

Time Frame

5 years

Title

R0 resection rates

Description

The proportion of patients achieved a complete resection with negative margin.

Time Frame

1 years

Title

Surgical and perioperative treatment safety

Description

Assessed by evaluation of treatment-related adverse events

Time Frame

1 years

Title

Surgery feasibility

Description

Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose

Time Frame

90 days after surgery

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 ≧ 18 years ≦ 75 of age. 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 or radiologic evaluation of tumor regression < 20% or unacceptable toxic effects during neoadjuvant chemotherapy. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment. Exclusion Criteria: Previous or concurrent cancer that is distinct in primary site or histology from colon 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Yanhong Deng, M.D.

Phone

86-13925106525

13925106525@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yanhong Deng, M.D.

Organizational Affiliation

Sixth Affiliated Hospital, Sun Yat-sen University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Sixth Affiliated Hospital of Sun Yat-sen University

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510655

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yanhong Deng, M.D.

Phone

86-13925106525

13925106525@163.com

12. IPD Sharing Statement

Citations:

PubMed Identifier

34688374

Citation

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.

Results Reference

derived

PubMed Identifier

34606846

Citation

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.

Results Reference

derived

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

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