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

Colorectal Cancer Clinical Trial

— PICC  

Official title:

Neoadjuvant PD-1 Blockade Toripalimab With or Without Celecoxib in Mismatch-repair Deficient or Microsatellite Instability-high Locally Advanced Colorectal Cancer (PICC): a Parallel-group, Randomized, Multi-cohort, Phase 2 Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03926338
• Other study ID #: GIHSYSU-14
• Status: Recruiting
• Phase: Phase 2
• Start date: May 10, 2019
• Est. completion date: April 1, 2030

Study information

• Verified date: March 2024
• Source: Sun Yat-sen University
• Contact: Yanhong Deng, M.D.
• Phone: 86-13925106525
• Email: dengyanh[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 112
• Est. completion date: April 1, 2030
• Est. primary completion date: April 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

1. Willing and able to provide written informed consent.

2. Histological or cytological documentation of adenocarcinoma of the colon or rectum.

3. Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).

4. Male or female subjects ? 18 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. 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]).

7. Non complicated primary tumor (obstruction, perforation, bleeding).

8. No previous any systemic anticancer therapy for colorectal cancer disease.

9. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.

Exclusion Criteria:

1. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization.

2. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.

3. Heart failure grade III/IV (NYHA-classification).

4. Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure.

5. Subjects with known allergy to the study drugs or to any of its excipients.

6. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.

7. Breast- feeding or pregnant women

8. Lack of effective contraception.

9. 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.

10. With any distant metastasis.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Cohort 1: Neoadjuvant treatment with toripalimab plus celecoxib for 3 months
Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 3 months) and Celecoxib (oral 200mg twice daily for 3 months) followed by surgical resection.
• Cohort 1: Neoadjuvant treatment with toripalimab monotherapy for 3 months
Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 3 months) followed by surgical resection.
• Cohort 2: Neoadjuvant treatment with toripalimab plus celecoxib for 6 months
Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 6 months) and Celecoxib (oral 200mg twice daily for 6 months) followed by surgical resection.
• Cohort 2: Neoadjuvant treatment with toripalimab monotherapy for 6 months
Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 6 months) followed by surgical resection.

Locations

Country	Name	City	State
China	The Sixth Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival (EFS)	Defined as the time from randomisation until the first occurrence of disease progression, second primary colorectal cancer, or death from any cause	3 years
Primary	Pathological complete response (pCR) rates	Proportion of patients experiencing a pCR to perioperative PD-1 antibody	1 year
Secondary	Overall survival (OS)	Defined as the time from randomization to death from any cause.	5 years
Secondary	R0 resection rates	The proportion of patients achieved a complete resection with negative margin.	1 years
Secondary	Surgical and perioperative treatment safety	Assessed by evaluation of treatment-related adverse events	1 years
Secondary	Surgery feasibility	Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose	30 days after surgery