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

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ClinicalTrials.gov Identifier: NCT03926338
Recruitment Status : Recruiting
First Posted : April 24, 2019
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
Yanhong Deng, Sun Yat-sen University

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.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Mismatch Repair-deficient (dMMR) Microsatellite Instability-high (MSI-H) Neoadjuvant Therapy Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor Drug: Neoadjuvant therapy with PD-1 inhibitor Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 10, 2019
Estimated Primary Completion Date : May 1, 2021
Estimated Study Completion Date : May 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Celecoxib

Arm Intervention/treatment
Experimental: PD-1 inhibitor plus COX inhibitor
Neoadjuvant therapy with PD-1 inhibitor (Toripalimab) plus COX inhibitor (Celecoxib)
Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor
Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 6 cycles) and Celecoxib (oral 200mg once daily for 12 weeks) followed by colectomy
Other Names:
  • Toripalimab
  • Celecoxib

Experimental: PD-1 inhibitor
Neoadjuvant therapy with PD-1 inhibitor (Toripalimab)
Drug: Neoadjuvant therapy with PD-1 inhibitor
Toripalimab (IV given over 30 min at a dose of 3mg/m2 on day 1, every 2 weeks for 6 cycles) followed by colectomy
Other Name: Toripalimab




Primary Outcome Measures :
  1. Rates of treatment-related surgery delay [ Time Frame: 1 year ]
    Treatment-related surgery delay was defined as treatment-related adverse events (TRAEs) leading to delayed surgery (the interval between the perioperative administration of the last toripalimab dose and surgery is more than 28 days).

  2. Rates of grade 3 or higher treatment-related adverse events (TRAEs) [ Time Frame: 1 year ]
    Rates of grade 3 or higher TRAEs for 90 days after the perioperative administration of the last toripalimab dose (or day 30 after surgery).


Secondary Outcome Measures :
  1. Pathological complete response (pCR) rates [ Time Frame: 1 year ]
    Proportion of patients experiencing a pCR to perioperative PD-1 antibody.

  2. Major pathological response rates [ Time Frame: 1 year ]
    The proportion of patients experiencing a major pathological response to perioperative PD-1 antibody.

  3. Disease-free survival (DFS) [ Time Frame: 3 years ]
    Defined as the time from randomization to relapse, metastasis or death from any cause.

  4. Overall survival (OS) [ Time Frame: 5 years ]
    Defined as the time from randomization to death from any cause.

  5. R0 resection rates [ Time Frame: 1 years ]
    The proportion of patients achieved a complete resection with negative margin.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 < 70 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 or have received neoadjuvant chemotherapy (the regimen is limited to the four drugs consisting of oxaliplatin, irinotecan, fluorouracil or capecitabine) but the tumor has not decreased in size by at least 20%.
  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 colon 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03926338


Contacts
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Contact: Yanhong Deng, M.D. 86-13925106525 13925106525@163.com

Locations
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China, Guangdong
The Sixth Affiliated Hospital of Sun Yat-sen University Recruiting
Guangzhou, Guangdong, China, 510655
Contact: Yanhong Deng, M.D.    86-13925106525    13925106525@163.com   
Sponsors and Collaborators
Sun Yat-sen University
Investigators
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Principal Investigator: Yanhong Deng, M.D. Sixth Affiliated Hospital, Sun Yat-sen University
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Responsible Party: Yanhong Deng, Director of Medical Oncology, Clinical Professor, Sun Yat-sen University
ClinicalTrials.gov Identifier: NCT03926338    
Other Study ID Numbers: GIHSYSU-14
First Posted: April 24, 2019    Key Record Dates
Last Update Posted: June 2, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Microsatellite Instability
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Genomic Instability
Pathologic Processes
Celecoxib
Cyclooxygenase Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action