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

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ClinicalTrials.gov Identifier: NCT03926338
Recruitment Status : Recruiting
First Posted : April 24, 2019
Last Update Posted : November 5, 2019
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
Colon Cancer MSI-H Drug: Neoadjuvant therapy with PD-1 inhibitor plus COX inhibitor Drug: Neoadjuvant therapy with PD-1 inhibitor Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 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. Rate of treatment-related surgery delay [ Time Frame: 1 year ]
    Treatment-related surgery delay was defined as the interval between the last dose of PD-1 inhibitor (Toripalimab) and surgery is more than 28 days.

  2. Frequency of 3/4 grade adverse events as assessed by common terminology criteria for adverse events (CTCAE) version 5.0 [ Time Frame: 1 year ]
    Frequency of 3/4 grade adverse events occurring up to 90 days after the last dose of Toripalimab or 30 days after surgery (whichever is longer).


Secondary Outcome Measures :
  1. Down-staging of primary tumors [ Time Frame: 1 year ]
    Down-staging of the resected tumour as measured by histopathological tumour diameter and stage according to the TNM staging system of American Joint Committee on Cancer (AJCC) (8th version).

  2. Proportion of patients experiencing major pathological response to neoadjuvant treatment [ Time Frame: 1 year ]
    The proportion of patients experiencing major pathological response will be computed with associated 95% confidence interval for each treatment arm

  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.



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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. CT or MRI scans (done within 30 days of registration) of the chest, abdomen and pelvis all without clear evidence of distant metastatic (M1) disease.
  7. Non complicated primary tumor (obstruction, perforation, bleeding).
  8. No previous any systemic anticancer therapy for colon 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 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.

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     History of Changes
Other Study ID Numbers: GIHSYSU-14
First Posted: April 24, 2019    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: September 2019

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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
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Anti-Inflammatory Agents, Non-Steroidal
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Celecoxib
Cyclooxygenase Inhibitors
Analgesics, Non-Narcotic
Analgesics
Cyclooxygenase 2 Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action