PD-1 Antibody Combined With COX Inhibitor in MSI-H/dMMR or High TMB Colorectal Cancer (PCOX)

PD-1 Antibody Combined With COX Inhibitor in MSI-H/dMMR or High TMB Colorectal Cancer: a Single Arm Phase II Study

PD-1(programmed death protein 1)antibody has been to approved in patients with MSI-H/dMMR advanced cancer and has achieved significant efficacy. It is reported that the objective response rate of Pembrolizumab and Nivolumab are 40% and 31.1% in MSI-H/dMMR (microsatellite instability-high/deficiency mismatch repair )colorectal cancer. What's more, most of the patients who had response for PD-1 antibody achieved a long duration of disease control. However, not all patients with MSI-H/dMMR was sensitive to PD-1 antibody despite it is a biomarker for PD-1 antibody treatment. There were about 50-60% of patients with MSI-H/dMMR were insensitive and we don't know why. What's more, it's reported that tumor mutation burden (TMB) may be another biomarker of response to PD-1 therapy. COX (cyclooxygenase)inhibitor has been proved to prevent adenomas in colorectal and it is safe for most of the patients. Preclinical models also showed that COX inhibitor could act with PD-1 antibody in mice and control disease progress. So, this study aims to evaluated efficacy and safety of combination of PD-1 antibody and COX inhibitor in patients with MSI-H/dMMR or high tumor mutation burden colorectal cancer.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: PD-1 antibody + cox inhibitor

Detailed Description

This is a single arm, phase two study. Eligible patients with advanced MSI-H/dMMR colorectal cancer were assigned to receive BAT1306 plus COX inhibitor. All patients will receive the study regimen every 3 weeks. Chest/abdomen/pelvic CT with IV contrast will be performed to assess clinical response.

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yanhong Deng, M.D.; Phone Number: 008613925106525; Email: dengyanh@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510655
      • Recruiting
      • The Sixth Affiliated Hospital of Sun Yat-sen University
      • Contact: Yanhong Deng, M.D.; Phone Number: 008613925106525; Email: dengyanh@mail.sysu.edu.cn
    • Guangzhou, Guangdong, China, 510655
      • Recruiting
      • Gastrointestinal Hospital, Sun Yat-sen University
      • Contact: Yanghong Deng, PhD; Phone Number: 008613925106525; Email: dengyanh@mail.sysu.edu.cn
      • Principal Investigator: Yanhong Deng, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent; able to comply with study and/or follow- up procedures;
2. Age:18-75 years old;
3. Histological or cytological documentation of colorectal cancer;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
5. There must be documentation by CT scan, MRI, or intraoperative palpation that tumor is unresectable;
6. Have had at least one lines of chemotherapy fail or refuse to receive chemotherapy;
7. Histologically confirmed metastatic or primary colorectal cancer as dMMR/MSI-H or whole exon sequence confirmed tumor mutation burden higher than 1000;
8. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Hemoglobin (Hb) ≥ 90g/ L, absolute neutrophil count (ANC) ≥ 1.5×109/ L, platelet count ≥ 100×109/ L; Total bilirubin ≤ 1.5×the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 ×ULN; Serum creatinine ≤1.5×the ULN.

Exclusion Criteria:

1. Previous treatment with other therapy targeting T-cell costimulation or immune checkpoint pathways;
2. Active, known, or suspected autoimmune disease (except for type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring only hormone replacement, or conditions not expected to recur in the absence of an external trigger);
3. A previous cancer active within the previous 5 years;
4. Subjects with known allergy to the study drugs or to any of its excipients;
5. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment;
6. Heart failure grade III/IV (NYHA-classification);
7. Patients with active infection within 1 week before enrollment (infection caused by fever above 38 °C);
8. Patients with severe lung disease (interstitial pneumonia, pulmonary fibrosis, severe emphysema);
9. Patients with active gastrointestinal bleeding;
10. Patients with serious complications (intestinal obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders);
11. Psychiatric disease or a history of central nervous system disease that affects clinical treatment;
12. Receive other anti-tumor treatments (including anti-tumor immunotherapy, interventional therapy and intra-serosal injection of anti-tumor drugs) or participate in other interventional clinical trials within two weeks before enrollment;
13. Breast- feeding or pregnant women;
14. Lack of effective contraception;
15. The investigator determined that the patient was not eligible for this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PD-1 antibody + cox inhibitor; BAT1306 + aspirin(celebrex when there is contraindication to aspirin) on day 1-21 every three weeks	Drug: PD-1 antibody + cox inhibitor; BAT1306 100mg /pembrolizumab 200mg on day 1 + aspirin 200mg oral (celebrex 400mg oral when there is contraindication to aspirin) on day 1-21 every three weeks Contraindication to aspirin : Allergic or intolerance to aspirin; With peptic ulcers; With hemophilia or other bleeding tendencies; Have the gentic disease glucose-6 phosphate dehydrogenase deficiency.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	CR(complete response) + PR (partial response)rate will be assessed according to the RECIST version 1.1 guidelines.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity assessed using the NCI common toxicity criteria, version 4.0.	The grade of toxicity will be assessed using the NCI common toxicity criteria, version 4.0.	2 years
Progression free survival	Time measured from the day of treatment to the date of first documented progression, or death from any cause.	2 years
Overall survival time	Estimated from the date of treatment to death from any cause.	5 years
disease control rate	CR + PR + SD(stable disease) rate will be assessed according to the RECIST version 1.1 guidelines.	6 months
duration of response	Time measured from the day of first documented PR or CR to the date of first documented progression, or death from any cause.	2 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Yanhong Deng, M.D., Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2018
• Primary Completion (Actual): August 20, 2022
• Study Completion (Estimated): August 31, 2025

Study Registration Dates

• First Submitted: August 17, 2018
• First Submitted That Met QC Criteria: August 17, 2018
• First Posted (Actual): August 20, 2018

Study Record Updates

• Last Update Posted (Actual): October 17, 2023
• Last Update Submitted That Met QC Criteria: October 15, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: PD-1 antibody; dMMR; MSI-H; COX inhibitor; tumor mutation burden
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunologic Factors; Antibodies; Cyclooxygenase Inhibitors
• Other Study ID Numbers: GIHSYSU13

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No