Cadonilimab for PD-1/PD-L1 Blockade-refractory, MSI-H/dMMR, Advanced Colorectal Cancer

NCT05426005 | Recruiting Phase 1 DMC

• 1 other identifier: CSWOG-C03
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

KEYNOTE-177 is currently the only randomized controlled phase III clinical trial evaluating the efficacy and safety of pembrolizumab versus standard chemotherapy combined with targeted first-line therapy for dMMR/MSI-H metastatic colorectal cancer. The study was conducted at 192 centers in 23 countries and enrolled a total of 307 subjects. The results of the study showed that the median PFS of pembrolizumab was 16.5 months, which was double the 8.2 months in the chemotherapy group (HR 0.60; 95% CI: 0.45-0.80; P = 0.0002). In addition, the ORR was 45.1% in the pembrolizumab group and 33.1% in the chemotherapy group, and a higher percentage of patients achieving a complete remission (CR) with pembrolizumab than in the chemotherapy group (13.1% vs. 3.9%). The U.S. FDA approved pembrolizumab in June 2020 for the first-line treatment of MSI-H/dMMR metastatic colorectal cancer. The results of the KEYNOTE-177 study showed that 29% of patients with dMMR/MSI-H metastatic colorectal cancer experienced direct disease progression (PD) after first-line pembrolizumab monotherapy. This may suggest that some dMMR/MSI-H patients have primary resistance to anti-PD-1 monotherapy. In the first-line treatment cohort of the CheckMate 142 study using nivolumab combined with ipilimumab, the proportion of patients with direct PD was 13%, suggesting that the combination of PD-1 inhibitors and anti-CTLA-4 mAb may have help overcome this primary resistance. In addition, in the second-line and above cohort of the CheckMate142 study, 12% of patients receiving nivolumab in combination with ipilimumab experienced PD directly, compared with 26% of patients receiving nivolumab alone. A study published on 《The Lancet Oncolog》 on the efficacy and safety of ipilimumab monotherapy and ipilimumab combined with anti-PD-1 monoclonal antibody in patients with anti-PD-1 monoclonal antibody-resistant melanoma Retrospective study. The study included 355 patients with unresectable metastatic stage III or IV melanoma who received ipilimumab monotherapy after failure of anti-PD-(L)1 monoclonal antibody (n=162), or Ipilimumab combined with anti-PD-1 therapy (n=193). The ORR was 31% in the combination arm, significantly higher than the 13% in the ipilimumab monotherapy arm. In addition, the median OS and PFS of the combination therapy group were 20.4 months and 3.0 months, respectively, which were also significantly higher than those of the single-agent group of 8.8 months and 2.6 months. The aim of this study was to evaluate the objective response rate (ORR) of Cadonilimab, a bispecific anti-PD-1/CTLA-4 antibody, for PD-1/PD-L1 blockade-refractory, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), advanced colorectal cancer.

Conditions

Colorectal Cancer Stage IV; Mismatch Repair-deficient (dMMR); Microsatellite Instability-high (MSI-H)

Keywords

PD-1; CTLA-4; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• 12-month Progression-free survival (PFS) rate

  The PFS was defined as the time from enrollment until tumor progression or death from any cause, whichever occurred first. The 12-month PFS rate was defined as the proportion of patients without disease progression or death at the 12th month after initiation of the study. treatment.

  2 years

Secondary Outcomes (3)

• Objective response rate (ORR)

  2 years

• Overall Survival (OS)

  5 years

• Toxicity assessed using the The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

  2 years

Study Arms (1)

Cadonilimab

EXPERIMENTAL

Cadonilimab alone

Drug: Cadonilimab

Interventions

Cadonilimab DRUG

Cadonilimab, 6 mg/kg every 2 weeks until disease progression, intolerable toxicity, or duration of treatment for 2 years

Cadonilimab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent.
• Histological or cytological documentation of adenocarcinoma of the colon or rectum.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).
• Subjects with stage IV colorectal cancer must have measurable or non measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1.
• Previous treatment with an anti-PD-1 or PD-L1 monoclonal antibody for advanced or metastatic colorectal cancer has failed. Treatment failure was defined as: disease progression or unacceptable toxicity during treatment or within 6 months after the last treatment.
• Adequate bone marrow, liver and renal function as assessed by the laboratory required by protocol.

You may not qualify if:

• Previously received anti-cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody.
• 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.5.0 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.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

The Sixth Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, 510655, China

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms; Turcot syndrome; Diabetes Mellitus, Insulin-Dependent, 12

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Central Study Contacts

Yanhong Deng, M.D.

CONTACT

+86-13925106525; 13925106525@163.com

Qin Zheng

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Medical Oncology, Clinical Professor

Study Record Dates

• First Submitted: June 15, 2022
• First Posted: June 21, 2022
• Study Start: February 7, 2023
• Primary Completion: July 1, 2025
• Study Completion (Estimated): July 1, 2027
• Last Updated: March 19, 2025

Record last verified: 2025-03

Locations

CN (1)