Cadonilimab as Neoadjuvant Therapy in Resectable Stage II-III MSI-H/dMMR Colorectal Cancer (MSI-H/dMMR)

Cadonilimab as Neoadjuvant Therapy in Resectable Stage II-III Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) Colorectal Cancer

This study will evaluate the safety, and tolerability of Cadonilimab as neoadjuvant treatment for resectable local advanced colorectal cancer patient with dMMR/MSI-H.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer; Neoadjuvant Therapy; Mismatch Repair-deficient (dMMR); Microsatellite Instability-high (MSI-H)
• Intervention / Treatment: Drug: Cadonilimab (®), a PD-1/CTLA-4 bi-specific antibody

Detailed Description

Colorectal cancer (CRC) is one of the most common malignant tumours of human beings. Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) CRC is a specific subtype of CRC, which accounts for approximately 15% ~20% of all CRC patients,and can not benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and thus lead to much worse prognosis than that of mismatch repair-proficient (pMMR)/ microsatellite stability (MSS). Neoadjuvant immunotherapy based on mismatch repair (MMR) status in CRC have reported some encouraging data. The NICHE study showed that 20 CRC patients with dMMR achived pathological remission, of which 19 patients with residual tumor ≤10%, 15 patients achived pathological complete remission. Another study (ClinicalTrials.gov, NCT03926338) which investigating the effect of neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, on mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer. The result revealed that all 34 patients had an R0 resection. 15 of 17 patients (88%) in the toripalimab plus celecoxib group and 11 of 17 patients (65%) in the toripalimab monotherapy group had a pathological complete response.

Cadonilimab (®), a PD-1/CTLA-4 bi-specific antibody, is being developed by Akeso, Inc. for the treatment of a range of solid tumours, including cervical cancer, lung cancer, gastric/gastroesophageal junction cancer, oesophageal squamous cell cancer, liver cancer and nasopharyngeal cancer. Cadonilimab was approved in China in June 2022 for use in patients with relapsed or metastatic cervical cancer (r/mCC) who have progressed on or after platinum-based chemotherapy.

Given the reported efficacy data about immunotherapy as neoadjuvant treatment in MSI-H/dMMR CRC, the aim of this study was to investigate the efficacy and safety of Cadonilimab as neoadjuvant treatment for resectable local advanced colorectal cancer patient with the dMMR/MSI-H.

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ying Liu, MD; Phone Number: +86-13783604602; Email: Yaya7207@126.com

Study Locations

• China
  • Henan
    • ZhengZhou, Henan, China, 450008
      • Henan Cancer Hospital/The affiliated Cancer Hospital of ZhengZhou university

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Male or female subjects > 18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Histological or cytological documentation of adenocarcinoma of the colon or rectum; Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR) in local site; For colon cancer must be determined by CT or MRI scans as locally advanced (T4) or cN1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm]). Participants should be eligible for radical resection of R0.
5. At least one measurable lesion as defined by RECIST 1.1
6. Willing and able to provide 2ml blood and archived tumor tissue sample for MSI status testing. Patients who do not have adequate archival tumor tissue available should undergo a fresh tumor biopsy
7. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.
8. Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 120 days following the last dose of study treatment; this may include barrier methods such as condom or diaphragm with spermicidal gel.

Exclusion Criteria:

1. Previous any systemic anticancer therapy for colorectal cancer disease, including chemotherapy, radiothapy or immunotherapy
2. 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.
3. Subjects with known allergy to monoclonal antibodies
4. Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 2 years prior to study drug treatment.
5. Concurrent with active autoimmune disease or Participants with a history of autoimmune disease who may recur
6. Subjects receiving immunosuppressive agents (such as steroids, or corticosteroids at physiologic replacement doses, equivalent to ≤ 10 mg prednisone daily ) for any reason within 14 days before the study drug treatment.
7. Uncontrolled hypertension or hyperglycemia within 14 days before the study drug treatment.
8. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrent within 14 days of study drug treatment)
9. History of interstitial lung disease, noninfectious pneumonia, or poorly controlled lung disease (including pulmonary fibrosis, acute lung disease).
10. Active systemic bacterial, viral, or fungal infection， requiring systemic treatment within 14 days before study drug treatment.
11. Positive test for hepatitis B virus surface antigen with HBV DNA> 500 IU/mL（> 2500copies/mL）at screening or untreated Chronic hepatitis B
12. Positive test for hepatitis C virus ribonucleic acid (if antihepatitis C virus antibody tested positive) at screening;
13. Known history of testing positive for human immunodeficiency virus (HIV)
14. Major surgery for any reason, except diagnostic biopsy, within 28 days of the first administration of study drug. The subject must fully recovered from prior treatment before the first administration of study drug
15. Previous allogeneic stem cell transplantation or organ transplantation
16. Previous history of myocarditis, cardiomyopathy, and malignant arrhythmias
17. Vaccination within 4 weeks of the first administration of study drug and throughout the study is prohibited, except for administration of inactivated vaccines (eg, inactivated influenza vaccines).
18. All other underlying medical condition (including laboratory abnormalities) that is detrimental to study drug administration, or may affect drug toxicity or AE interpretation, or may result in inadequate or reduced adherence to study drug; Alcohol or drug abuse or dependence
19. Pregnancy or lactation
20. Concurrent participated in another therapeutic 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: Experimental: Cadonilimab (®), a PD-1/CTLA-4 bi-specific antibody; Neoadjuvant therapy with Cadonilimab	Drug: Cadonilimab (®), a PD-1/CTLA-4 bi-specific antibody; 10mg/kg, Q3W for 4 cycles; Other Names: Neoadjuvant therapy with Cadonilimab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response (pCR) rates	Proportion of patients experiencing a pCR to perioperative PD-1/CTLA-4 bi-specific antibody	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major pathological response rates	The proportion of patients experiencing a major pathological response to perioperative PD-1/CTLA-4 bi-specific antibody	1 year
R0 resection rates	The proportion of patients experiencing a R0 resection after perioperative treatment with PD-1/CTLA-4 bi-specific antibody	1 year
Relapse-free survival (DFS)	Defined as the time from radical surgery to relapse, metastasis or death from any cause	3 years
The incidence of Treatment-related Adverse Events	Assessed by evaluation of treatment-related adverse events	1 year
Number of participants with any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative Cadonilimab dose	Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative Cadonilimab dose	1 year

Collaborators and Investigators

• Sponsor: LiuYing
• Investigators: Principal Investigator: Ying Liu, MD, Henan Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 20, 2023
• Primary Completion (Estimated): December 20, 2023
• Study Completion (Estimated): December 20, 2023

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: June 18, 2023
• First Posted (Actual): June 22, 2023

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 18, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Genomic Instability; Colorectal Neoplasms; Microsatellite Instability; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Antibodies, Bispecific
• Other Study ID Numbers: 2023-061-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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