Sintilimab and Chidamide in Combination With or Without IBI305 in Advanced or Metastatic pMMR/MSS Colorectal Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of sintilimab and chidamide in combination with or without IBI305(bevacizumab) in patients with standard treatment failure of advanced or metastatic pMMR/MSS colorectal adenocarcinoma.

Detailed Description
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In this study, we explored the potential effectiveness of combining PD-1 monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide, with or without IBI305(bevacizumab), in MSS/pMMR unresectable locally advanced or metastatic colorectal cancer patients who failed standard chemotherapy and testified this new combination in preclinical models. Fourty-eight patients were randomized into two groups: the doublet group, who received sintilimab 200 mg every 3 weeks and chidamide 30 mg orally twice weekly, and the triplet group, who received sintilimab, chidamide, and bevacizumab 7.5 mg/kg every 3 weeks.

Official Title
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A Randomized Phase 2 Clinical Trial Evaluating Sintilimab and Chidamide in Combination With or Without IBI305 in Patients With Standard Treatment Failure of Advanced or Metastatic pMMR/MSS Colorectal Carcinoma

Conditions
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Advanced Microsatellite Stable Colorectal Cancer, Metastatic Microsatellite-stable Colorectal Cancer

Intervention / Treatment
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* Drug: Sintilimab
* Drug: Chidamide
* Drug: IBI305


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of unresectable locally advanced, recurrent or metastatic colorectal adenocarcinoma. Tumor tissues were identified as mismatch repair-proficient (pMMR) by immunohistochemistry (IHC) method or microsatellite stability (MSS) by polymerase chain reaction (PCR). Subjects must have failed at least two lines of prior treatment. Subjects must have one measurable lesion according to RECIST v1.1 at least. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 18-75 years old. Life expectancy of at least 12 weeks. Adequate bone marrow, liver, renal and coagulation function as assessed by the laboratory required by protocol Exclusion Criteria: Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody or histone deacetylase (HDAC) inhibitor. Received last dose of anti-tumor therapy (chemotherapy, targeted therapy, tumor immunotherapy or arterial embolization) within 3 weeks of the first dose of study medication. Received radiotherapy with 4 weeks of the first dose of study medication. Underwent major operation within 4 weeks of the first dose of study medication or open wound, ulcer or fracture. Known symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis. Subjects received prior treatment and have stable disease more than 4 weeks from first dose of study medication are permitted to enroll. Active, known or suspected autoimmune disease or has a history of the disease within the last 2 years. Interstitial lung disease requiring corticosteroids. Active or poorly controlled serious infections. Significant malnutrition. Symptomatic congestive heart failure (NYHA Class II-IV) or symptomatic or poorly controlled arrhythmia. Uncontrolled hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg) despite standard treatment. Within 6 months prior to the enrollment, history of gastrointestinal perforation and/or fistula, gastrointestinal ulcer, bowel obstruction, extensive bowel resection, Crohn's disease, or ulcerative colitis, intra-abdominal abscesses, or long-term chronic diarrhea. History or evidence of inherited bleeding diathesis or coagulopathy or thrombus Any life-threatening bleeding within 3 months prior to the enrollment. High risk of bleeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized in approximately a 1:1 ratio to receive sintilimab and chidamide with or without IBI305.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The triplet group (sintilimab + chidamide + IBI305)<br>Every 3 weeks, patients received sintilimab 200 mg and IBI305(bevacizumab) 7.5 mg/kg on day one and chidamide 30 mg orally twice weekly. | Drug: Sintilimab<br>* 200mg IV on Day 1 Q3W<br>Drug: Chidamide<br>* 30mg PO BIW each 3-week cycle<br>Drug: IBI305<br>* 7.5mg/kg IV on Day 1 Q3W<br>* Other names: Bevacizumab;|
| Active Comparator: The doublet group (sintilimab + chidamide)<br>Every 3 weeks, patients received sintilimab 200 mg on day one and chidamide 30 mg orally twice weekly. | Drug: Sintilimab<br>* 200mg IV on Day 1 Q3W<br>Drug: Chidamide<br>* 30mg PO BIW each 3-week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The progression-free survival (PFS) rates at 18 weeks | The proportion of patients without disease progression or death at the 18th week after initiation of the study treatment | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | The proportion of patients with a PR or CR | 2 year | 
| Progression-free survival (PFS); | The time from enrollment until tumor progression or death from any cause, whichever occurred first | 2 year | 
| Overall Survival (OS); | The time calculated from enrollment until death from any cause, with living patients censored at the last known survival date | 2 year | 
| Disease control rate (DCR) | The proportion of patients with a PR, CR, or SD | 2 year | 
| Duration of response (DoR) | For patients who achieved a complete response (CR) or partial response (PR), the time from the first tumor assessment demonstrating response until disease progression or death, whichever occurred first | 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Carcinoma, pMMR, Microsatellite-stable