Tislelizumab Combined With Fruquintinib for Metastatic pMMR/MSS Colorectal Cancer

PD-1 Antibody (Tislelizumab) Combined With VEGFR 1/2/3 Inhibitor (Fruquintinib) for ARID1A-mutated Metastatic pMMR/MSS Colorectal Cancer: an Open-label, Multi-center, Phase II Clinical Trial

This is an open-label phase II study, with the aim of investigating the efficacy and safety of Tislelizumab + Fruquintinib combination therapy in ARID1A-mutated pMMR/MSS metastatic colorectal cancer who have been treated with standard chemotherapy that includes fluoropyrimidine, oxaliplatin, and irinotecan. Patients with hypermutated CRC that carries POLE/POLD1 mutations cannot be included.

Study Overview

• Status: Withdrawn
• Conditions: Metastatic Colorectal Cancer; mCRC
• Intervention / Treatment: Drug: Tislelizumab & Fruquintinib

Detailed Description

In this open-label phase II study, patients with ARID1A-mutated pMMR/MSS metastatic colorectal cancer who have been treated with standard chemotherapy that includes fluoropyrimidine, oxaliplatin, and irinotecan, will be scheduled for Tislelizumab (200mg ivdrip Q3W day1) + Fruquintinib (5mg/day Q3W day1-14) until intolerable toxicity, disease progression or death. Primary endpoint of this study is ORR and secondary endpoints are OS, PFS, DCR and safety.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangzhou, China
    • Xiaoshi Zhang
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-Sen University, Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 18-80 years old (including 18 and 80);
• Histologically confirmed colorectal adenocarcinoma and biopsy pathology confirmed MSS/pMMR;
• Gene testing confirmed ARID1A gene mutation (nonsynonymous);
• No signs of intestinal obstruction; Or intestinal obstruction has been relieved after proximal colostomy;
• Has received and failed ≥ 2 line of chemotherapy or progressed on or intolerable to oxaliplatin, irinotecan and fluorouracil chemotherapy after diagnosed with mCRC;
• ECOG PS 0-2;
• Able to swallow tablets;
• Life expectancy of greater than 3 months;
• Adequate bone marrow and organ function;
• If female and of childbearing potential, must:
• Have a negative pregnancy test ≤14 days prior to initiating study treatment
• Agree to avoid pregnancy during and for 3 months after study treatment

If male with a partner of childbearing potential, must:

• Agree to use adequate, medically approved, contraceptive precautions during and for 3 months after the last dose of study treatment.
• Able and willing to provide written informed consent for the study.

Exclusion Criteria:

• Any active autoimmune disease or history of autoimmune disease;
• Those who are using immunosuppressive agents, or systemic or absorbable local hormone therapy to achieve immunosuppressive purpose, and continue to use within 2 weeks before enrollment;
• Severe allergic reaction to other monoclonal antibodies;
• Subjects with clinical symptoms of untreated active brain metastasis or meningeal metastasis;
• Have received other PD-1 antibody therapy or other immunotherapy targeting PD-1/PD-L1 in the past;
• Patients with high TMB (≥ 30Muts/Mb) and germline or somatic POLE/POLD1 gene mutations in the exonuclease domain;
• There are clinical symptoms or diseases of heart that are not well controlled, such as: (a) heart failure of NYHA level 2 or above (b) unstable angina pectoris (c) myocardial infarction occurred within 1 year (d) clinically significant supraventricular or ventricular arrhythmia needs treatment or intervention;
• Known hereditary or acquired bleeding and thrombophilia or being treated with thrombolysis or anticoagulation;
• Urinary protein ≥ ++, or the 24-hour urine protein quantification greater than 1.0g;
• Clinically significant bleeding symptoms or clear bleeding tendency within 3 months before enrollment;
• Subjects with active infection;
• Congenital or acquired immune deficiency (such as HIV infected persons), or active hepatitis (hepatitis B: HBsAg positive and HBV DNA ≥ 10^4 copies/ml; hepatitis C: HCV antibody positive);
• Other advanced malignant tumors within 5 years (except cured skin basal cell carcinoma, cervical carcinoma in situ, ovarian cancer, thyroid cancer and breast cancer);
• Live vaccine may be inoculated less than 4 weeks before the study medication or during the study period;
• Known or suspected to be allergic to the study drug or to any drug given in this trial;
• Have any other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions that makes the subject not eligible according to the judgment of the investigator.

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: patients with mCRC; Tislelizumab 200mg ivdrip every 3 weeks; Fruquintinib 5mg qd day 1-14, every 3 weeks	Drug: Tislelizumab & Fruquintinib; combinational treatment of Tislelizumab and Fruquintinib until PD, intolerable toxicity, death or withdrawal of informed consent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The proportion of patients with a confirmed complete response or partial response	up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	PFS is defined as the time from enrollment to the first documented progressive disease (PD) or death due to any cause, whichever occurred first.	up to 3 years
Overall Survival (OS)	OS is defined as the time from enrollment to death due to any cause.	up to 3 years
Disease control rate	The proportion of patients with a best overall response of confirmed complete or partial response, or stable disease (CR+ PR + SD).	up to 3 years
Incidence of Treatment-Emergent Adverse Events	Safety and tolerance evaluated by incidence, severity and outcomes of adverse events (AEs) and categorized by severity in accordance with the NCI CTC AE Version 5.0.	until 60 days after last patient last study drug treatment

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Hutchmed; BeiGene
• Investigators: Principal Investigator: Peirong Ding, M.D., Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2025
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: January 10, 2023
• First Submitted That Met QC Criteria: January 10, 2023
• First Posted (Actual): January 19, 2023

Study Record Updates

• Last Update Posted (Actual): July 9, 2024
• Last Update Submitted That Met QC Criteria: July 5, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• 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; Antineoplastic Agents; Antineoplastic Agents, Immunological; Tislelizumab
• Other Study ID Numbers: SL-B2022-653-01

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