Ivosidenib Plus mFOLFOXIRI and Celecoxib for BRAF-targeted Therapy-refractory BRAF V600E-mutant Colorectal Cancer Patients

NCT07809893 | Recruiting Phase 2

• 1 other identifier: CSWOG-C11
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

BRAF-mutated colorectal cancer, primarily driven by the BRAF V600E mutation, accounts for approximately 5-10% of all colorectal cancer cases and is associated with aggressive disease progression and poor prognosis, particularly in metastatic settings. Following first- and second-line treatments, including chemotherapy and targeted therapy, the median overall survival of patients is typically less than 24 months, and tumor progression is rapid once resistance develops. Previous studies have demonstrated that immune checkpoint inhibitors, such as anti-PD-1 therapies, show limited efficacy in microsatellite-stable (MSS) colorectal cancers but may hold promise when combined with other agents to overcome resistance mechanisms. Ivonescimab, a bispecific antibody targeting PD-1 and VEGF, has shown antitumor activity in various solid tumors by simultaneously inhibiting immune evasion and angiogenesis. The combination of ivonescimab with intensive chemotherapy like FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) and the COX-2 inhibitor celecoxib aims to enhance antitumor immunity, reduce inflammation, and improve vascular normalization in resistant tumors. However, there are no reported studies on this specific combination for chemotherapy- and BRAF inhibitor-resistant BRAF-mutated colorectal cancer. Therefore, the aim of this study is to evaluate the efficacy and safety of ivonescimab combined with FOLFOXIRI and celecoxib in patients with chemotherapy- and BRAF inhibitor-resistant BRAF-mutated advanced colorectal cancer, with a focus on assessing objective response rate (ORR) and tolerability.

Conditions

Colorectal Cancer

Keywords

BRAF V600E mutation

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR)

  Defined as the proportion of patients who are assessed for best overall response as complete response (CR) or partial response (PR) according to RECIST version 1.1. If the response reaches CR or PR, it must be confirmed at least 4 weeks (28 days) after the initial evaluation.

  3 years

Secondary Outcomes (4)

• Disease control rate (DCR)

  3 years

• Progression-free survival (PFS)

  3 years

• Overall survival (OS)

  3 years

• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  3 years

Study Arms (1)

Ivonescimab +mFOLFOXIRI +celecoxib

EXPERIMENTAL

Patients receive Ivonescimab and mFOLFOXIRI on day1 of every two weeks and celecoxib on day 1-14 of every two weeks

Drug: Ivonescimab +mFOLFOXIRI +celecoxib

Interventions

Ivonescimab +mFOLFOXIRI +celecoxib DRUG

Ivonescimab（AK112）10mg/kg, intravenously for 60 minutes, followed by mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) every 2 weeks, celecoxib 400mg oral everyday.

Also known as: Oxaliplatin, Irinotecan, 5-Fluorouracil, Leucovorin, Ivonescimab, celecoxib

Ivonescimab +mFOLFOXIRI +celecoxib

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed the informed consent form voluntarily.
• Aged 18-70.
• Colorectal adenocarcinoma with definite histological evidence, with evidence of distant metastasis;
• Diagnosed with colon or rectal adenocarcinoma, with evidence of distant metastasis;
• Genetic testing indicates a BRAF V600E mutation;
• Previously received first-line treatment including FOLFOX/CAPOX or FOLFIRI/CAPIRI and experienced disease progression or intolerance. Among them, patients who used oxaliplatin in adjuvant therapy should have experienced disease progression within 12 months after completing adjuvant therapy; Previously received anti-BRAF V600E targeted therapy and failed, including but not limited to vemurafenib, dabrafenib, and encorafenib;
• Patients must have measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• Adequate organ function based on the following laboratory test values obtained within 7 days prior to treatment: neutrophil count ≥1.5×109/L, platelet count ≥75×109/L, serum total bilirubin ≤1.5× upper limit of normal value (UNL), aspartate transferase ≤2.5×UNL, alanine transferase ≤2.5×UNL, serum creatinine ≤2.5×UNL;
• Female subjects must be either postmenopausal for at least 1 year, have undergone surgical sterilization at least 6 weeks prior, or must agree to use appropriate contraceptive measures;
• Male subjects must agree to use appropriate contraceptive measures to prevent their partners from becoming pregnant;
• Willing and able to comply with research protocols and visit plans.

You may not qualify if:

• Prior to enrollment, ctDNA testing shows known KRAS mutation, NRAS mutation, or ERBB2 gene amplification; tumor tissue testing shows mismatch repair gene deficiency or high microsatellite instability, KRAS mutation, NRAS mutation, or ERBB2 gene amplification;
• Presence of intestinal obstruction, active bleeding, or intestinal perforation requiring emergency intervention;
• Underwent major surgery or severe trauma in the previous 4 weeks;
• Active coronary artery disease, severe/unstable angina, or newly diagnosed angina or myocardial infarction within 12 months prior to study participation;
• Occurrence of thrombotic or embolic events within the past 6 months;
• New York Heart Association (NYHA) class II or higher congestive heart failure;
• Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis;
• Any active, known, or suspected autoimmune disease.
• Presence of interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic disease;
• Any unresolved treatment-related adverse events of grade 2 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (excluding peripheral neuropathy, anemia, hair loss, and skin pigmentation);
• Previous treatment with programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies;
• Known or suspected history of allergy to any of the related drugs used in the study;
• Pregnant or breastfeeding women.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

Gastrointestinal Hospital, Sun Yat-sen University

Guangzhou, Guangdong, 510655, China

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Oxaliplatin; Irinotecan; Fluorouracil; Leucovorin; Celecoxib

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

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Camptothecin; Alkaloids; Heterocyclic Compounds; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Benzenesulfonamides; Sulfonamides; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles

Study Officials

• Yanhong Deng

  Sixth Affiliated Hospital, Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yanhong Deng, M.D.

CONTACT

00862019325106525; dengyanh@mail.sysu.edu.cn

Zehua Wu

CONTACT

00862015902020757; wuzh88@mail.sysu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• 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: January 28, 2026
• First Posted: September 9, 2026
• Study Start: August 10, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): June 30, 2028
• Last Updated: September 9, 2026

Record last verified: 2026-09

Locations

CN (1)