Dual EGFR/HER2 Blockade Combined With Irinotecan for the Treatment of HER2-Positive Metastatic Colorectal Cancer

NCT07059338 | Not Yet Recruiting Phase 2

• 1 other identifier: 2025ZSLYEC-160
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

In colorectal cancer (CRC), HER2 has emerged as a critically targeted biomarker in recent years. Although multiple clinical trials have demonstrated the potential of HER2-targeted therapies in HER2-positive (overexpressed/amplified) metastatic CRC (mCRC), the duration of treatment response remains short with rapid disease progression. This underscores the urgent need to develop novel therapeutic strategies for HER2-positive mCRC. The EGFR pathway is constitutively activated in CRC and mediates resistance to HER2-targeted therapies through the formation of EGFR-HER2 heterodimers. Notably, EGFR-targeting antibodies combined with irinotecan can reverse irinotecan chemoresistance. Building upon these mechanisms, this study proposes to evaluate the combination of trastuzumab (anti-HER2), cetuximab beta (anti-EGFR), and irinotecan in chemotherapy-refractory HER2-positive mCRC.

Conditions

HER2 Positive; Colorectal Cancer (CRC)

Keywords

colorectal cancer

Outcome Measures

Primary Outcomes (1)

• 6-month progression-free-survival rates

  Progression-free survival defined as the time from randomization to documented disease progression according to RECIST or death from any cause. We computed the 6-month PFS rate based on the available follow-up data.

  2 years

Secondary Outcomes (4)

• Objective response rate

  2 years

• Disease control rate

  2 years

• overall survival

  3 years

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

  3 years

Other Outcomes (3)

• Treatment-emergent genetic variants analysis by ctDNA sequencing

  2 years

• Baseline proteomic predictive biomarkers for treatment efficacy

  3 years

• Treatment-induced proteomic alterations

  3 years

Study Arms (1)

Trastuzumab +Cetuximab β+Irinotecan

EXPERIMENTAL

Treatment regimen: All agents will be administered via intravenous infusion, consisting of trastuzumab (4 mg/kg every 2 weeks), cetuximab beta (500 mg/m² every 2 weeks) in combination with irinotecan (180 mg/m² every 2 weeks). Comprehensive radiological and laboratory assessments will be conducted after every 4 treatment cycles (8 weeks).

Drug: Trastuzumab +Cetuximab β+Irinotecan

Interventions

Trastuzumab +Cetuximab β+Irinotecan DRUG

Trastuzumab 4 mg/kg , Cetuximab β: 500 mg/m² ,Irinotecan 180 mg/m², repeat once every 2 weeks

Also known as: HER2 and EGFR dual-targeted therapy combined with irinotecan

Trastuzumab +Cetuximab β+Irinotecan

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed and dated informed consent must be obtained voluntarily from the subject prior to performing any study-related procedures (non-routine care), in accordance with regulatory and institutional guidelines.
• to 75 years of age, inclusive.
• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum with evidence of distant metastasis.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• HER2-positive tumor with wild-type KRAS, NRAS, and BRAF genes confirmed by testing at any time prior to screening. HER2 positivity is defined as: Immunohistochemistry (IHC) showing HER2 3+ staining in \>50% of tumor cells; or HER2 2+ by IHC with positive fluorescence in situ hybridization (FISH): HER2/CEP17 ratio ≥2.0 in \>50% of tumor cells; or Next-generation sequencing (NGS) of tissue or circulating tumor DNA (ctDNA) demonstrating HER2 copy number ≥6.
• Adequate organ function as evidenced by:
• Absolute neutrophil count ≥1.5×10\^9/L Platelet count ≥75×10\^9/L Serum total bilirubin ≤1.5×upper normal limit (UNL) Aspartate aminotransferase (AST) ≤2.5×UNL Alanine aminotransferase (ALT) ≤2.5×UNL Serum creatinine ≤1.5×UNL
• Disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, including: Subjects who received oxaliplatin in the adjuvant setting must have experienced disease progression within 6 months after completing adjuvant therapy.Patients who decline standard therapy due to intolerable toxicity are eligible.
• Presence of at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Willing and able to comply with the study protocol and visit schedule

You may not qualify if:

• Known KRAS, NRAS, or BRAF mutations detected by ctDNA testing prior to enrollment; or tumors with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).
• Concurrent intestinal obstruction, active bleeding, or perforation requiring emergency surgery.
• Major surgery (e.g., laparotomy, thoracotomy, or organ resection via laparoscopy) or significant trauma within 4 weeks prior to study entry (surgical incision must be fully healed before enrollment).
• Active coronary artery disease within 12 months before screening, including severe/unstable angina, newly diagnosed angina, or myocardial infarction.
• History of thrombosis or embolism within 6 months, including cerebrovascular accident (transient ischemic attack included), pulmonary embolism, or deep vein thrombosis.
• Congestive heart failure classified as New York Heart Association (NYHA) Class II or higher.
• HIV infection or AIDS; untreated active hepatitis (HBV-DNA ≥500 IU/mL for hepatitis B; detectable HCV-RNA for hepatitis C); or HBV/HCV co-infection.
• Interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases (e.g., diabetes, hypertension, pulmonary fibrosis, acute pneumonia).
• Persistent ≥Grade 2 toxicities (per CTCAE v5.0) from prior therapies (excluding peripheral neuropathy, anemia, alopecia, or skin hyperpigmentation).
• Known or suspected hypersensitivity to any study drugs.
• Pregnancy or lactation.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

The Sixth Affiliated Hospital of Sun Yat-sen University

Guangzhou, China

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Irinotecan

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)

Camptothecin; Alkaloids; Heterocyclic Compounds

Central Study Contacts

Yanhong Deng

CONTACT

86-13925106525; 13925106525@163.com

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: Professor

Study Record Dates

• First Submitted: June 5, 2025
• First Posted: July 10, 2025
• Study Start: July 11, 2025
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): December 30, 2028
• Last Updated: July 10, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)