RC48 Plus Bevacizumab or Pyrotinib in HER2-Positive Metastatic Breast Cancer After T-DXd Failure: A Phase II Study

NCT ID: NCT07065435

Last Updated: 2025-07-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-01
• Study Completion Date: 2026-01-01

Brief Summary

This multicenter, Phase II study (RADIANT-BC01) evaluates the efficacy and safety of Disitamab Vedotin (RC48) in combination with either bevacizumab or pyrotinib in adult patients with HER2-positive metastatic breast cancer whose disease has progressed on prior trastuzumab deruxtecan (T-Dxd) therapy.

Eligible participants will be randomized 1:1 to receive RC48 plus bevacizumab (7.5 mg/kg IV every 2 weeks) or RC48 plus pyrotinib (320 mg orally once daily). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.

The primary endpoint is objective response rate (ORR); key secondary endpoints include progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety.

This study aims to identify new post-T-Dxd treatment options and improve outcomes for patients with advanced HER2-positive breast cancer.

Detailed Description

Despite the remarkable benefits of trastuzumab deruxtecan (T-Dxd) as second-line therapy, resistance inevitably develops in HER2-positive metastatic breast cancer, and no standard treatment exists after T-Dxd failure. Disitamab Vedotin (RC48) is a novel antibody-drug conjugate (ADC) targeting HER2, with a cathepsin-cleavable linker and MMAE payload that has demonstrated encouraging antitumor activity and tolerability in earlier studies. Preclinical and real-world data suggest that combining RC48 with anti-angiogenic agents (bevacizumab) or a pan-HER tyrosine kinase inhibitor (pyrotinib) may enhance tumor penetration, overcome resistance mechanisms, and provide synergistic effects without overlapping toxicity.

RADIANT-BC01 is designed as two parallel Simon two-stage cohorts: one evaluating RC48 + bevacizumab and the other RC48 + pyrotinib. In each arm, 14 patients will be enrolled in the first stage, with progression to a total of 37 patients if at least five responses are observed. Patients must have received at least two cycles of prior T-Dxd, possess measurable disease per RECIST 1.1, an ECOG performance status of 0-2, and adequate organ function. Key exclusion criteria include uncontrolled comorbidities, active interstitial lung disease, and prior adverse reactions to study agents.

The study's primary objective is to determine the ORR of each combination regimen. Secondary objectives encompass PFS, DCR, DOR, OS, and safety assessments. Exploratory biomarker analyses will be conducted on serial blood and stool samples to identify predictors of response and resistance. Tumor assessments occur every 6 weeks, with safety evaluations at each treatment visit and a follow-up period of 90 days post-treatment, then every 3 months for survival status. By exploring these combination strategies, RADIANT-BC01 seeks to establish new therapeutic options for patients who have exhausted current HER2-targeted treatments.

Conditions

HER2 + Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

RC48 + Bevacizumab

Participants receive Disitamab Vedotin (RC48) at 2.0 mg/kg IV every 2 weeks plus Bevacizumab 7.5 mg/kg IV every 2 weeks. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.

Group Type: EXPERIMENTAL

Disitamab Vedotin (RC48)

Intervention Type: DRUG

A HER2-targeted antibody-drug conjugate comprising a humanized anti-HER2 monoclonal antibody linked via a cathepsin-cleavable MC-VC-PAB linker to the microtubule inhibitor MMAE (drug-to-antibody ratio ≈4). Administered intravenously at 2.0 mg/kg every 2 weeks.

Bevacizumab

Intervention Type: DRUG

A recombinant humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) to inhibit tumor angiogenesis. Administered intravenously at 7.5 mg/kg every 2 weeks in combination with RC48.

RC48 + Pyrotinib

Participants receive Disitamab Vedotin (RC48) at 2.0 mg/kg IV every 2 weeks plus Pyrotinib 320 mg orally once daily (post-meal). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or initiation of new anticancer therapy.

Group Type: EXPERIMENTAL

Disitamab Vedotin (RC48)

Intervention Type: DRUG

A HER2-targeted antibody-drug conjugate comprising a humanized anti-HER2 monoclonal antibody linked via a cathepsin-cleavable MC-VC-PAB linker to the microtubule inhibitor MMAE (drug-to-antibody ratio ≈4). Administered intravenously at 2.0 mg/kg every 2 weeks.

Pyrotinib

Intervention Type: DRUG

An irreversible pan-HER tyrosine kinase inhibitor targeting HER1, HER2, and HER4, inhibiting downstream PI3K/Akt and MAPK signaling. Administered orally at 320 mg once daily (post-meal) in combination with RC48.

Interventions

Disitamab Vedotin (RC48)

A HER2-targeted antibody-drug conjugate comprising a humanized anti-HER2 monoclonal antibody linked via a cathepsin-cleavable MC-VC-PAB linker to the microtubule inhibitor MMAE (drug-to-antibody ratio ≈4). Administered intravenously at 2.0 mg/kg every 2 weeks.

Intervention Type: DRUG

Bevacizumab

A recombinant humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) to inhibit tumor angiogenesis. Administered intravenously at 7.5 mg/kg every 2 weeks in combination with RC48.

Intervention Type: DRUG

Pyrotinib

An irreversible pan-HER tyrosine kinase inhibitor targeting HER1, HER2, and HER4, inhibiting downstream PI3K/Akt and MAPK signaling. Administered orally at 320 mg once daily (post-meal) in combination with RC48.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age ≥18 years.

2. Histologically or cytologically confirmed HER2-positive (IHC 3+ or IHC 2+ with ISH amplification) advanced or metastatic breast cancer.

3. Prior treatment with trastuzumab deruxtecan (T-DXd) and documented disease progression during or after therapy.

4. At least one measurable lesion at baseline as defined by RECIST v1.1.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Adequate organ and marrow function, including:

Absolute neutrophil count ≥1.5 × 10⁹/L Platelet count ≥100 × 10⁹/L Hemoglobin ≥9 g/dL ALT and AST ≤2.5 × ULN Total bilirubin ≤1.5 × ULN Creatinine clearance ≥50 mL/min Estimated life expectancy of ≥12 weeks. Ability to understand and willingness to sign a written informed consent form.

Exclusion Criteria

1. Prior treatment with disitamab vedotin (RC48).

2. Active infections requiring systemic therapy (bacterial, viral, or fungal).

3. History of interstitial lung disease or non-infectious pneumonitis requiring corticosteroid therapy.

4. Uncontrolled cardiovascular disease, including but not limited to: uncontrolled hypertension, recent myocardial infarction (within 6 months), unstable angina, or congestive heart failure.

5. Pregnant or breastfeeding women.

6. Concurrent malignancy other than adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless disease-free for ≥5 years.

7. Participation in another interventional clinical trial with investigational agents not yet completed.

8. Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements or jeopardize their safety.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

RenJi Hospital

OTHER

Sponsor Role: collaborator

Anhui Provincial Hospital

OTHER_GOV

Sponsor Role: collaborator

The Affiliated Hospital of Xuzhou Medical University

OTHER

Sponsor Role: collaborator

The First Hospital of Jilin University

OTHER

Sponsor Role: collaborator

Shanghai Minhang Central Hospital

OTHER

Sponsor Role: collaborator

Zhejiang Cancer Hospital

OTHER

Sponsor Role: collaborator

Huai'an First People's Hospital

OTHER

Sponsor Role: collaborator

The First Affiliated Hospital with Nanjing Medical University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

The First Affiliated Hospital with Nanjing Medical University

Nanjing, Jiangsu, China

Site Status: RECRUITING

Countries

China

Central Contacts

Wei Li, Ph.D

Role: CONTACT

liwei1218@njmu.edu.cn

025-68307102

Facility Contacts

Wei Li, Ph.D

Role: primary

liwei1218@njmu.edu.cn

025-68307102

Other Identifiers

NJMU-BC07

Identifier Type: -

Identifier Source: org_study_id