Optimal Application Timing of ADC Drugs for Advanced Breast Cancer

A Prospective, Randomized Controlled Phase II Trial Investigating the Optimal Timing of Antibody Drug Conjugates in Advanced HER2-Negative Breast Cancer Patients

This study plans to initiate a prospective, randomized controlled trial to investigate the optimal timing of antibody drug conjugate (ADC) therapy in the management of advanced Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer.

Primary Objective:

To compare the difference in PFS2 (Time from randomization to disease progression after second therapy) between antibody-drug conjugate (ADC) followed by chemotherapy versus chemotherapy followed by ADC in the treatment of advanced HER2-negative breast cancer.

Secondary Objectives:

To compare overall survival (OS), adverse events, patient-reported outcomes, and cost-effectiveness between the two treatment sequences. Additionally, to identify potential biomarkers predictive of benefit from frontline ADC therapy.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer Females
• Intervention / Treatment: Drug: Antibody drug conjugate; Drug: Chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dan Lyu; Phone Number: 0086-19800367870; Email: lvdan9303@163.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China
      • Recruiting
      • Liaoning Cancer Hospital & Institute
      • Contact: Liaoning Cancer Hospital & Institute; Phone Number: 86-19800367870; Email: lvdan9303@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female patients aged 18-75 years;
2. Histologically confirmed advanced HER2-negative breast cancer, including IHC 2+/ISH-, IHC 1+/ISH-, and IHC 0/ISH- subtypes;
3. Completed first-line combination chemotherapy for advanced/metastatic disease (specific regimen not restricted), with disease progression (PD) evaluated per RECIST criteria (HR-positive patients must have received at least one line of endocrine therapy);
4. Electrocorticography (ECOG) performance status < 2;
5. Estimated life expectancy ≥ 12 weeks;

6. Adequate bone marrow function, defined as:

   • ANC ≥ 1.5 × 10⁹/L
   • Platelets ≥ 90 × 10⁹/L
   • Hemoglobin ≥ 90 g/L

7. Adequate hepatic and renal function, defined as:

   • Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
   • AST or ALT ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases)
   • Creatinine clearance ≥ 60 mL/min
8. Signed informed consent obtained prior to any study-related procedures or treatments, confirming the patient's willingness to participate and comply with study requirements.

Exclusion Criteria:

1. Prior treatment with an ADC after disease recurrence or metastasis;
2. Pregnant or breastfeeding women;
3. No evaluable recurrent or metastatic lesions as defined by RECIST 1.1 criteria;
4. Symptomatic brain parenchymal and/or leptomeningeal metastases with symptoms not adequately controlled by treatment;
5. History of other malignancies within the past 5 years, except for adequately treated carcinoma in situ of the cervix, cutaneous squamous cell carcinoma, or well-controlled localized basal cell carcinoma of the skin;
6. Psychiatric disorders or other conditions that may interfere with patient compliance;
7. Recent history of serious and uncontrolled systemic diseases, such as clinically significant cardiovascular disease, pulmonary disease, metabolic disorders, or arterial/venous thromboembolic events;
8. Concurrent use of other investigational drugs, or participation in another clinical trial within 30 days prior to enrollment;
9. Known or suspected allergy to any study drug or its excipients;
10. Any other condition that, in the opinion of the investigator, renders the patient unsuitable for participation in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ADC followed by chemotherapy group; Patients will receive an ADC agent as second-line treatment until disease progression or unacceptable toxicity, followed by physician's choice of chemotherapy as third-line treatment	Drug: Antibody drug conjugate; The selection of ADC agents will be based on the patient's molecular subtype. For Hormone receptor (HR)+/HER2-low patients, anti-HER2 ADCs such as trastuzumab deruxtecan may be used. For HR+/HER2-zero patients, TROP-2-targeted ADCs such as sacituzumab govitecan are preferred. For HR-/HER2-low patients, either anti-HER2 ADCs or Trophoblast cell surface antigen 2 (TROP-2) ADCs may be considered. For HR-/HER2-zero patients, TROP-2 ADCs will be used. The specific ADC regimen will be determined at the discretion of the investigators.; Drug: Chemotherapy; The chemotherapy regimen will consist of standard second-line agents such as capecitabine, eribulin, vinorelbine, or gemcitabine. The specific chemotherapy regimen will be determined at the discretion of the investigators.
Active Comparator: Chemotherapy followed by ADC group; Patients will receive physician's choice of chemotherapy as second-line treatment until disease progression or unacceptable toxicity, followed by an ADC agent as third-line treatment.	Drug: Antibody drug conjugate; The selection of ADC agents will be based on the patient's molecular subtype. For Hormone receptor (HR)+/HER2-low patients, anti-HER2 ADCs such as trastuzumab deruxtecan may be used. For HR+/HER2-zero patients, TROP-2-targeted ADCs such as sacituzumab govitecan are preferred. For HR-/HER2-low patients, either anti-HER2 ADCs or Trophoblast cell surface antigen 2 (TROP-2) ADCs may be considered. For HR-/HER2-zero patients, TROP-2 ADCs will be used. The specific ADC regimen will be determined at the discretion of the investigators.; Drug: Chemotherapy; The chemotherapy regimen will consist of standard second-line agents such as capecitabine, eribulin, vinorelbine, or gemcitabine. The specific chemotherapy regimen will be determined at the discretion of the investigators.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival 2 (PFS2)	Progression-free survival 2 (PFS2) is defined as the time from randomization to disease progression or death (whichever occurs first) following the second treatment.	Up to approximately 20 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time from randomization to death from any cause.	Up to approximately 40 months
Patient-Reported Outcomes (PROs)	Defined as reports directly from patients regarding their health status, functional status, and treatment experience during the period from randomization to disease progression, without interpretation by clinicians or others.	Up to approximately 20 months
Time to Progression (TTP)	Defined as the time from randomization to disease progression.	Up to approximately 20 months
Adverse event	Defined as the occurrence of adverse events after enrollment, evaluated according to NCI CTCAE version 5.0.	Up to approximately 20 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cost-effectiveness	Defined as the total treatment-related costs incurred after patient enrollment.	Up to approximately 20 months
Exploratory Endpoint	The correlation between baseline tumor mutation burden level and progression-free survival 2 (PFS2).	Up to approximately 20 months

Collaborators and Investigators

• Sponsor: Liaoning Cancer Hospital & Institute
• Collaborators: National Cancer Center, China
• Investigators: Principal Investigator: Tao Sun, Liaoning Cancer Hospital & Institute; Principal Investigator: Bo Lan, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: July 31, 2025
• First Submitted That Met QC Criteria: June 17, 2026
• First Posted (Actual): June 18, 2026

Study Record Updates

• Last Update Posted (Actual): June 18, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Breast cancer; Antibody drug conjugate; HER2-negative; Timing of application
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Amino Acids, Peptides, and Proteins; Proteins; Therapeutics; Pharmacologic Actions; Chemical Actions and Uses; Antibodies; Immunoglobulins; Blood Proteins; Serum Globulins; Globulins; Immunoconjugates; Drug Therapy
• Other Study ID Numbers: OPTIMA-BC

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
• product manufactured in and exported from the U.S.: No