The purpose of this study is to assess the safety and efficacy of RC48 (a HER2 antibody drug conjugate with MMAE payload) in combination with gemcitabine or capecitabine (with or without trastuzumab/inetetamab), for treatment of patients with HER2-positive advanced breast cancer (ABC) who have developed disease progression or intolerance to prior therapy with a topoisomerase I inhibitor antibody-drug conjugate (TOP1i-ADC).
This is a randomized, open-label, parallel-controlled, multi-centered, phase 3 clinical study enrolling patients with HER2-positive ABC who have experienced disease progression or intolerance to prior TOP1i-ADC treatment, with ≤ 3 lines of systemic therapy received in the recurrent/metastatic setting. The study consists of two main parts: Part 1: Run-in Phase and Part 2: Randomized Controlled Trial. Part 1: Run-in Phase The primary objective of the Run-in Phase is to preliminarily verify whether the addition of trastuzumab or inetetamab to the combination regimen of RC48 plus chemotherapy can enhance the anti-tumor efficacy and whether it is associated with any specific toxicities. This phase comprises two regimens, and 30 patients will be randomized 1:1 to receive treatment with either of the two regimens: RC48 plus Gemcitabine or Capecitabine; RC48 plus Gemcitabine or Capecitabine, plus Trastuzumab or Inetetamab. . Part 2: Randomized Controlled Trial The primary objective of this part is to assess the anti-tumor activity and safety of the optimal regimen identified in Part 1 in patients with HER2-positive ABC who have failed prior TOP1i-ADC treatment. Eligible patients will be stratified and randomized 1:1 to either the experimental group or the control group. 238 patients are expected to be enrolled in Part 2. Experimental group: RC48 plus Gemcitabine or Capecitabine ± Trastuzumab or Inetetamab. Control group: Trastuzumab or Inetetamab plus Gemcitabine or Capecitabine.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
2.0mg/kg every two weeks
1000mg/m2 on days 1 and 8 every three weeks
1000 mg/m2 twice daily on days 1 to14 every three weeks
Median progression free survival (by investigator)
Progression-Free Survival (PFS), analyzed using the Kaplan-Meier method, is defined as the time from randomization to the first occurrence of disease progression or death, whichever comes first. For subjects without evidence of disease progression or death at the time of analysis, data will be censored at the date of their last tumor assessment.
Time frame: The observation period for this endpoint is up to 36 months, and will be terminated early upon disease progression or death.
Objective Response Rate (by investigator)
Objective response rate (ORR), defined as best overall response of either complete or partial response based on RECIST 1.1 criteria, will be assessed among participants who have measurable disease at screening and start protocol therapy.
Time frame: Baseline at screening and the time of the identification of disease progression, assessed up to 36 months.
Median overall survival (by investigator)
Overall Survival (OS), analyzed using the Kaplan-Meier method, is defined as the time from randomization to death from any cause. For participants who remain alive at the time of analysis, data will be censored at the date of last contact or informed consent withdrawal.
Time frame: The observation period for this endpoint will be terminated upon death or if disease progression occurs after 1 year of follow-up.
Duration of response (by investigator)
Duration of Overall Response (DOR) is defined as the time from the first documentation of meeting the criteria for Complete Response (CR) or Partial Response (PR) to the first date of objectively confirmed disease recurrence, progression, or death from any cause. For disease progression, the reference shall be the smallest tumor measurements recorded since the initiation of treatment.
Time frame: The observation period for this endpoint is up to 36 months, and will be terminated early upon disease progression or death.
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6 mg/kg once every three weeks, with an initial loading dose of 8 mg/kg
6 mg/kg once every three weeks, with an initial loading dose of 8 mg/kg
Disease control rate (by investigator)
Disease control rate (DCR) is defined as the percentage of participants with CR, PR, or stable disease (SD) by investigator per RECIST v1.1.
Time frame: The observation period for this endpoint is up to 36 months, and will be terminated early upon disease progression or death.
Adverse events
The number of participants who experienced an adverse event (AE) based on the Common Toxicity Criteria for Adverse events Version 5.0 (CTCAEv5) as reported on case report forms, whether or not considered related to the investigational medicines.
Time frame: The observation period for this endpoint is up to 36 months.