Reverse HER2-negative Immune Resistant Breast Cancer (Resilire)

November 13, 2025 updated by: Zhimin Shao, Fudan University
This is a Phase II, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitor in HER2-negative breast cancer patients who progressed during previous immune checkpoint inhibitors.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a Phase II, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitors in metastatic HER2-negative breast cancer patients who progressed during or following previous immune checkpoint inhibitors. HER2-negative breast cancers include luminal breast cancers and triple-negative breast cancers.

Current clinical studies on immunotherapy for luminal breast cancer are limited, with inconsistent results across trials. The KEYNOTE-028 study reported an objective response rate (ORR) of only 12% for pembrolizumab in PD-L1-positive, previously treated advanced luminal breast cancer patients, demonstrating limited efficacy. The GIADA phase II trial revealed a pathological complete response (pCR) rate of 16.3% with neoadjuvant chemotherapy followed by immunotherapy in luminal breast cancer. Additionally, trials such as NCT02779751 and NCT03051659 also indicated limited clinical benefits from immunotherapy. However, the I-SPY2 platform showed that combinations like olaparib, paclitaxel, and immunotherapy or wP-AC chemotherapy with immunotherapy could improve pCR rates in high-risk patients. Despite advancements, immunotherapy benefits are limited in luminal breast cancer compared to other cancers, with advanced-stage patients more likely to develop resistance.

Recent clinical studies on advanced triple-negative breast cancer have shown that immunotherapy combined with chemotherapy demonstrates superior clinical efficacy compared to traditional chemotherapy alone. Phase III trials such as IMPassion130 and Keynote-522 have confirmed that PD-1/PD-L1 inhibitors used with chemotherapy significantly improve progression-free survival, overall survival, and pathological complete response rates. However, compared to other malignancies, triple-negative breast cancer patients still show relatively low overall response rates to immunotherapy: treatment-naïve patients achieve objective response rates of only 10-20% with immunotherapy monotherapy, though this improves to 56% when combined with chemotherapy, extending median progression-free survival to 7.2 months. Unfortunately, efficacy decreases significantly in later treatment lines, with objective response rates falling to just 10.6-15.9% after multiple previous treatments. Thus, strategies to overcome immunotherapy resistance or increase the sensitivity of immunotherapy efficacy are urgently needed for HER2-negative breast cancer patients.

The preclinical results of our center show that retinoic acid can enhance the anti-tumor immune response by promoting the peroxidation of macrophages, increasing the infiltration and function of cytotoxic CD8+ T cells, inhibiting the growth of tumors in mice. Based on the preclinical study, the investigators designed this study to enroll metastatic HER2-negative breast cancer patients who have progressed during or following immunotherapy, and to explore the efficacy of retinoic acid combined with immunotherapy at a clinical level, providing new strategies of combined treatment for HER2-negative breast cancer patients.

Study Type

Interventional

Enrollment (Estimated)

10

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Shanghai Municipality
      • Shanghai, Shanghai Municipality, China, 200032
        • Recruiting
        • Fudan University Shanghai Cancer Center
        • Contact:
        • Contact:
          • Wenjuan Zhang, Doctor
          • Phone Number: 8664175590

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • ECOG Performance Status of 0, 1, or 2
  • Metastatic or locally advanced, histologically confirmed luminal breast cancer (defined as: ER positive when immunohistochemistry shows >1% positive tumor cells, PR positive when >1% tumor cells are positive, and HER2 negative when scored as 0-1+ or when HER2 2+ shows no amplification by FISH or CISH) or triple negative breast cancer (defined as: ER negative when immunohistochemistry shows <1% positive tumor cells, PR negative when <1% tumor cells are positive, and HER2 negative when scored as 0-1+ or when HER2 2+ shows no amplification by FISH or CISH).
  • Radiologic/objective evidence of recurrence or disease progression after immunotherapy (combined with targeted therapy or chemo ) for metastatic breast cancer (MBC)
  • Adequate hematologic and end-organ function, laboratory test results, obtained within 14 days prior to initiation of study treatment.

For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm

  • Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
  • have the cognitive ability to understand the protocol and be willing to participate and to be followed up.

Exclusion Criteria:

  • Symptomatic, untreated, or actively progressing CNS metastases
  • Active or history of autoimmune disease or immune deficiency
  • Significant cardiovascular disease
  • History of malignancy other than breast cancer within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death
  • Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded) within 3 weeks prior to initiation of study treatment.
  • Pregnancy or breastfeeding, or intention of becoming pregnant during the study
  • History of allergies to the drug components of this trial
  • History of eosinophilosis or mastocytosis
  • Patients who have been using oral steroid hormones for a long time will need to stop for 4 weeks if they have used them occasionally in the past

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: retinoic acid with anti-PD-1 immunotherapy
Drug: anti-PD-1 antibody and chemotherapy
PD-1 antibody SHR1210 200mg q2w chemotherapy (whether and which should be given depends on the treatment regimen before enrollment)
Drug: Retinoic Acid
Retinoic acid 20mg tid, p.o.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate (ORR)
Time Frame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Immune changes in peripheral blood
Time Frame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Clinical Benefit Rate (CBR)
Time Frame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Clinical benefit rate (CBR) is defined as the proportion of subjects who achieve a complete response (CR), partial response (PR), or have durable stable disease (SD) after treatment. It is intended to measure a clinically meaningful and broader disease control effect. CBR includes subjects who have achieved CR and PR, as well as those who have maintained SD for a specified duration (≥24 weeks). The evaluation is based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Subjects must have measurable tumor lesions at baseline. The efficacy assessment is categorized into CR, PR, SD, and Progressive Disease (PD) according to RECIST 1.1 criteria.
Baseline until disease progression or loss of clinical benefit, assessed up to 6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Control Rate (DCR)
Time Frame: Baseline through end of study, assessed up to 6 months
Baseline through end of study, assessed up to 6 months
Progression Free Survival (PFS)
Time Frame: Randomization to death from any cause, through the end of study, assessed up to 6 months
Randomization to death from any cause, through the end of study, assessed up to 6 months
Safety and treatment-related AEs
Time Frame: Randomization to death from any cause, through the end of study, assessed up to 12 months
Randomization to death from any cause, through the end of study, assessed up to 12 months
Biomarker analysis
Time Frame: Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Retinoic acid related genes, cell functions and microbes will be measured in pre-treatment and post-treatment samples (tumor tissue, blood and fecal samples) to predict therapy response.
Baseline until disease progression or loss of clinical benefit, assessed up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fudan University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 12, 2025

Primary Completion (Estimated)

October 1, 2026

Study Completion (Estimated)

October 1, 2027

Study Registration Dates

First Submitted

December 9, 2024

First Submitted That Met QC Criteria

December 9, 2024

First Posted (Actual)

December 12, 2024

Study Record Updates

Last Update Posted (Actual)

November 17, 2025

Last Update Submitted That Met QC Criteria

November 13, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2411307-7

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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