Neoadjuvant Study of DV in Combination Toripalimab or Sequence Chemotherapy in HR-negative, HER2 Low-expressing Breast Cancer

A Randomized, Multicenter, Open-Label Phase II Neoadjuvant Study to Evaluate the Safety and Efficacy of Disitamab Vedotin in Combination Toripalimab or Sequence Chemotherapy in Participants With HR-negative, HER2 Low-expressing Breast Cancer

The purpose of this study is to evaluate the Safety and Efficacy of Neoadjuvant study of DV in combination Toripalimab i or sequence chemotherapy in HR-negative, HER2 low-expressing Breast Cancer

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Disitamab Vedotin Injection （18 weeks）; Drug: Toripalimab （18weeks）; Drug: Carboplatin; Drug: Disitamab Vedotin Injection （12 weeks）; Drug: Sequential Epirubicin; Drug: Sequential CTX; Drug: Toripalimab （12weeks）

Detailed Description

This is an open-label, randomized, multicenter, Phase II Neoadjuvant Therapy Study designed to evaluate the Safety and Efficacy of Neoadjuvant study of DV in combination Toripalimab or sequence chemotherapy in HR-negative, HER2 low-expressing Breast Cancer The primary objectives of the study are to explore combination neoadjuvant therapy in participants with previously untreated HR-negative, HER2 low-expressing breast cancer, by assessment of tpCR and EFS.

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

Contacts and Locations

• Study Contact: Name: Changling Li; Phone Number: +8610-58075763; Email: changling.li@remegen.com

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410008
      • Not yet recruiting
      • Xiangya Hospital Central South University
      • Contact: Juan Huang, M.D
    • Changsha, Hunan, China, 410031
      • Not yet recruiting
      • Hunan Cancer Hospital
      • Contact: Quzhang Ouyang, M.D
  • Shanghai
    • Shanghai, Shanghai, China
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Zhimin Shao, M.D.
  • Tianjin
    • Tianjin, Tianjin, China, 300060
      • Not yet recruiting
      • Tianjin Medical University Cancer Institute & Hospital
      • Contact: Jin Zhang, M.D
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310005
      • Not yet recruiting
      • Zhejiang Cancer Hospital
      • Contact: Yang Yu, M.D

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Voluntarily participate and sign the informed consent form;
2. Ages≥18 years;
3. Invasive breast tumour tissue with low HER2 expression confirmed by the central laboratory, defined as HER2 protein expression of IHC 1+ or IHC 2+ with no amplification by in situ hybridisation (ISH) (according to the Breast Cancer HER2 Detection Guidelines, 2019 edition) by immunohistochemistry; and specimens from the primary site of the tumour for HER2 detection (wax blocks, biopsies, or fresh tissues are acceptable) are available for HER2 detection
4. Tumour hormone receptor (HR)-negative, defined as IHC-stained invasive carcinoma with a proportion of cells positive for both ER and PgR nuclear staining of <1% according to ASCO/CAP guideline 2020;
5. Histologically confirmed invasive carcinoma of the breast according to AJCC 8th edition investigator-assessed clinical staging T1cN1-2M0, or T2-3N0-2M0
6. Subjects who tolerate and are scheduled to undergo radical breast cancer surgery and have not received any prior anti-tumour systemic therapy for breast cancer, as assessed by the research centre;
7. ECOG PS 0 or 1 point
8. At least one measurable lesion according to RECIST v1.1 criteria;
9. Cardiac function: New York Heart Association (NYHA) class <3; left ventricular ejection fraction ≥55%;

10. Bone marrow or organ function, the following criteria should be met within 7 days prior to study dosing (normal values are based on the clinical trial centre, no transfusion of blood, haematopoietic stimulating factors, albumin or blood products within 14 days prior to the test):

    1. haemoglobin ≥ 90 g/L;
    2. absolute neutrophil count (ANC) ≥ 1.5 × 109 /L;
    3. platelets ≥ 100 × 109 /L;
    4. serum total bilirubin ≤ 1.5 times the Upper Limit of Normal (ULN);
    5. Albuminous Transaminase (AST) and Albuminous Transaminase (ALT) ≤ 2.5 × ULN;
    6. International Normalised Ratio (INR) and Activated Fractional Thromboplastin Time ≤ 1.5 × ULN;
    7. Creatinine Clearance (CrCl) ≥ 60 mL/min according to the Cockcroft-Gault formula method;

11. Female subjects of childbearing potential who meet the following criteria:

    1. A serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of β-human chorionic gonadotropin [β-hCG]) must be negative within 72 hours prior to the first dose of study intervention. Subjects with false-positive results and confirmed non-pregnancy will be eligible for participation in the study.
    2. Must agree to contraception for the duration of the study and for at least 6 months after the last dose of study drug .
    3. Must agree not to breastfeed or donate eggs from the time of signing the informed consent until 6 months after the last dose of study drug .
    4. If sexually active and likely to result in pregnancy, use of at least 2 acceptable contraceptive methods, at least 1 of which must be highly effective, must be continued from the time of informed consent for at least 6 months after the last dose of study drug

12. Male subjects of fertile potential who meet the following criteria:

    1. It is necessary to agree not to donate sperm from the time of signing the informed consent form until at least 4 months after the last dose of study drug.
    2. If sexual intercourse with a person of childbearing potential is likely to result in pregnancy, continuous use of at least 2 acceptable contraceptives, at least 1 of which must be highly effective, beginning at the time of informed consent and continuing until at least 4 months after the last dose of study drug. Beginning at the time of informed consent and continuing for at least 4 months after the last dose of study drug.
    3. If sex with a pregnant or breastfeeding patient, condom use must be continuous from the time of informed consent and continue until at least 4 months after the last dose of study drug.
13. Be able to understand the requirements of the trial and be willing and able to comply with the trial and follow up procedural arrangements.

Exclusion Criteria:

1. With bilateral invasive breast cancer
2. Previous history of invasive breast cancer
3. Previous carcinoma in situ of the breast with adjuvant endocrine therapy within 5 years of surgery
4. Use of investigational drugs or major surgery within 4 weeks prior to start of study drug administration
5. Live or live attenuated vaccine administered within 4 weeks prior to the start of study drug administration or planned to be administered during the study period
6. History of previous allogeneic haematopoietic stem cell transplantation or organ transplantation
7. Prior treatment with PD-(L)1, PD-L2, CTLA4 inhibitors and other antibody-coupled drugs;
8. Uncontrolled or significant cardiovascular disease, including (but not limited to): any of the following within 6 months prior to the first dose: e.g., congestive heart failure (NYHA class III or IV), myocardial infarction or cerebral infarction (except for lacunar cerebral infarction), pulmonary embolism, unstable angina, or arrhythmia requiring treatment at screening; primary cardiomyopathy (e.g., dilated cardiomyopathy, Primary cardiomyopathies (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy); history of clinically significant prolongation of the QTc period, grade II type II AV block or grade III AV block or QTc interval (F method) >470 msec (women) or >450 msec (men); atrial fibrillation (EHRA grade ≥2b); uncontrolled hypertension that is judged by the investigator to be unsuitable; and Hypertension, judged by the investigator to be unsuitable for participation in the study;
9. History of interstitial lung disease requiring treatment or current severe lung disease including, but not limited to, active tuberculosis, interstitial lung disease;
10. Ongoing active infection that requires systemic treatment;
11. Have an active autoimmune disease requiring systemic treatment within the past 2 years (e.g., use of corticosteroids or immunosuppressive drugs, etc.), allowing for relevant replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency)
12. A clear past or present history of a neurological or psychiatric disorder, including epilepsy or dementia
13. Ongoing grade ≥2 sensory or motor neuropathy;
14. Concomitant disease that, in the investigator's judgement, is a serious hazard to the subject's safety or interferes with the subject's ability to complete the clinical study;
15. Positive HIV test results; patients with active hepatitis B or C (HBsAg positivity accompanied by HBV DNA titres above the upper limit of normal; HCVAb positivity accompanied by HCV RNA titres above the upper limit of normal); and persistent coronavirus (COVID-19) infection.
16. Hypersensitivity reactions or delayed hypersensitivity reactions to components of Disitamab Vedotin and Toripalimab or analogues are known;
17. Known hypersensitivity or delayed hypersensitivity to epirubicin, cyclophosphamide, carboplatin preparations or components or similar drugs;
18. Other malignancy within 5 years prior to signing the informed consent (except for non-melanoma skin cancer, cervical carcinoma in situ or other tumours that have been effectively treated and are considered cured);

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Disitamab Vedotin + Toripalimab; Disitamab Vedotin with Toripalimab Arm	Drug: Disitamab Vedotin Injection （18 weeks）; 2.0mg/kg, intravenous infusion，D1, every 2 weeks, Every 6 weeks is a treatment cycle. A total of 3 cycles (18 weeks) of treatment are performed.; Other Names: DV,RC48-ADC; Drug: Toripalimab （18weeks）; 3.0 mg/kg, intravenous infusion, D1, every 2 weeks; Other Names: JS001
Experimental: Disitamab Vedotin + Toripalimab+Carboplatin; Disitamab Vedotin + Toripalimab with Carboplatin Arm	Drug: Disitamab Vedotin Injection （18 weeks）; 2.0mg/kg, intravenous infusion，D1, every 2 weeks, Every 6 weeks is a treatment cycle. A total of 3 cycles (18 weeks) of treatment are performed.; Other Names: DV,RC48-ADC; Drug: Toripalimab （18weeks）; 3.0 mg/kg, intravenous infusion, D1, every 2 weeks; Other Names: JS001; Drug: Carboplatin; AUC 3 Q2W or AUC1.5 QW intravenous infusion
Experimental: Disitamab Vedotin + Toripalimab sequential Epirubicin+ CTX+ Toripalimab; Disitamab Vedotin + Toripalimab sequential Epirubicin+ CTX with Toripalimab Arm	Drug: Disitamab Vedotin Injection （12 weeks）; 2.0mg/kg, intravenous infusion，D1, every 2 weeks, Every 6 weeks is a treatment cycle. A total of 2 cycles (12 weeks) of treatment are performed.; Other Names: DV,RC48-ADC; Drug: Sequential Epirubicin; According to body surface area, 90mg/m2, intravenous infusion, D1, every 3 weeks, A total of 12 weeks of treatment are performed.; Other Names: Epirubicin; Drug: Sequential CTX; According to body surface area,600mg/m2, intravenous infusion, D1, every 3 weeks, A total of 12 weeks of treatment are performed.; Other Names: CTX, cyclophosphamide; Drug: Toripalimab （12weeks）; 3.0 mg/kg, intravenous infusion, D1, every 2 weeks, A total of 2 cycles (12 weeks) of treatment are performed. Sequential therapy 3.0 mg/kg, intravenous infusion, D1, every 2 weeks, A total of 2 cycles (12 weeks) of treatment are performed.; Other Names: JS001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total pathological complete response (tpCR) rate (ypT0/Tis ypN0)	Defined as the proportion of participants with a pathological assessment of pCR (ypTO/Tis, ypNO) in the analyzed population;	1 month after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS is defined as the time from the date of randomisation until the date of death due to any cause.	Date of randomization to date of death due to any cause, up to 5 years after the last subject randomized
Adverse events	To evaluate safety including adverse event rate and adverse event grade	Up to approximately 2 months after surgery
Change in cluster of differentiation 8 (CD8)	CD8 in tumor samples by biopsy at baseline and by surgery immediately after surgery would be evaluated by HE or immune staining.	At baseline to surgery
Health-related quality of life - EORTC-QLQ-C30	Change from baseline in the physical functioning subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores. Scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden	Up to approximately 2 years
Residual cancer burden score	According to the extent of the residual cancer in the primary breast cancer site (mm*mm), the residual cancer (mm*mm), cell density of residual cancer (%), proportion of carcinoma in situ (%), number of positive lymph nodes and maximum diameter of lymph node metastasis (mm), the RCB index and corresponding RCB classification can be obtained. The RCB index and the corresponding RCB grade can be obtained based on the maximum diameter of the cancer (mm).	1 month after surgery
Change in programmed cell death protein L1 (PD-L1)	PD1 in tumor samples by biopsy at baseline and by surgery immediately after surgery would be evaluated by HE or immune staining.	At baseline to surgery
Breast pathological complete response（bpCR）	Defined as the proportion of participants with a pathological assessment of bpCR in the analyzed population	1 month after surgery
Objective remission rate (ORR)	Objective response rate.ORR assessed according to the evaluation criteria for the efficacy of solid tumors (RECIST 1.1)	Baseline to surgery
Disease free survival（DFS）	From the date of surgery to the first local, regional, contralateral or distant recurrence, and death from any cause including 3- and 5-year event-free survival	Up to approximately 3 or 5 years
Event free survival (EFS)	The time from random assignment to disease progression, including local progression before surgery; disease recurrence-local, regional, distant, ipsilateral noninvasive, or contralateral (invasive or noninvasive)-or death from any cause;	Up to approximately 3 or 5 years
Change in tumor-infiltrating lymphocytes (TILs)	Defined as infiltrating lymphocytes isolated from tumor tissue.TILs in tumor samples by biopsy right before the first neoadjuvant therapy (baseline) and by surgery immediately after surgery would be evaluated by HE or immune staining.	At baseline to surgery

Collaborators and Investigators

• Sponsor: RemeGen Co., Ltd.
• Investigators: Study Director: Changling Li, RemeGen Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 17, 2024
• First Submitted That Met QC Criteria: January 17, 2024
• First Posted (Actual): January 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Breast Cancer; HR-negative; HER2 low-expressing
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Immunoconjugates; Cyclophosphamide; Carboplatin; Epirubicin; Disitamab vedotin
• Other Study ID Numbers: RC48-C024

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