Compare Efficacy, Safety and Immunogenicity of HLX02 and Herceptin in Previously Untreated HER2 +Overexpressing Metastatic Breast Cancer

Double-blind, Randomized, Multicenter, Phase III Clinical Study to Compare the Efficacy and to Evaluate the Safety and Immunogenicity of Trastuzumab Biosimilar HLX02 and EU-sourced Herceptin® in Previously Untreated HER2 Overexpressing Metastatic Breast Cancer

This is a Phase III, double-blind, randomized multicenter study to compare the efficacy and to evaluate the safety and immunogenicity of HLX02 and European Union (EU)-sourced Herceptin® in patients with human epidermal growth factor receptor 2 (HER2)-positive, locally recurrent or previously untreated metastatic breast cancer.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Biological: HLX02; Drug: docetaxel; Biological: Herceptin®

Detailed Description

This is a Phase III, double-blind, randomized multicenter study to compare the efficacy and to evaluate the safety and immunogenicity of HLX02 and European Union (EU)-sourced Herceptin® in patients with human epidermal growth factor receptor 2 (HER2)-positive, recurrent or previously untreated metastatic breast cancer. Eligible patients will be assessed centrally for HER2 status and the presence of at least one measurable target lesion before randomization. Patients will undergo a tumor assessment for evaluation of response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) every 6 weeks up to 24 weeks (regardless of the number of cycles actually given); thereafter, assessments will be done every 9 weeks (after Cycles 11, 14, and 17) or earlier in the case of clinical signs of progression.

• Study Type: Interventional
• Enrollment (Actual): 649
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Chinese PLA General Hospital
  • Beijing, China
    • Cancer Hospital, Chinese Academy of Medical Sciences
  • Beijing, China
    • Beijing Cancer Hospital
  • Beijing, China
    • Peking Union Medical College Hospital
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated Hospital of Anhui Medical University
    • Hefei, Anhui, China
      • The Second Hospital of Anhui Medical University
  • Beijing
    • Beijing, Beijing, China
      • Beijing Friendship Hospital, Capital Medical University
  • Chongqing
    • Chongqing, Chongqing, China
      • Chongqing University Cancer Hospital
  • Fujian
    • Fuzhou, Fujian, China
      • Fujian Medical University Union Hospital
    • Fuzhou, Fujian, China
      • Fujian Cancer Hospital
    • Xiamen, Fujian, China
      • The First Affiliated Hospital of Xiamen University
  • Guangdong
    • Guangzhou, Guangdong, China
      • Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
    • Guangzhou, Guangdong, China
      • Affiliated Cancer Hospital and Institute of Guangzhou Medical University
    • Guangzhou, Guangdong, China
      • First Affiliated Hospital of Guangzhou University of TMC
    • Guangzhou, Guangdong, China
      • The First Affiliated Hospital of Guangdong College of Pharmacy
    • Guanzhou, Guangdong, China
      • Sun Yat-sen University, Cancer Center
    • Shenzhen, Guangdong, China
      • The University of Hong Kong-Shenzhen Hospital
    • Zhanjiang, Guangdong, China
      • Affiliated Hospital of Guangdong Medical University
  • Guangxi
    • Liuzhou, Guangxi, China
      • Liuzhou General Hospital
    • Nanning, Guangxi, China
      • Guangxi Medical University Affiliated Tumor Hospital
  • Hebei
    • Baoding, Hebei, China
      • Affiliated Hospital of Hebei University
    • Cangzhou, Hebei, China
      • Hebei Cangzhou Central Hospital
    • Shijiazhuang, Hebei, China
      • The Fourth Hospital of Hebei Medical University
  • Heilongjiang
    • Harbin, Heilongjiang, China
      • Harbin Medical University Cancer Hospital
  • Henan
    • Zhengzhou, Henan, China
      • Henan Cancer Hospital
  • Hubei
    • Wuhan, Hubei, China
      • Hubei Cancer Hospital
    • Wuhan, Hubei, China
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
    • Wuhan, Hubei, China
      • Union Hospital, Tongji Medical College of Huazhong University of Science & Technology
  • Hunan
    • Changsha, Hunan, China
      • The Third Xiangya Hospital of Central South University
    • Changsha, Hunan, China
      • The 2nd Xiangya Hospital of Central South University
  • Inner Mongolia
    • Chifeng, Inner Mongolia, China
      • Neimenggu Chifeng Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Jiangsu Province Hospital
    • Nanjing, Jiangsu, China
      • Jiangsu Cancer Hospital
    • Nanjing, Jiangsu, China
      • Nanjing Bayi Hospital
    • Nanjing, Jiangsu, China
      • The Affiliated Drum Tower Hospital of Nanjing University
    • Nantong, Jiangsu, China
      • Nantong Tumor Hospital
    • Wuxi, Jiangsu, China
      • Wuxi 4th People's Hospital
    • Xuzhou, Jiangsu, China
      • XuZhou Central Hospital
    • Yangzhou, Jiangsu, China
      • Northern Jiangsu People's Hospital
  • Jiangxi
    • Nanchang, Jiangxi, China
      • The Second Affiliated Hospital Of NanChang University
  • Jilin
    • Chang chun, Jilin, China
      • The First Hospital of Jilin University
    • Changchun, Jilin, China
      • Jilin Cancer Hospital
    • Changchun, Jilin, China
      • Jilin Province People's Hospital
  • Liaoning
    • Dalian, Liaoning, China
      • The Second Hospital of Dalian Medical University
    • Shenyang, Liaoning, China
      • The First Hospital of China Medical University
    • Shenyang, Liaoning, China
      • General Hospital of The Northern Theater of The Chinese People's Liberation Army
    • Shenyang, Liaoning, China
      • Liaoning Cancer Hospital & Institute
  • Qinghai
    • Xining, Qinghai, China
      • Affiliated Hospital of Qinghai University
  • Shandong
    • Jining, Shandong, China
      • Affiliated hospital of Jining Medical University
  • Shangdong
    • Jinan, Shangdong, China
      • Jinan Central Hospital
    • Yantai, Shangdong, China
      • Yantai Yuhuangding Hospital
  • Shanghai
    • Shanghai, Shanghai, China
      • Fudan University Shanghai Cancer Center
    • Shanghai, Shanghai, China
      • Ruijin Hospital of Shanghai Jiaotong University School of Medicine
  • Shangxi
    • Xi'an, Shangxi, China
      • Shannxi Provincial Tumor Hospital
  • Shanxi
    • Xi'an, Shanxi, China
      • The First Affiliated Hospital of Xi'an Jiaotong University
    • Xi'an, Shanxi, China
      • The 2nd Hospital of Xi'An Jiaotong University
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital, Sichuan University
    • Nanchong, Sichuan, China
      • Nanchong Central Hospital
  • Tianjing
    • Tianjing, Tianjing, China
      • Tianjin Medical University Cancer Institute & Hospital
  • Yunnan
    • Kunming, Yunnan, China
      • Yunnan cancer hospital
  • Zhejiang
    • HanGzhou, Zhejiang, China
      • The First Affiliated Hospital, College of Medicine, Zhejiang University
    • Hangzhou, Zhejiang, China
      • Zhejiang Cancer hospital
    • Hangzhou, Zhejiang, China
      • Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
    • Hangzhou, Zhejiang, China
      • The Second Affiliated Hospital of Zhejiang University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Patients have voluntarily agreed to participate and given written informed consent.
• Male or female ≥18 years of age on day of signing the informed consent form (ICF).
• Histologically or cytologically confirmed adenocarcinoma of the breast.
• Recurrent disease not amenable to curative surgery or radiation therapy, or metastatic disease with an indication for a taxane-containing therapy.
• Availability of formalin-fixed paraffin-embedded (FFPE) tissue block from the primary tumor, or a metastatic lesion, to confirm HER2-positivity by the central laboratory, based on FISH amplification ratio ≥2.0 or IHC score 3+, and for hormone status (ER/PgR) determination (local or central laboratory). If not possible, a fresh biopsy is required.
• No prior systemic anticancer agent such as chemotherapy, biological or targeted agent for metastatic disease with the exception of hormonal therapy, which must be stopped at least 2 weeks before randomization. Use of herbal remedies or traditional Chinese medicines for anticancer, hematologic or liver function, or anti-infective treatment must be stopped at the time of the ICF signature (at least 2 weeks before randomization).
• For patients with recurrent disease, prior neo-/adjuvant therapy containing trastuzumab and/or lapatinib must have been stopped at least 12 months before the diagnosis of recurrent (local or metastatic) disease. If trastuzumab/lapatinib was not used, prior neo-/adjuvant therapy with a taxane must have been stopped at least 6 months before the diagnosis of recurrent (local or metastatic) disease. If only other cytotoxics were given, they must be stopped at least 4 weeks before randomization. Any hormonal therapy must be stopped at the time of the ICF signature.
• Measurable disease (at least one measurable target lesion assessed by CIR; bone-only or central nervous system [CNS]-only metastases are not allowed).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• LVEF within institutional range of normal at baseline (within 42 days before randomization) as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scan.
• Adequate hematologic, hepatic and renal function as indicated by the following laboratory values:
• Absolute neutrophil count (ANC) ≥1,500/μL without granulocyte-colony stimulating factor (G-CSF) or other medical support
• Platelets ≥100,000/μL
• Hemoglobin ≥9 g/dL without transfusion or other medical support within 14 days
• Serum creatinine ≤1.5 x upper limit of normal (ULN) and creatinine clearance rate ≥50 mL/min, calculated according to Cockroft-Gault formula
• Serum total bilirubin ≤1.5 x ULN (unless the patient has documented ·Gilbert's syndrome) without any medical support within 14 days
• Serum aspartate aminotransferase/glutamicoxaloacetic transaminase (AST/SGOT) or serum alanine aminotransferase/glutamate-pyruvate transaminase (ALT/SGPT) ≤2.5 x ULN (≤5 x ULN in the case of liver metastases) provided alkaline phosphatase (ALK) is ≤2.5 x ULN. In the case of bone metastasis, serum ALK can be >2.5 x ULN if AST and ALT are ≤1.5 x ULN without any medical support within 14 days
• International normalized ratio (INR), and activated partial prothrombin time (aPTT) or partial prothrombin time (PTT) ≤1.5 x ULN.
• Estimated life expectancy ≥3 months.
• Female patients are eligible to enter and participate in the study if they are of: Non-childbearing potential. Childbearing potential, have a negative serum pregnancy test at Screening, are not breast feeding, and use highly-effective or acceptable contraceptive measures before study entry and throughout the study until 7 months after the last investigational/comparator product administration. Highly-effective or acceptable contraceptive measures.
• Male patients with partners of childbearing potential are eligible to enter and participate in the study if they, and their female partners, are willing to use highly-effective or acceptable contraceptive measures before study entry and throughout the study until 7 months after the last investigational/comparator product administration.

Exclusion Criteria

• Previously- or currently-treated (systemic chemotherapy, biological, or targeted agent, or any other anticancer agent) metastatic breast cancer with the exception of hormonal therapy.
• Known brain metastasis or other CNS metastasis that is either symptomatic or untreated. Central nervous system metastases that have been treated by complete resection and/or radiotherapy demonstrating stability or improvement are not an exclusion criterion provided they are stable as shown by computed tomography (CT) scan for at least 4 weeks before Screening without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants.
• Participation in another clinical study within 4 weeks before enrollment (3 months for studies involving monoclonal therapy) or the intention of participating in another clinical study during any part of the study period.
• History of other malignancy within the last 5 years, except for carcinoma in-situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent.
• Known history of human immunodeficiency virus (HIV). Clinically significant active infection requiring therapy; positive tests for hepatitis B; or hepatitis C.
• Underlying medical conditions or current severe, uncontrolled systemic disease that, in the Investigator's opinion, will make the administration of study drug hazardous. A major surgical procedure within 4 weeks prior to enrollment or anticipation of the need for major surgery during the course of study.
• Current uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or unstable angina.
• History of chronic heart failure based on any New York Heart Association (NYHA) criteria, or left ventricular hypertrophy. Current serious cardiac arrhythmia requiring treatment or clinically significant conduction defects as seen on electrocardiogram (ECG). History of myocardial infarction within 6 months of randomization. History of LVEF decline to below 50% during or after previous trastuzumab neo-adjuvant or adjuvant therapy. Significant cardiac murmurs either on examination or ECHO.
• History of prior exposure to doxorubicin >360 mg/m² (or equivalent). Use of oral, injected or implanted hormonal methods of contraception. Chronic daily use of corticoids (equivalent to >10 mg/day methylprednisolone) by oral intake (inhalation is permitted).
• Known hypersensitivity to any of the study drugs.
• Residual non-hematologic toxicity ≥ Grade 2 from prior therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HLX02+docetaxel	Biological: HLX02; 8 mg/kg administered intravenously over 90 minutes as a loading dose on Day 1, Cycle 1 then 6 mg/kg every 3 weeks for subsequent cycles.; Drug: docetaxel; 75 mg/m2 will be administered on Day 2, Cycle 1.then be given every 3 weeks on Day 1 of each subsequent cycle
Active Comparator: Herceptin®+docetaxel	Drug: docetaxel; 75 mg/m2 will be administered on Day 2, Cycle 1.then be given every 3 weeks on Day 1 of each subsequent cycle; Biological: Herceptin®; 8 mg/kg administered intravenously over 90 minutes as a loading dose on Day 1, Cycle 1 then 6 mg/kg every 3 weeks for subsequent cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR 24	calculated as the proportion of patients with a best response of complete response (CR) or partial response (PR) from first assessment until Week 24 according to RECIST 1.1.	From time of First treatment to week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS up to 12 months	The probability of being alive without documented progression up to 12 months after randomization	From time of first treatment to 12 months
ORR at Week 6, 12, 18, and 24 by CIR	the probability of being alive 12, 24, and 36 months after randomization	From week 6 to week 24
DoR	The time from first documentation of CR or PR to the first documentation of progression.	Up to 2 years
DCR	The proportion of patients who achieve CR, PR, or stable disease (SD) of at least 12 weeks	Up to 2 years
CBR	The proportion of patients who achieve CR, PR, or durable SD (SD ≥24 weeks)	Up to 2 years
Overall survival at 12, 24, and 36 months	the probability of being alive 12, 24, and 36 months after randomization	From time of first treatment to 36 months

Collaborators and Investigators

• Sponsor: Shanghai Henlius Biotech

Publications and helpful links

General Publications

• Xu B, Zhang Q, Sun T, Li W, Teng Y, Hu X, Bondarenko I, Adamchuk H, Zhang L, Trukhin D, Wang S, Zheng H, Tong Z, Shparyk Y, Wang Q; HLX02-BC01 Investigators. Efficacy, Safety, and Immunogenicity of HLX02 Compared with Reference Trastuzumab in Patients with Recurrent or Metastatic HER2-Positive Breast Cancer: A Randomized Phase III Equivalence Trial. BioDrugs. 2021 May;35(3):337-350. doi: 10.1007/s40259-021-00475-w. Epub 2021 Apr 7.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): November 23, 2018
• Study Completion (Actual): September 28, 2021

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: March 17, 2017
• First Posted (Actual): March 20, 2017

Study Record Updates

• Last Update Posted (Actual): June 7, 2022
• Last Update Submitted That Met QC Criteria: June 4, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Trastuzumab
• Other Study ID Numbers: HLX02-BC01; 2016-000206-10 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No