Clinical trial NCT03084237: Compare Efficacy, Safety and Immunogenicity of HLX02 and Herceptin in Previously Untreated HER2 +Overexpressing Metastatic Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Lead sponsor: Shanghai Henlius Biotech
Sponsor class: INDUSTRY
First posted: 2017-03-20
Enrollment: 652
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: ORR 24
timeFrame: From time of First treatment to week 24
Secondary outcomes:
measure: DoR
timeFrame: Up to 2 years
measure: DCR
timeFrame: Up to 2 years
measure: CBR
timeFrame: Up to 2 years
measure: Median PFS up to 12 Months
timeFrame: From time of first treatment to 12 months
measure: Overall Survival at 12, 24, and 36 Months
timeFrame: From time of first treatment to 36 months
Other outcomes:
Locations:
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Hefei
country: China
facility: The Second Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: Beijing Friendship Hospital, Capital Medical University
state: Beijing
city: Chongqing
country: China
facility: Chongqing University Cancer Hospital
state: Chongqing
city: Fuzhou
country: China
facility: Fujian Cancer Hospital
state: Fujian
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University
state: Fujian
city: Guangzhou
country: China
facility: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
state: Guangdong
city: Guangzhou
country: China
facility: First Affiliated Hospital of Guangzhou University of TMC
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
state: Guangdong
city: Guanzhou
country: China
facility: Sun Yat-sen University, Cancer Center
state: Guangdong
city: Shenzhen
country: China
facility: The University of Hong Kong-Shenzhen Hospital
state: Guangdong
city: Zhanjiang
country: China
facility: Affiliated Hospital of Guangdong Medical University
state: Guangdong
city: Liuzhou
country: China
facility: Liuzhou General Hospital
state: Guangxi
city: Baoding
country: China
facility: Affiliated Hospital of Hebei University
state: Hebei
city: Cangzhou
country: China
facility: Hebei Cangzhou Central Hospital
state: Hebei
city: Shijiazhuang
country: China
facility: The Fourth Hospital of Hebei Medical University
state: Hebei
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
state: Hubei
city: Changsha
country: China
facility: The 2nd Xiangya Hospital of Central South University
state: Hunan
city: Changsha
country: China
facility: The Third Xiangya Hospital of Central South University
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Nanjing Bayi Hospital
state: Jiangsu
city: Nanjing
country: China
facility: The Affiliated Drum Tower Hospital of Nanjing University
state: Jiangsu
city: Nantong
country: China
facility: Nantong Tumor Hospital
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi 4th People's Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Central Hospital
state: Jiangsu
city: Yangzhou
country: China
facility: Northern Jiangsu People's Hospital
state: Jiangsu
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University
state: Jiangxi
city: Chang chun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Changchun
country: China
facility: Jilin Province People's Hospital
state: Jilin
city: Dalian
country: China
facility: The Second Hospital of Dalian Medical University
state: Liaoning
city: Shenyang
country: China
facility: General Hospital of the Northern Theater of the Chinese People's Liberation Army
state: Liaoning
city: Shenyang
country: China
facility: Liaoning Cancer Hospital & Institute
state: Liaoning
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Liaoning
city: Xining
country: China
facility: Affiliated Hospital of Qinghai University
state: Qinghai
city: Jining
country: China
facility: Affiliated Hospital of Jining Medical University
state: Shandong
city: Jinan
country: China
facility: Jinan Central Hospital
state: Shangdong
city: Yantai
country: China
facility: Yantai Yuhuangding Hospital
state: Shangdong
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Shanghai
country: China
facility: Ruijin Hospital of Shanghai Jiaotong University School of Medicine
state: Shanghai
city: Xi'an
country: China
facility: Shannxi Provincial Tumor Hospital
state: Shangxi
city: Xi'an
country: China
facility: The 2nd Hospital of Xi'An Jiaotong University
state: Shanxi
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
state: Shanxi
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Nanchong
country: China
facility: Nanchong Central Hospital
state: Sichuan
city: Tianjing
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
state: Tianjing
city: Kunming
country: China
facility: Yunnan Cancer Hospital
state: Yunnan
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
state: Zhejiang
city: HanGzhou
country: China
facility: The First Affiliated Hospital, College of Medicine, Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Cancer Hospital, Chinese Academy of Medical Sciences
city: Beijing
country: China
facility: Chinese PLA General Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Davao City
country: Philippines
facility: Metro Davao Medical and Research Center, Inc.
state: Davao
city: San Juan
country: Philippines
facility: Cardinal Santos Medical Center
state: La Union
city: Manila
country: Philippines
facility: Manila Doctors Hospital
state: Metro Manila
city: Pasig City
country: Philippines
facility: The Medical City
state: Metro Manila
city: Cebu City
country: Philippines
facility: Cebu Doctors University Hospital
city: Kryvyi Rih
country: Ukraine
facility: CI Kryvyi Rih Oncological Dispensary of DRC
state: Dnepropetrovsk
city: Dnipro
country: Ukraine
facility: CNE"City Clin Hosp#4"of Dnipro City Council Dept of Chemotherapy SI Dnipropetrovsk MA of MOHU
state: Dnipropetrovsk
city: Ivano-Frankivs'k
country: Ukraine
facility: CI Carpathian Clinical Oncological Center
state: Ivano-Frankivsk
city: Uzhgorod
country: Ukraine
facility: CNE CCCH of Uzh CC Oncological Center, Ther Dept, SHEI UNU
state: Outer Carpathian
city: Uzhgorod
country: Ukraine
facility: Transcarpathian Regional Clinical Oncological Dispensary
state: Outer Carpathian
city: Lutsk
country: Ukraine
facility: Communal Enterprise Volyn Regional Medical Center of Oncology of Volyn Regional Council
state: Warren
city: Chernihiv
country: Ukraine
facility: CTPI Chernihiv Regional Oncological Dispensary
city: Chernivtsi
country: Ukraine
facility: CI Chernivtsi RC Oncological Dispensary
city: Kharkiv
country: Ukraine
facility: Communal Non-profit Enterprise Regional Center of Oncology
city: Kherson
country: Ukraine
facility: CI of Kherson Reg Council Kherson Regional Oncologic Dispensary
city: Khmelnytskyi
country: Ukraine
facility: Khmelnytskyi Regional Oncological Dispensary
city: Kropyvnytskyi
country: Ukraine
facility: Treatment-Diagnostic Center of Private Enterprise of PPC Atsynus
city: Kyiv
country: Ukraine
facility: National Institute of Cancer
city: Kyiv
country: Ukraine
facility: CNE Kyiv City Clin Oncological Center of Ex Body of Kyiv CC(KCSA)
city: Kyiv
country: Ukraine
facility: Kyiv Сity Clinical Oncological Center
city: Lviv
country: Ukraine
facility: CI of LRC Lviv Oncological Regional Treatment and Diagnostic Center
city: Odesa
country: Ukraine
facility: CI Odesa Regional Clinical Hospital
city: Odesa
country: Ukraine
facility: Odesa Regional Oncologic Dispensary
city: Poltava
country: Ukraine
facility: Poltava Reg Cl Onc Dispensary of PRC Chemotherapy Dept HSEI of Ukr UMSA
city: Sumy
country: Ukraine
facility: RCI Sumy Regional Clinical Oncological Dispensary Dept of of Chemotherapy Sumy SU
city: Vinnytsia
country: Ukraine
facility: Podilskyi Regional Oncological Center
city: Zaporizhzhia
country: Ukraine
facility: CI Zaporizhzhia RC Onc Dispensary of ZRC Dept of Breast Pathology SI Zaporizhzhia MA of PGE of MoHU
city: Zaporizhzhia
country: Ukraine
facility: CI Zaporizhzhia Regional Clinical Oncological Dispensary of ZRC
Study officials:
References:
citation: 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.