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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03084237
• Other study ID #: HLX02-BC01
• Secondary ID: 2016-000206-10
• Status: Completed
• Phase: Phase 3
• Start date: November 2016
• Est. completion date: September 28, 2021

Study information

• Verified date: April 2024
• Source: Shanghai Henlius Biotech
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 652
• Est. completion date: September 28, 2021
• Est. primary completion date: November 23, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

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.
• 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

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Henlius Biotech

Countries where clinical trial is conducted

China,  Philippines,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 by central imaging review (CIR).; Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions,Complete Response (CR): Disappearance of all target lesions.Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to<10 mm, Partial Response (PR): At least a 30% decrease in the sum ofdiameters of target lesions, taking as reference thebaseline sum diameters.Overall Response (OR) = CR + PR.	From time of First treatment to week 24
Secondary	DoR	The time from first documentation of CR or PR to the first documentation of progression.; Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1),At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or Unequivocal progression of existing non-target lesions (Note: the appearance of one or more new lesions is also considered progression).	Up to 2 years
Secondary	DCR	The percentage of patients who achieve CR, PR, or stable disease (SD) of at least 12 weeks	Up to 2 years
Secondary	CBR	The proportion of patients who achieve CR, PR, or durable SD (SD =24 weeks)	Up to 2 years
Secondary	Median PFS up to 12 Months	Median Progression Survival time assessed at 12 months.The probability of being alive without documented progression up to 12 months after randomization.	From time of first treatment to 12 months
Secondary	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