Submitted by: Jamie Anne Y. Lee 2017-11-06 00:00:00 Last Updated by: Quintiles 2018-10-26 15:32:41 Export to PDF

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

PHRR171108-001718

HLX02-BC01

2017-CT0418

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

HLX02 is being developed as a proposed biosimilar to the approved drug, Herceptin® to meet the need for an alternative to this high-priced biologic agent. The efficacy and safety of trastuzumab have already been demonstrated during the development of Herceptin®. The objective of this Phase III study is to compare the efficacy and to evaluate safety and immunogenicity of HLX02 + docetaxel and EU-sourced Herceptin® + docetaxel in patients with HER2-positive, recurrent or previously untreated metastatic breast cancer.                         

A maximum of 304 patients will be enrolled in each arm to yield 289 evaluable patients per arm for the primary efficacy analysis in the intent-to-treat (ITT) population.  Subjects will be stratified for estrogen receptor/progesterone receptor (ER/PgR) status, prior neo-/adjuvant therapy with Herceptin®, and ethnicity (Asian and non-Asian), then randomized into 2 treatment arms in a 1:1 ratio to receive HLX02 or EU-sourced Herceptin® in combination with docetaxel according to the current standard of care. HLX02 or EU-sourced Herceptin® will be administered intravenously, initially at a loading dose of 8 mg/kg on Day 1, Cycle 1 then at a dose of 6 mg/kg once every 3 weeks in 3-weekly cycles for up to a maximum of 12 months. Docetaxel 75 mg/m2 will be administered intravenously  once every 3 weeks for at least 8 cycles and thereafter at the Investigator’s discretion for up to a maximum of 12 months.      All patients will undergo a Safety Follow-up Visit 30 (±2) days after the last dose of study drug. Cardiac safety monitoring and immunogenicity testing will continue up to 12 months after randomization in all patients.                                                                Survival Follow-up will occur every 3 months until 12 months after randomization;thereafter, overall survival (OS) data will be collected by telephone call every 3 months for up to 36 months after randomization.                                    The evaluation of tumor response will be measured according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The Investigator will assess the response 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.            Blood samples will be collected for standard laboratory analysis: Haematology, Blood chemistry, Coagulation, pregnancy test, pharmacokinetic testing and immunogenicity test (anti-drug antibodies). Urine samples are collected for routine urinalysis and pregnancy test. Tissue samples are collected at the time of screening for tumor analysis

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2017-12-31 37 2021-01-31 0000-00-00

Ongoing

Institution Classification Region LTO #
Shanghai Henlius Biotech, Inc. Private Business China Not Applicable
Institution Classification Region LTO #
Quintiles Philippines, Inc. Private Business NCR CDRR-NCR-CRO-02
Institution Amount Region
Shanghai Henlius Biotech, Inc. N/A China
Name E-Mail Phone Number Postal Address
Elena Lam QMNL.HealthRegistrymailbox@quintiles.com +6328783111 Unit 7A, 7/F, 8 Rockwell Building, Hidalgo Drive, Rockwell Center, Makati City, 1210 Philippines
Name E-Mail Phone Number Postal Address
Liang Wan liang.wan@quintilesims.com +862124227988 5F Building A,388 Feng Lin Road Shanghai 200032 China
Name Expertise Affiliation
Gracieux Fernando, MD Medical Oncology Manila Doctors Hospital
Vanina Htun, MD Medical Oncology Metro Davao Medical and Research Center
Guia Elena Imelda R. Ladrera, MD Medical Oncology Lung Center of the Philippines
Rosalinda Pulido, MD Medical Oncology St. Frances Cabrini Medical Center
Ma. Luisa Abesamis-Tiambeng, MD Medical Oncology Cardinal Santos Medical Center
Ma. Noemi Alsay-Uy, MD Medical Oncology Cebu Doctors' University Hospital
Fatima Fuerte Medical Oncology The Medical City
Chita Matunog Medical Oncology San Pedro Hospital
Project Location Institutional Ethics Review Board
Manila Doctors Hospital Manila Doctors Hospital Institutional Review Board
Metro Davao Medical and Research Center Metro Davao Medical and Research Center – Ethics Review Committee
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
St. Frances Cabrini Medical Center N/A
Cardinal Santos Medical Center Cardinal Santos Medical Center Ethics Review Committee
Cebu Doctors' University Hospital Cebu Doctors' University Hospital - Institutional Ethics Review Committee
The Medical City The Medical City - Institutional Review Board
San Pedro Hospital N/A

Previously Untreated HER2-Overexpressing Metastatic Breast Cancer

The primary objective of the study is to compare the efficacy of HLX02 versus EU-sourced Herceptin® in combination with docetaxel using ORR up to Week 24 (ORR24) after up to 8 cycles of treatment to demonstrate clinical bioequivalence.

The secondary objectives of the study are as follows:
-To evaluate the safety, tolerability, and immunogenicity of HLX02 and EU-sourced Herceptin® given in combination with docetaxel.
-To compare the efficacy of HLX02 versus EU-sourced Herceptin® in combination with docetaxel, in terms of duration of response (DoR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS) up to 12 months, and OS at 12, 24, and 36 months.
-To measure the exposure to trastuzumab following HLX02 or EU-sourced Herceptin®.

Completed

  • China
  • Philippines
  • Poland
  • Ukraine

Clinical Trial

20170629155354

2017-09-29

Date Amendment Classification Reason
2018-02-20 Amendments related to the protocol

Key inclusion criteria: 
• 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 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. 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 (i.e. a disease-free interval of ≥12 months). 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 (i.e. a disease-free interval of ≥6 months). 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 (at least 2 weeks before randomization)
• 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 performance status of 0-1 
• Left ventricular ejection fraction (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 
• 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 (within 7 days of the first investigational product administration), are not breast feeding, and use highly-effective or acceptable contraceptive measures before study entry and throughout the study until 6 months after the last investigational product administration 
• Male patients with partners of childbearing potential are eligible to enter and participate in the study if they are willing to use highly-effective or acceptable contraceptive measures before study entry and throughout the study until 6 months after the last investigational product administration 
Key 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 
• 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 (defined as a procedure that would require more than 3 weeks without study treatment) within 4 weeks prior to enrolment 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 of any New York Heart Association criteria, or left ventricular hypertrophy. Current serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia) or clinically significant conduction defects as seen on electrocardiogram. History of myocardial infarction within 6 months of randomization. History of LVEF decline to below 50% during or after prior 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 
• Known hypersensitivity to any of the study drugs                                                                        • Residual non-hematologic toxicity ≥ Grade 2 from prior therapy.

Interventional

HLX02 (Active Ingredient: Trastuzumab)

HLX02 is developed as a proposed biosimilar to Herceptin® to meet the need for alternatives to high-priced biologic agents in oncology treatments. This study will be conducted in patients with HER2-positive, recurrent or previously untreated metastatic breast cancer. The patients will be stratified for estrogen receptor/progesterone receptor (ER/PgR) status, prior neo-/adjuvant therapy with Herceptin®, and ethnicity (Asian and non-Asian), then randomized into 2 treatment arms in a 1:1 ratio to receive HLX02 or EU-sourced Herceptin® in combination with docetaxel according to the current standard of care.                                         HLX02 (proposed biosimilar to trastuzumab) or EU-sourced Herceptin® (trastuzumab) will be administered intravenously as a loading dose of 8 mg/kg over 90 minutes on Day 1, Cycle 1, and then every 3 weeks for subsequent cycles at 6 mg/kg over 30-90 minutes (i.e. any duration between 30 and 90 minutes from Cycle 2 onwards) if the previous dose was well tolerated. If an infusion-related reaction (IRR) occurs, the infusion should be immediately interrupted and the patient should be monitored until resolution of all symptoms. These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol. Serious reactions must be treated with supportive therapy such as oxygen, beta-agonists, and corticosteroids. If a second episode of serious IRR occurs despite prophylactic use of steroids treatment will be permanently discontinued. Treatment with HLX02 or Herceptin® will continue for a maximum of 12 months, or until Investigator-assessed disease progression, excessive toxicity, Investigator’s judgment, withdrawal of consent, lost to follow-up, death, start of a new anticancer therapy, or study termination whichever occurs first. HLX02 or Herceptin® administration may be delayed but no dose reduction is allowed. If a patient misses a dose of HLX02 or Herceptin® by less than 1 week after the planned date, the usual maintenance dose (6 mg/kg) should be given as soon as possible. If a patient misses a dose of HLX02 or Herceptin® for ≥1 week (i.e. the 2 sequential administrations are given ≥4 weeks apart), a re-loading dose of HLX02 or Herceptin® (8 mg/kg) should be given. Subsequent maintenance HLX02 or Herceptin® doses of 6 mg/kg will then be given every 3 weeks, starting 3 weeks later. If re-loading is required, docetaxel administration (at the dose that was last tolerated) will be restarted on the same day as the re-loading dose, to coincide with the start of a new cycle. If a patient has a study drug interruption ≥9 weeks for a trastuzumab-related toxicity, they will be discontinued from the study.

Randomized

Double Blind

This is a randomized, double-blind, bioequivalence study with limited access to the randomization code. The treatment each patient receives will not be disclosed to the Investigator, study center staff, patient, Sponsor, or CRO with the exception of the designated unblinded study team at the time of the first database lock for the primary analysis.                   The vials of HLX02 and Herceptin® are not identical in appearance. To ensure the Investigator and subject stay blinded, an unblinded pharmacist team at each centre will reconstitute the study drug for each patient. After the drug has been reconstituted, the unblinded pharmacist or designee will label the intravenous bag with the correct subject number so the study team will not know what treatment is contained therein. The blind must not be broken during the course of the study unless, in the opinion of the Investigator, it is absolutely necessary to safely treat the subject. If it is medically imperative to know what study drug the subject is receiving, the study drug should be temporarily discontinued if, in the opinion of the Investigator, continuing the drug could negatively affect the outcome of the patient’s treatment. The decision to break the blind in emergency situations remains the responsibility of the Investigator and will not be delayed or refused by the Sponsor; however, the Investigator may contact the CRO Medical Monitor prior to breaking the blind to discuss the unblinding and what would be in the best interests of the subject. The Investigator should ensure that the code is broken only in accordance with the protocol. The Investigator should promptly notify the CRO Medical Monitor of the emergency unblinding and the reason for breaking the blind and this should be clearly documented by the Investigator in the subject’s source documentation. The process for breaking the blind will be handled through the IWRS/IVRS using an emergency unblinding personal identification number. If the blind is broken, it may be broken for only the subject in question.

Parallel

The main purpose of the study is to determine whether the study drug is as effective as the comparator (EU-sourced Herceptin®) in patients with breast cancer (human epidermal growth factor receptor 2 [HER2]-positive, recurrent or previously untreated metastatic breast cancer) in combination with docetaxel chemotherapy. Overall, the study will compare how similar the study drug is to the EU-sourced Herceptin® in terms of:                                                                          • Its effectiveness 
• How safe it is (i.e. if there are any side effects), and how  the body’s immune system will react to it.
• How it is processed by the body.

Phase III

50

11

Early completion of global study recruitment

31 Dec 2017

Utilization Utilization Info
No records found.

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