A Randomised, Double-blind, Parallel Group, Equivalence, Multicentre Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of HD201 to Herceptin® in Patients with HER2+ Early Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 503
- 试验地点
- 15
- 主要终点
- total pathological complete response rate (tpCR)
研究概览
简要总结
In the TROIKA study, the proposed biosimilar HD201 will be compared to its reference product Herceptin®. The aim of the study is to demonstrate equivalence of HD201 and Herceptin® in terms of efficacy, safety and pharmacokinetics.
详细描述
This is a randomised, double-blind, parallel group, equivalence, multicentre Phase III study. 500 patients with HER2+ early breast cancer (EBC) will be randomised (1:1) to receive either HD201 in combination with chemotherapy (n=250) or Herceptin® in combination with chemotherapy (n=250).
HD201 or Herceptin® will be administered every 3 weeks for 8 cycles(24 weeks). After administration of the final neoadjuvant study drug dose, surgery will be done within 3-8 weeks followed by an adjuvant treatment period for 10 cycles.
Patients completing the 18 cycles of treatment and those discontinuing the study will attend an End of Treatment (EOT) visit 4 weeks (+/- 2 days), after last administration of study medication, followed by a follow-up period of 2 years.
Patients will attend study visits every 3 weeks. At each visit, patients will undergo a complete physical examination, vital signs, weight, performance status, clinical laboratory tests and adverse events (AEs), concomitant medication will be recorded. After the EOT visit patients will be followed every 6 months for an additional 24 months or until death, whichever occurs first, to collect data on cardiac safety and disease status.
Cardiac safety will be assessed by echocardiography or multigated acquisition (MUGA) scan to evaluate the left ventricular ejection fraction (LVEF) (at screening, before cycle 5, before surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the completion of trastuzumab (more frequent if necessary)) and by means of a 12-lead ECG (at screening, before cycle 5, before surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the completion of trastuzumab).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Able and willing to give written informed consent.
- •Females ≥ 18 years of Age
- •Eastern Cooperative Oncology Group (ECOG) performance Status (PS) <
- •Known Hormone receptor (oestrogen receptor and progesterone receptor) status.
- •HER2 overexpressed as assessed by
- •Immunohistochemistry (IHC) or
- •Fluorescent in situ hybridisation (FISH); FISH positive is defined as FISH amplification Ratio ≥ 2.0 / number of HER2 gene copies per cell >2
- •Chromogenetic in stu hybridisation (CISH) positive
- •Patients with IHC score 3+ or positive FISH/CISH test
- •Patients with an IHC score 2+ must also have a positive FISH/CISH test
- •LVEF ≥ 50% or within the normal Level of the Institution, as assessed by echocardiography or MUGA scan.
- •Life expectancy > 12 weeks.
- •Adequate bone marrow function as evidenced by the following:
- •Absolute neutrophils count ≥ 1,500/μL
- •Haemoglobin ≥ 9 g/dL
- •Platelet count ≥ 100,000/μL Up to 5% Deviation is acceptable.
- •Adequate hepatic and renal function as evidenced by the following:
- •Creatinine clearance ≥ 60mL/min
- •total Bilirubin ≤ 1.5x upper limit of normal (ULN)
- •AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN Up to 10% deviation is acceptable.
- •Ability to comply with the study protocol.
- •Female patients of childbearing potential must have a negative Serum pregnancy test within 7 days prior to first dose of study treatment and agree to use effective contraception (intrauterine device, diaphragm, diaphragm with spermicide or a reliable barrier method, eg condom with spermicide) throughout the study period and 7 months after discontinuation of study drug.
- •Non-metastatic, unilateral, newly diagnosed, operable early breast cancer (EBC) of clinical stage II and III including inflammatory breast cancer. Histologically confirmed primary invasive carcinoma of the breast.
排除标准
- •Patients meeting any of the following criteria must not be enrolled in the study:
- •Metastatic (stage IV) with exception of supraclavicular nodes.
- •Bilateral breast cancer
- •Multicentric breast cancer
- •History of any prior invasive breast carcinoma, except for subjects with a past history of ductal carcinoma in situ (DCIS) treated with surgery.
- •History of malignant neoplasms within 5 years prior to randomisation, except for curatively treated carcinoma in situ of uterine cervix, basal cell carcinoma of the skin or squamous cell carcinoma of the skin (malignant neoplasms occurring more than 5 years prior to randomisation are permitted if curatively treated with surgery only).
- •Previous history of radiation therapy, anti-neoplastic immunotherapy, chemotherapy or anti-neoplastic biotherapy (including prior HER2 directed therapy).
- •Major surgery within 2 weeks prior to randomisation
- •Serious cardiac illness that would preclude the use of trastuzumab such as:
- •history of documented congestive heart failure (CHF) (New York Heart Association, NYHA, class III or greater heart disease)
- •LVEF < 50% by echocardiography or MUGA scan
- •angina pectoris requiring anti-anginal medication
- •evidence of transmural infarction on electrocardiogram (ECG)
- •uncontrolled hypertension (systolic > 180 mmHg and/or diastolic > 100 mmHg)
- •clinically significant valvular heart disease
- •high-risk uncontrolled arrhythmias.
- •Serious pulmonary illness enough to cause dyspnoea at rest or requiring supplementary oxygen therapy.
- •Known history of active hepatitis B virus (HBV) and active hepatitis C virus (HCV) infection.
- •Known HIV infection by patient declaration.
- •Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
- •Known hypersensitivity to the IMPs, non-IMPs or any of the ingredients or excipients of the IMPs or non-IMPs.
- •Known hypersensitivity to murine proteins.
- •Pre-existing peripheral sensory or motor neuropathy ≥ grade 2 (as defined by NCI-CTCAE v4.03).
- •Lactating or pregnant woman. A pregnancy test is required for all women of childbearing potential including women who had menopause onset within 2 years prior to randomisation. Women of childbearing potential must agree to use contraceptive methods during the study and for 7 months after the last dose of IMP.
- •Participation in any clinical study or having taken any investigational therapy during the 1-month period immediately preceding administration of the first dose.
- •Patients unwilling to follow the study requirements.
研究组 & 干预措施
HD201 in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2-8), followed by surgery, then adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, and subsequent 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: HD201 (Drug)
HD201 in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2-8), followed by surgery, then adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, and subsequent 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Docetaxel (Drug)
HD201 in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2-8), followed by surgery, then adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, and subsequent 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Epirubicin (Drug)
HD201 in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2-8), followed by surgery, then adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, and subsequent 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Cyclophosphamide (Drug)
Herceptin® in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2 -8) for cycles 2-8, followed by surgery, and subsequent adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, then 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Herceptin (Drug)
Herceptin® in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2 -8) for cycles 2-8, followed by surgery, and subsequent adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, then 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Docetaxel (Drug)
Herceptin® in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2 -8) for cycles 2-8, followed by surgery, and subsequent adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, then 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Epirubicin (Drug)
Herceptin® in combination with docetaxel
8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2 -8) for cycles 2-8, followed by surgery, and subsequent adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, then 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
total pathological complete response rate (tpCR)
时间窗: After 24 weeks (end of cycle 8)
To compare the total pathological complete response rate (tpCR) in patients treated with HD201 plus chemotherapy to that in patients treated with Herceptin® plus chemotherapy.
次要结局
- Plasma half life (Pharmacokinetic)(Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks))
- Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)(From baseline through study completion until 18 months or until death, whichever came first)
- Cardiac dysfunction(Within 28 days before start of treatment, before cycle 5,12 and 16 (1 cycle is 3 weeks), before surgery (after 24 weeks), at end of treatment (4 weeks from last administration of drug medication) and one year after completion of trastuzumab therapy.)
- Clearance (Pharmacokinetic)(Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks))
- total breast pathological complete response rate (bpCR)(After 24 weeks (end of cycle 8))
- Event-free Survival (EFS)(From date of randomisation until death from any cause or two years after End of Treatment, whichever comes first)
- Immunogenecity(At baseline (within 28 days before start of treatment), before surgery (after 24 weeks), at end of treatment (4 weeks from last administration of drug medication) and one year after completion of trastuzumab therapy.)
- Area under the curve (AUC, Pharmacokinetic)(Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks))
- Overall response rate (ORR)(After 24 weeks (end of cycle 8))
- Overall Survival (OS)(From date of randomisation until death from any cause or two years after End of Treatment, whichever comes first)