| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Epidermal Growth Factor Receptor 2 positive (HER2+) metastatic breast cancer (MBC) |
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| E.1.1.1 | Medical condition in easily understood language |
| HER2+ breast cancer tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells, where the disease has spread to distant sites |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Part 1: To compare the independently assessed best overall response rate (ORR) (according to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 criteria) at Week 24 with Hercules plus taxane versus Herceptin® plus taxane in patients who have not received previous first line treatment for HER2+ MBC. Part 2: The primary objective is to descriptively compare the safety, immunogenicity, and tolerability profile of single agent Hercules and Herceptin® and; to compare the immunogenicity of Hercules and Herceptin® by examining clinical immunogenic response. |
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| E.2.2 | Secondary objectives of the trial |
| SECONDARY OBJECTIVES Part 1 of the study: •To compare independently assessed clinical activity at Week 24 between treatment arms by measuring: time to tumor progression (TTP); progression-free survival (PFS); overall survival (OS); duration of response (DR). •To descriptively compare the safety, immunogenicity, and tolerability profile of Hercules and Herceptin® given in combination with a taxane. •To compare the populations pharmacokinetic (PopPK) AUC, Cmax, minimum drug concentration (Cmin), clearance, volume of distribution (Vd), and T1/2, profiles of Hercules and Herceptin®. Part 2 of the study: •To compare the clinical activity at Week 48 between treatment arms by measuring: PFS, OS and DR, and OS at 36 months or after 300 deaths, whichever occurs first, as observed from the time of randomization. EXPLORATORY OBJECTIVES: To assess the impact of shed ECD fragments of the HER2 receptor (HER2/ECD) in serum on PK and efficacy parameters. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| During Part 1 of the study, for both the Hercules and Herceptin® treatment arms, PK sampling for Cmin and Cmax (end of infusion) will be collected for all patients. A PopPK subset, 30 patients in each treatment arm (N=60), will have additional blood samples collected. PopPK modeling will be used to assess AUC, Cmax, Cmin, clearance, Vd, and T1/2 at various time points in the PopPK. Patients randomized into the main study will sign an additional consent form for the PopPK subset. |
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| E.3 | Principal inclusion criteria |
| 1.≥18 years of age. 2.Histologically confirmed diagnosis of breast cancer. 3.Locally recurrent or MBC that is not amenable to curative surgery and/or radiation. 4.Documentation of HER2 gene amplification by fluorescent in situ hybridization (FISH); as defined by a ratio >2.0) or documentation of HER2-overexpression by immunohistochemistry (IHC) (defined as IHC3+, or IHC2+ with FISH confirmation) based on sponsor-identified central laboratory prior to randomization (see Section 7.1.1). Archival tumor tissue samples can be used. 5.Documentation of estrogen receptor/progesterone receptor (ER/PgR) status (positive or negative) based on either a local or central laboratory report must be available before randomization. 6.Pathologically confirmed breast cancer with at least one measurable metastatic target lesion (based on RECIST criteria, Version 1.1). Bone, central nervous system (CNS), and skin lesions, as well as lesions that were irradiated, biopsied or had any form of local intervention or surgical manipulation are only to be assessed as non-target lesions. Baseline imaging studies and submitted for central confirmation of target lesions must have been performed in the 4 weeks preceding randomization. 7.Patients with a history of CNS metastases or cord compression are eligible if they have been successfully treated and are off steroids for at least 4 weeks before first dose of investigational product. Patients with newly detected CNS metastases must be successfully treated (e.g., radiotherapy, stereotactic radiosurgery) before being considered for the trial. Patients with known or suspected brain metastases must undergo a baseline brain computed tomography (CT) or magnetic resonance imaging (MRI). 8.Patients previously treated with trastuzumab or lapatinib in the adjuvant setting are allowed if metastatic disease was diagnosed at least one year after the last dose of treatment. 9.Prior treatment with hormonal agents or bisphosphonates/denosumab is allowed. Bisphosphonates/denosumab can be given simultaneously with study treatment but cannot start after randomization and is considered an indication of progressive disease (PD). Hormonal agents must be discontinued prior to beginning study therapy. 10.Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 2. 11.Screening laboratory values within the following parameters: •Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500/mm3). •Platelet count ≥100 x 109/L (100,000/mm3). •Hemoglobin ≥9.0 g/dL (90 g/L), without a prior transfusion in the last 2 weeks. •Serum creatinine ≤1.5 x upper limit of normal (ULN). •Total bilirubin ≤1.0 x ULN (>1 ULN if documented Gilbert’s disease). •Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x ULN. •AST and/or ALT <1.5 x ULN, if alkaline phosphatase > 2.5 x ULN. •Alkaline phosphatase >2.5 x ULN, if bone metastases present and no liver dysfunction present. 12.Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO). 13.The patient is willing to comply with the protocol and procedures for the duration of the study, including all scheduled visits and examinations. 14.The patient is either not of childbearing potential or is willing to practice birth control by using two different highly effective methods of contraception, or abstain from sexual intercourse for the duration of the study and follow-up. In particular, patients of childbearing potential must: •Female patients are to use a method which results in less than 1% failure rate per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or vasectomized partner. Have a negative human chorionic gonadotropin (hCG) serum pregnancy test at screening and by urinary test on Day 1. •Male patients without vasectomy are required to use a condom with spermicide and their female partner to use another form of contraception which should followed from the time of the first dose of study medication until 8 weeks following the last dose of study treatment. 15.Written informed consent signed by the patient or her legal representative (if patient is unable to provide) prior to any study-related procedures not standard of care. |
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| E.4 | Principal exclusion criteria |
| 1.Prior systemic therapy in the metastatic disease setting. This includes: chemotherapy, signal transduction inhibitors (e.g., lapatinib), HER2 targeted therapy (e.g., trastuzumab), or other investigational anticancer therapy. 2.Prior treatment with neoadjuvant or adjuvant anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose >800 mg/m2. 3.Participation in the active treatment phase of an investigational drug study ≤28 days prior to randomization. 4.Patients with bone or skin as the only site of disease. Patients with skin lesions measurable by CT scans or MRI as only site of measurable disease are allowed. 5.Surgery or radiotherapy ≤2 weeks preceding Day 1. Target lesions have to be outside the irradiated fields and the patient has fully recovered from surgery or radiotherapy. 6.Presence of unstable angina or a history of CHF according to the New York Heart Association criteria, history of myocardial infarction <1 year from randomization, clinically significant valvular disease, serious cardiac arrhythmia requiring treatment, uncontrolled hypertension or known pulmonary hypertension. 7.Peripheral sensory or motor neuropathy Grade 2 or higher according to the National Cancer Institute-Common Terminology Criteria (NCI-CTC) Version 4.03 [19]. 8.Any other cancer, including contralateral breast cancer, within 5 years prior to screening with the exception of adequately treated ductal carcinoma in situ, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin. 9.Immunocompromized patients, including known seropositivity for human immunodeficiency virus, or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen or antibody to hepatitis C virus with confirmatory testing). 10.Patients with documented severe hypersensitivity reaction to trastuzumab, paclitaxel, docetaxel or excipients used in their formulations, including murine protein remnants. 11.Evidence of significant medical illness or abnormal laboratory finding (including dyspnea at rest or serious pulmonary illness) that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in, and completion of, the study, or could preclude the evaluation of the patient’s response. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the best ORR where objective response is defined as a CR or PR according to RECIST 1.1 based on central tumor evaluation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The ratio of the best ORRs at Week 24 will be statistically compared |
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| E.5.2 | Secondary end point(s) |
-Time to tumor progression
-Progression free survival
-Overall survival
-Duration of response |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Time to tumor progression (TTP): responseThe analysis will be performed at Week 24 and 48 for Part 1 and Part 2, respectively, for the ITT population.
-Progression free survival: will be analyzed in the same manner as TTP.
-Overall survival
- OS will be analyzed in the same manner as TTP.
-Duration of response: will be analyzed in the same manner as TTP at Week 48 only |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 68 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Austria |
| Brazil |
| Bulgaria |
| Chile |
| Czech Republic |
| Egypt |
| France |
| Georgia |
| Germany |
| Greece |
| India |
| Italy |
| Latvia |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Thailand |
| Turkey |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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