E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER-2 positive breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To demonstrate the therapeutic equivalence of TX05 (proposed biosimilar trastuzumab) to Herceptin (trastuzumab) based on the pathologic complete response (pCR) rate following neoadjuvant chemotherapy, defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0), in subjects with human epidermal growth factor receptor positive (HER2+) invasive early breast cancer (EBC). |
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E.2.2 | Secondary objectives of the trial |
To compare objective response rate (ORR) between the 2 treatment arms; immunogenicity, safety, and tolerability will also be assessed. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed written informed consent. 2. Females ≥ 18 years of age. 3. Histologically confirmed HER2 overexpressing invasive primary operable Stage II/IIIa breast cancer by American Joint Committee on Cancer 7th Edition staging criteria. Tumor tissue sample must be available for central analysis. 4. Planned surgical resection of breast tumor (lumpectomy or mastectomy, and SN biopsy or ALND). 5. Planned neoadjuvant chemotherapy. 6. HER2 overexpression as assessed by: - Gene amplification by fluorescent in-situ hybridization (FISH), chromogenic in-situ hybridization (CISH), or dual in-situ hybridization (DISH) (as defined by the manufacturer’s kit instruction); OR - Overexpression by immunohistochemistry (IHC) categorized as IHC 3+; OR - Overexpression by immunohistochemistry categorized as IHC2+ with FISH, CISH, or DISH confirmation. Central review will be performed retrospectively for subjects who were determined to be HER2 positive by use of either an approved assay listed in Appendix 1 or two different analytical test methods that were not considered Sponsor approved. The results from non-approved IHC and in-situ hybridization analytical tests must be unequivocal (i.e., IHC result must be categorized as IHC3+). If a subject’s tumor HER2 status cannot be determined by using an approved assay (see Appendix 1) or two different HER2 assays performed locally, a tissue sample can be sent to the central laboratory early in Screening for evaluation; results of the assessment will be returned to the investigator for inclusion in subjects’ source documents. 7. Ipsilateral, measurable tumor longest diameter > 2 cm. 8. Known estrogen receptor (ER) and progesterone receptor (PR) hormone status prior to randomization. If ER/PR status is not available locally, testing may be performed by central laboratory during Screening. 9. ECOG performance status of 0 or 1. 10. Adequate bone marrow, hepatic, and renal functions as evidenced by the following: - Absolute neutrophils count ≥ 1,500/μL - Hemoglobin ≥ 9 g/dL - Platelet count ≥ 100,000/μL - Creatinine clearance ≥ 40 mL/min - Total bilirubin ≤ 1.5 x upper limit of normal (ULN) - Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 x ULN - Alkaline phosphatase ≤ 5 x ULN 11. LVEF ≥ 50% or within the normal level of the institution, as assessed by echocardiography or MUGA scan. 12. Able to comply with the study protocol. 13. Female subjects of childbearing potential must have a negative serum pregnancy test within 1 week of first administration of study drug and agree to use effective contraception (hormonal contraceptive, intrauterine device, diaphragm with spermicide, or condom with spermicide) throughout the study period and for 6 months after last administration of study drug. |
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E.4 | Principal exclusion criteria |
1. Participation in any interventional clinical study or having taken any investigational therapy during the 2 month period immediately preceding administration of the first dose of study drug. 2. Bilateral breast cancer. 3. Inflammatory breast cancer. 4. Metastases. 5. Previous chemotherapy, biologic therapy, radiation, or surgery for any active malignancy, including breast cancer. 6. Subjects with one or more of the following conditions: - Cardiac insufficiency (New York Heart Association III or IV); myocardial infarction, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident, unstable angina pectoris, uncontrolled arrhythmia, or pulmonary embolus within the previous 12 months prior to the first administration of study drug. - Clinically significant active infection. - Poorly controlled diabetes mellitus. - Uncontrolled hypertension (blood pressure > 150/100 mmHg despite optimal medical therapy). - Major surgery, significant traumatic injury, or radiation therapy within 4 weeks of first administration of study drug. - Grade 3 hemorrhage within 4 weeks of first administration of study drug. 7. Pre-existing clinically significant (≥ Grade 2) peripheral neuropathy. 8. History of malignancy within the last 5 years, except adequately excised squamous or basal cell carcinoma of the skin, cervical carcinoma in situ, and superficial bladder cancer. 9. Severe dyspnea at rest requiring supplementary oxygen therapy. 10. Known positive status for human immunodeficiency virus. 11. Known acute or chronic-active infection with hepatitis B surface antigen or hepatitis C virus. 12. History or presence of a medical condition or disease that in the investigator's opinion would place the subject at an unacceptable risk for study participation. 13. Lactating or pregnant female. 14. Women of childbearing potential who do not consent to use highly effective methods of birth control (e.g. true abstinence [periodic abstinence {e.g. calendar ovulation, symptothermal, post-ovulation methods} and withdrawal are not acceptable methods of contraception], sterilization, or other non-hormonal forms of contraception) during treatment and for at least 6 months after the last administration of study drug. Subjects must agree to not breast-feed while receiving study drug. 15. Subject has known sensitivity to any of the products to be administered during the study, including mammalian cell derived drug products, trastuzumab, murine proteins, or to any of the excipients. 16. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range despite optimal medical therapy. 17. Subject likely to not be available to complete all protocol required study visits or procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of subjects in each treatment arm who achieve pCR, defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0). Pathology of the tumor sample and pathologic response will be assessed locally and reviewed centrally by a qualified pathologist. The primary efficacy analysis will be based on the central pathological review. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Following completion of neoadjuvant systemic treatment AND completion of surgery. |
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E.5.2 | Secondary end point(s) |
ORR, defined as the percentage of subjects having Complete or Partial Response at the EOT/ET Visit, according to RECIST version 1.1 (see Appendix 4), as assessed by the investigator. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Belarus |
Brazil |
Bulgaria |
Chile |
Georgia |
Hungary |
India |
Italy |
Korea, Republic of |
Peru |
Philippines |
Poland |
Romania |
Russian Federation |
Slovakia |
Thailand |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |