E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
First line treatment in HER2 positive progressive or recurrent locally advanced or metastatic breast cancer (MBC) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006198 |
E.1.2 | Term | Breast cancer recurrent |
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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 |
•Progression Free Survival (PFS): to compare the efficacy of he combination of T-DM1 plus pertuzumab and/or T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel/paclitaxel in patients with HER2 positive progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer patients, based on tumor assessments reviewed by an independent review facility (IRF). • To compare the safety of the combination of T-DM1 plus pertuzumab and T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel or paclitaxel in the aforementioned patient population. |
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E.2.2 | Secondary objectives of the trial |
Compare the combination of T-DM1 plus pertuzumab and T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel/paclitaxel with respect to: • Overall Response Rate (ORR) by IRF assessment • Overall Survival Rate (OS) • 1-year Survival Rate • PFS and ORR based on investigator tumor assessment • Clinical Benefit Rate (CBR: CR+PR + [SD ≥ 6 months]) based on IRF and investigator tumor assessment • Time to Treatment Failure (TTF) by IRF assessment • Duration of Response (DR) based on IRF assessment • Safety and tolerability • Quality of Life (QoL), Productivity and Health Resource • ORR and PFS as assessed by IRF for patient subsets defined by having low or high HER2 mRNA expression • Pharmacokinetics of T-DM1 in the presence and absence of pertuzumab and pharmacokinetics of pertuzumab in the presence of T-DM1 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a) Disease specific inclusion criteria: 1. HER2-positive breast cancer as defined by IHC 3+ and /or ISH positive, prospectively confirmed by a Sponsor designated central laboratory prior to enrollment. Archival tumor samples obtained from primary or metastatic sites are acceptable. 2. Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and be a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent. Patients with standard curative options available to them will be excluded from the trial. 3. Patients may have measurable and/or non-measurable disease which must be evaluable per RECIST 1.1. b) General inclusion criteria: 4. Signed written informed consent approved by the institution’s Independent Ethical Committee (IEC). 5. Age ≥ 18 years. 6. ECOG Performance Status 0 or 1. 7. Adequate organ function as determined by the following laboratory results, within approximately 14 days prior to randomization: 8. For women of childbearing potential and men with partners of childbearing potential, agreement to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for 6 months after the last dose of study treatment. Male patients whose partners are pregnant must use condoms for the duration of the study treatment and for 6 months after the last dose of study treatment. Specific country and/or local requirements for contraception will be followed. 9. A negative pregnancy test must be available for premenopausal women and for women less than 12 months after the onset of menopause. |
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E.4 | Principal exclusion criteria |
a) Disease related Exclusion Criteria: History of systemic anti-cancer therapy after the diagnosis of MBC cancer. 1. An interval of < 6 months from the last dose of vincaalkaloid or taxane cytotoxic chemotherapy in the neoadjuvant or adjuvant setting until the time of metastatic diagnosis. 2. Hormone therapy < 7 days prior to randomization. 3. Trastuzumab (neoadjuvant/adjuvant setting) < 21 days prior to randomization. 4. Prior T-DM1 or pertuzumab therapy. 5. Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment. 6. History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome. 7. Brain metastases that are either untreated, progressive or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms from brain metastases within 60 days prior to the first study treatment dose. 8. Radiotherapy for the treatment of locally advanced disease or for metastatic sites of disease performed within 14 days prior to study enrollment, and/or radiation of > 30% of marrowbearing bone. 9. Symptomatic hypercalcemia requiring use of bisphosphonate therapy within 21 days prior to the first study treatment. Patients who receive bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. 10. Current peripheral neuropathy Grade ≥ 2 per NCI-CTCAE version 4.0. 11. History of exposure to the following cumulative doses of anthracyclines as specified below. o Doxorubicin > 500 mg/m2 o Liposomal doxorubicin > 900 mg/m2 o Epirubucin > 720 mg/m2 o Mitoxantrone > 120 mg/m2 o Idarubicin > 90 mg/m2 If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 13. Cardiopulmonary dysfunction b) General exclusion criteria: 14. Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures). 15. Current pregnancy and lactation. 16. Major surgical procedure or significant traumatic injury within approximately 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment. 17. Concurrent, serious, uncontrolled infections or current known infection with HIV, active hepatitis B and/or hepatitis C. 18. Current chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisone equivalent). 19. History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity to trastuzumab, murine proteins or docetaxel/paclitaxel. 20. Known hypersensitivity to any of the study drugs, including excipients, of any drugs formulated in polysorbate 80. 21. Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Progression Free Survival (PFS): to compare the efficacy of he combination of T-DM1 plus pertuzumab and/or T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel/paclitaxel in patients with HER2 positive progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer patients, based on tumor assessments reviewed by an independent review facility (IRF). • To compare the safety of the combination of T-DM1 plus pertuzumab and T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel or paclitaxel in the aforementioned patient population. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 101 |
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 | Information not present in EudraCT |
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 |
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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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The end of the study will be reached when the cut-off date for final OS analysis is reached. OS will be analyzed when 677 deaths have been reported (assumed 78 months after FPI), or until the trial is terminated by the Sponsor, whichever occurs first. |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |