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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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 | 19.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006198 |
E.1.2 | Term | Breast cancer recurrent |
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 |
•Progression Free Survival (PFS): to compare the efficacy of he combination of trastuzumab emtansine plus pertuzumab and/or trastuzumab emtansine 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 performed by an independent review facility (IRF).
• To compare the safety of the combination of trastuzumab emtansine plus pertuzumab versus trastuzumab emtansine 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 trastuzumab emtansine plus pertuzumab versus trastuzumab emtansine plus
pertuzumab-placebo versus trastuzumab plus docetaxel/paclitaxel with respect to:
• Overall Response Rate (ORR) by IRF assessment
• Overall Survival Rate (OS)
• Overall Survival (OS) truncated at 2 years
• 1-year Survival Rate
• PFS and ORR based on investigator tumor assessment
• Time to Treatment Failure (TTF) by IRF assessment
• Duration of Response (DR) based on IRF assessment
• Safety and tolerability
• Patient-Reported Outcomes (PRO) and Health Resource Utilization
• Productivity and Health Resource
• ORR and PFS as assessed by IRF, as well as OS, for patient subsets defined by having low or high HER2 mRNA expression
• Pharmacokinetics of trastuzumab emtansine in the presence and absence of pertuzumab and
pharmacokinetics of pertuzumab in the presence of trastuzumab emtansine |
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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 |
RCR and clinical genotyping sample collection requires additional patient consent. All RCR specimens will be destroyed no later than 15 years after the final freeze of the respective clinical database unless regulatory authorities require that specimens be maintained for a longer period. If no consent has been given for long term storage, all samples will be destroyed no later than 5 years after the final freeze of the respective clinical database unless regulatory authorities require that specimens be maintained for a longer period. |
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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 are not eligible.
3. Patients must 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 serum 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:
1. History of systemic anti-cancer therapy after the diagnosis of MBC cancer or for recurrent locally advanced disease with the
exception of prior hormonal regimens for recurrent locally
advanced disease or MBC.
2. 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.
3. Hormone therapy < 7 days prior to randomization.
4. Trastuzumab and/or lapatinib (neoadjuvant/adjuvant setting) < 21 days prior to randomization.
5. Prior trastuzumab emtansine or pertuzumab therapy.
6. Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment.
7. 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.
8. Brain metastases (symptomatic or not symptomatic) that have not been treated previously, are 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.
9. 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.
10. 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.
11. Current peripheral neuropathy Grade ≥ 2 per NCI-CTCAE version 4.0.
12. Abnormal liver function
13. 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.
14. Cardiopulmonary dysfunction b) General exclusion criteria:
15. Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures).
16. Current pregnancy and lactation.
17. 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.
18. Concurrent, serious, uncontrolled infections or current known infection with HIV or active hepatitis B and/or hepatitis C.
19. Current chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisone equivalent).
20. History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity to trastuzumab, murine proteins or docetaxel/paclitaxel.
21. Known hypersensitivity to any of the study drugs, including excipients, of any drugs formulated in polysorbate 80.
22. 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 trastuzumab emtansine plus pertuzumab and/or trastuzumab emtansine 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 trastuzumab emtansine plus pertuzumab versus trastuzumab emtansine plus pertuzumab-placebo versus trastuzumab plus docetaxel or paclitaxel in the aforementioned patient population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary PFS endpoint analysis will be performed when approximately 678 PFS events have occurred, as assessed by the
IRF. This is assumed to be approximately 40 months from enrollment of first patient (FPI). |
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E.5.2 | Secondary end point(s) |
Overall survival (OS) is a key secondary endpoint. OS is defined by, the time from the date of randomization to the date of death from any cause. The one-year survival rate will also be determined. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoint of OS will be conducted when 639 deaths have been reported (expected approximately 67 months after FPI). Two interim analyses of OS will be conducted prior to the final analysis. The end of the study will be reached when the cut-off date for the final OS analysis is reached and the database is locked or upon study termination by sponsor, whichever occurs first. |
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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.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.5 | 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 | 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 |
Australia |
Austria |
Bahamas |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Colombia |
Costa Rica |
Czech Republic |
France |
Germany |
Greece |
Guatemala |
Hungary |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lithuania |
Malaysia |
Mexico |
New Zealand |
Panama |
Peru |
Philippines |
Poland |
Portugal |
Romania |
Russian Federation |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Kingdom |
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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 is defined as LPLV which will occur following the final OS analysis. The latter is planned to occur after a minimum follow-up of 46 months from LPI, as detailed in Section 8. The Sponsor may also terminate this study at any time. |
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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 |