E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2 positive metastatic breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
HER2 positive breast cancer that has spread |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive 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 |
The primary objective of this study is to evaluate the safety and tolerability of trastuzumab emtansine. |
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E.2.2 | Secondary objectives of the trial |
•Progression free survival (PFS)
•Overall survival (OS)
•Overall response rate (ORR) = partial response (PR) + complete response (CR)
•Clinical benefit rate (CBR)
•Duration of response (DoR)
•Time To Response (TTR)
Pharmacoeconomics outcome objective
•Health Resource Utilization |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. HER2-positive disease determined locally i.e., IHC 3 + and/or gene-amplified by ISH as per institutional practice, (however, both tests should be performed wherever possible and only one positive result is required for eligibility)
2. Histologically or cytologically confirmed invasive BC
3. Prior treatment for BC in the advanced/metastatic, unresectable locally advanced or metastatic setting must include an anti-HER2 agent and chemotherapy in combination or sequential administration (complementary hormonal therapy is allowed)
4. Documented progression of incurable, unresectable, locally advanced, or mBC, defined by the investigator: progression must occur during or after most recent treatment for locally advanced/mBC or within 6 months after completing adjuvant therapy
5. Measurable and/or non-measurable disease
6. Signed written informed consent approved by the institution’s independent Ethical Committee (EC)
7. Age ≥ 18 years
8. Left ventricular ejection fraction ≥ 50% by either ECHO or MUGA
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2
10. Adequate organ function
11. For women of childbearing potential and men with partners of childbearing potential agreement by the patient and/or partner to use a highly effective non-hormonal form of contraception.
12. Negative serum pregnancy test for women of childbearing potential and for all women not meeting the definition of postmenopausal, and who have not undergone surgical
sterilization with a hysterectomy and/or bilateral oophorectomy. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing potential.
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E.4 | Principal exclusion criteria |
1. History of treatment with trastuzumab emtansine
2. Prior enrolment into a clinical study containing trastuzumab emtansine regardless of having received trastuzumab emtansine or not
3. History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers with a similar curative outcome as those mentioned above
4. History of receiving any anti-cancer drug/biologic or investigational treatment within 21 days prior to first study treatment except hormone therapy, which can be given up to 7 days prior to first study treatment; recovery of treatment-related toxicity consistent with other eligibility criteria
5. History of exposure to the following cumulative doses of anthracyclines:
• Doxorubicin or liposomal doxorubicin > 500 mg/m2
• Epirubicin > 900 mg/m2
• Mitoxantrone >120 mg/m2
• If another anthracycline, or more than one anthracycline, has been used, the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.
6. History of radiation therapy within 14 days of first study treatment. The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1) prior to first study treatment.
7. CNS only disease
8. Brain metastases which are symptomatic. NOTE: A 14 days window after end of radiotherapy must be observed. Patient must not be receiving steroids to control symptoms.
9. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab treatment
10. History of symptomatic congestive heart failure (CHF; New York Heart Association [NYHA] Classes II−IV) or serious cardiac arrhythmia requiring treatment
11. History of myocardial infarction or unstable angina within 6 months of first study treatment
12. Current dyspnea at rest due to complications of advanced malignancy or requirement for continuous oxygen therapy
13. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease)
14. Pregnancy or lactation
15. Currently known active infection with HIV, hepatitis B virus, or hepatitis C virus
16. History of intolerance (such as Grade 3−4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins
17. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol throughout
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this study will be AEs Grade ≥ 3, specifically, liver dysfunction, pneumonitis, allergic reactions, thrombocytopenia and all Grade ≥ 3 AEs related to trastuzumab emtansine. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be performed when all (1000) patients have been followed up for safety and efficacy for up to a period of 2 years after last patient enrolled in the trial.
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E.5.2 | Secondary end point(s) |
Efficacy is the secondary endpoint. Efficacy endpoints will be: PFS, OS, ORR, CBR, duration of response, and time to tumor response.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be performed when all (1000) patients have been followed up for safety and efficacy for up to a period of 2 years after last patient enrolled in the trial.
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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 | No |
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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 230 |
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 |
European Union |
Argentina |
Australia |
Brazil |
Canada |
Costa Rica |
Croatia |
Dominican Republic |
Ecuador |
El Salvador |
Guatemala |
Hong Kong |
India |
Korea, Republic of |
Mexico |
Panama |
Peru |
Saudi Arabia |
Taiwan |
Trinidad and Tobago |
Turkey |
United Arab Emirates |
Venezuela, Bolivarian Republic of |
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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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Last Patient Last Visit (LPLV) as per definition is the last data collection point which can be a clinic visit or a laboratory sample. LPLV is expected to occur two years after the last patient first visit. |
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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 | 5 |
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 | 5 |
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 |