| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with HER2-positive unresectable, locally advanced or metastatic breast cancer with progressive disease who have previously received a taxane and trastuzumab, at the minimum, in any breast cancer disease setting. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 compare the efficacy of T-DM1 vs. capecitabine plus lapatinib in patients with HER2-positive unresectable, locally advanced or metastatic breast cancer as measured by PFS based on an independent review of tumor assessments.
• To compare the efficacy of T-DM1 versus capecitabine plus lapatinib in patients with
HER2-positive, unresectable, locally advanced breast cancer or MBC as measured by
overall survival (OS) and to assess landmark (1-year and 2-year) survival rates within
each treatment group, as appropriate.
• To access the safety of T-DM1 realtive to the safety of capecitabine plus lapatinib. |
|
| E.2.2 | Secondary objectives of the trial |
To compare
•PFS between 2 treatment arms based on investigator review of tumor assessments
•the overall objective response rate between 2 treatment arms based on both investigator and independent review of tumor assessments.
•the clinical benefit rate (the proportion of patients with complete response, partial response, or stable disease at 6 mo. after randomization) between 2 treatment arms based on both investigator and independent review of tumor assessments
•time to treatment failure (TTF) between 2 treatment arms
•the time to symptom progression between 2 treatment arms as measured by the FACT-Breast-Trial Outcome Index
•resource expenditure due to hospitalizations and hospital visits for reasons other than defined study evaluations will be compared between 2 treatment arms.
To estimate the duration of objective response within each treatment arm based on both investigator and independent review of tumor assessments |
|
| 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 |
| DNA Repository Substudy in assocation with trastuzumab-MCC-DM1 (T-DM1) study TDM4370g/BO21977 dated 29 October 2010 [Note, this substudy is not considered a "clinical trial" as defined by the EU Clinical Trial Directive]. |
|
| E.3 | Principal inclusion criteria |
a. Disease-Specific Criteria
1. Prospective centrally confirmed HER2-positive MBC.
2. Histologically or cytologically confirmed invasive breast cancer: incurable, unresectable, locally advanced breast cancer previously treated with multimodality therapy or MBC.
3. Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced, or metastatic setting must include both: A taxane, alone or in combination with another agent and Trastuzumab, alone or in combination with another agent in the adjuvant, unresectable, locally advanced or metastatic setting.
4. Documented progression of incurable unresectable, locally advanced, or metastatic breast cancer, 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 nonmeasurable disease. Patients with CNS-only disease are excluded.
b. General Criteria
6. Age ≥ 18 years
7. Cardiac ejection fraction ≥ 50% by either ECHO or MUGA
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Adequate organ function.
• For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective, non-hormonal form of contraception. |
|
| E.4 | Principal exclusion criteria |
a. Cancer-Related Criteria
1. History of treatment with trastuzumab emtansine
2. Prior treatment with lapatinib or capecitabine.
3. Peripheral neuropathy of Grade ≥ 3 per NCI CTCAE
4. History of other malignancy within the last 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.
5. History of receiving any anti-cancer drug/biologic or investigational treatment within 21 days prior to randomization except hormone therapy, which can be given up to 7 days prior to randomization; recovery of treatment-related toxicity consistent with other eligibility criteria
6. History of radiation therapy within 14 days of randomization, The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1) prior to randomization.
7. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including steroids, to control symptoms from brain metastases within 2 months (60 days) before randomization
b. Cardiopulmonary Function
8. History of symptomatic CHF or serious cardiac ventricular arrhythmia requiring treatment
9. History of myocardial infarction or unstable angina within 6 months of randomization
10. Current dyspnea at rest due to complications of advanced malignancy or current requirement for continuous oxygen therapy
c. General Criteria
11. Current severe, uncontrolled systemic disease
12. Pregnancy or lactation
13. Current known active infection with HIV, hepatitis B virus, or hepatitis C virus
14. Presence of conditions that could affect gastrointestinal absorption
15. History of intolerance (such as Grade 3−4 infusion reaction) to trastuzumab
16. Known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase deficiency
17. Current treatment with sorivudine or its chemically related analogs, such as brivudine.
18. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol (i.e., unable to swallow pills).
19. Have discontinued from the TDM4370g/BO21977 study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Incidence, nature and severity of adverse events
2. Overall survival and landmark survival rate
3. Progression-free survival (PFS) by Independent Review Committee assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Through study completion or early study discontinuation
2. Time from randomization to death
3. Time from randomization to the first occurrence of progression or death |
|
| E.5.2 | Secondary end point(s) |
1. Duration of objective response
2. Objective response
3. Progression-free survival by Investigator assessment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. First occurrence of a documented objective response until the time of disease progression
2. Confirmed response at least 28 days after initial documentation of response
3. Time from randomization to the first occurrence of progression or death
|
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| Colombia |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| India |
| Italy |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| Slovenia |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
|
| 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
|
| The study will be considered completed when approximately 632 deaths have been reported and the final analysis of OS is completed. This is defined as the end of the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 53 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 53 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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