| 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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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| 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 objectives for this study are as follows:
• To explore the efficacy of T-DM1 compared with the combination of trastuzumab and docetaxel in patients with HER2-positive, unresectable, locally advanced breast cancer and/or metastatic breast cancer who have not received prior chemotherapy for metastatic disease, as measured by PFS based on investigator assessments
• To evaluate the safety of T-DM1 compared with the combination of trastuzumab and docetaxel in this population |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows:
• To explore the efficacy of T-DM1 compared with the combination of trastuzumab and docetaxel in patients with HER2-positive, unresectable, locally advanced breast cancer and/or metastatic breast cancer who have not received prior chemotherapy for metastatic disease, as measured by the 12-month PFS rate, median PFS, duration of overall survival, survival rate at 12 months, objective response rate, duration of objective response, and clinical benefit rate (the proportion of patients with CR or PR or stable disease for ≥ 6 months since randomization)
• To characterize the PK properties of T-DM1 in this patient population
• To compare the time to symptom progression, as measured by the Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) and the patient's assessment of pain, in the two treatment arms |
|
| 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 association with trastuzumab-MCC-DM1 study TDM4450g.
Protocol date: 24 April 2008. Version 1.
The primary objective of this study is to perform exploratory analyses to generate hypotheses identifying genes associated with treatment response, toxicity, or disease risk. If such genetic hypotheses are identified, they may be tested in future clinical studies within this therapeutic area.
Note, this study is not defined as a clinical trial under the scope of the EU Clinical Trial Directive. |
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| E.3 | Principal inclusion criteria |
a. Disease-Specific Criteria
1. Histologically or cytologically confirmed adenocarcinoma of the breast with locally advanced or metastatic disease, and a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease after failing initial attempts at local control. The disease must be considered to be unresectable.
2. HER2-positive (IHC 3+ or gene-amplified by FISH-positive) based on local laboratory assay results
3. No prior chemotherapy for their MBC (hormonal therapy is allowed.)
4. Measurable disease per modified RECIST
Patients should have at least one target lesion ≥2 cm on conventional CT scan or ≥1 cm on a spiral CT scan.
5. Tumor blocks or 11 unstained slides available for confirmatory central laboratory HER2 testing
b. General Criteria
6. Age ≥18 years
7. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
8. Adequate organ function, evidenced by the following laboratory results within approximately 21 days prior to randomization:
Absolute neutrophil count >1500 cells/mm[3]
Platelet count > 100,000 cells/mm[3]
Hemoglobin > 9.0 g/dL
Patients are allowed to be transfused with red blood cells to obtain this level.
Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)
SGOT (AST) and/or SGPT (ALT), and alkine phosphatase ≤2.5 ×ULN, with the following exception
Patients with bone metastases: alkaline phosphatase ≤5 ×ULN
Serum Creatinine < 1.5 × ULN
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.5 ×ULN (unless on therapeutic anticoagulation or due to a lupus anticoagulant)
10. For women of childbearing potential and for men with partners of childbearing potential, agreement to use an highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or the partner. Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study treatment. Male patients whose partners are pregnant should use condoms for the duration of the study.
Specific country requirements will be followed (e.g., in the United Kingdom, women of childbearing potential and male subjects and their partners of childbearing potential must use two methods of contraception [one of which must be a barrier method] for the duration of the study).
|
|
| E.4 | Principal exclusion criteria |
a. Cancer-Related Criteria
1. History of any chemotherapy for MBC
Prior hormonal therapy is allowed.
2. An interval of <6 months from the completion of cytotoxic chemotherapy (excluding hormonal therapy) in the neo-adjuvant or adjuvant setting until the time of metastatic diagnosis. Patients who progress on or within 12 months on single-agent trastuzumab will be considered eligible (unless trastuzumab has been given ≤ 21 days prior to randomization).
3. Trastuzumab ≤ 21 days prior to randomization
4. Hormone therapy < 7 days prior to randomization
5. Current peripheral neuropathy of Grade ≥3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0
6. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those previously mentioned.
7. Previous radiotherapy for the treatment of unresectable, locally advanced metastatic breast cancer is not allowed if:
More than 25% of marrow-bearing bone has been irradiated.
The last fraction of radiotherapy has been administered within approximately 3 weeks prior to randomization.
8. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastases within 2 months prior to randomization. CT or magnetic resonance imaging (MRI) scan of the brain is mandatory (within approximately 28 days prior to randomization) in cases of clinical suspicion of brain metastases or in a patient with any prior history of brain metastases.
9. History of exposure to the following cumulative doses of anthracyclines:
Doxorubicin or liposomal doxorubicin > 500 mg/m[2]
Epirubicin > 900 mg/m[2]
Mitoxantrone > 120mg/m[2] and idarubicin > 90 mg/m[2]
If another anthracycline or more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 500 mg/m[2] of doxorubicin.
b. Cardiopulmonary Function
10. Current unstable angina
11. History of symptomatic congestive heart failure (CHF; New York Heart Association [NYHA] classes II−IV), or ventricular arrhythmia requiring treatment
12. History of myocardial infarction within 6 months prior to randomization
13. LVEF below 50% within approximately 28 days prior to randomization
14. History of a decrease in LVEF <40% or symptomatic CHF with previous trastuzumab treatment
15. Cardiac troponin I ≥ 0.2 ng/mL within approximately 28 days prior to randomization
16. Severe dyspnea at rest because of complications of advanced malignancy or requiring current continuous oxygen therapy
General Criteria
17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures)
18. 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
19. Current pregnancy or lactation
20. History of receiving any investigational treatment within approximately 28 days prior to randomization
21. Current known infection with HIV, active hepatitis B and/or hepatitis C virus
22. History of intolerance (including Grade 3−4 infusion reaction) or hypersensitivity to trastuzumab, murine proteins, or docetaxel
23. Known hypersensitivity to any of the study drugs, including the excipients, or any drugs formulated in polysorbate 80
24. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by investigator tumor assessments using RECIST, or death on study from any cause. Death on study is defined as death from any cause within 30 days of the last dose of study drug prior to crossover.
The first documented PD event prior to crossover in the control arm will be included in the analysis of the primary endpoint of PFS. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Information not present in EudraCT |
| 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.8.3 |
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 | 42 |
| 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 |
|
| 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
|
| Follow-up for survival will continue until the last patient has completed 24 months of follow-up after treatment discontinuation, and the study will end at that point. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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