| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2+ metastatic breast cancer |
|
| 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 | 10006279 |
| E.1.2 | Term | Breast neoplasm |
|
| 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 of this trial are to demonstrate the efficacy and cardiac safety of Myocet when given in combination with trastuzumab and paclitaxel in patients with HER2+ metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
- Overall survival
- Objective Response rate (Complete and partial) in the final Analyses
- Safety Profile
Objective Response rate is defined as the fraction of patients with complete or partial response as assessed by the Response Evaluation Criteria In Solid Tumors (RECIST). For the primary analysis, response will be the responses as defined by a blinded independent review board.
Overall survival is defined as the time from randomization to the date of death.
The Safety Profile will compare treatment arms for worst grade adverse events; non-cardiac deaths and other serious adverse events; and worst grade laboratory abnormalities. Non-cardiac toxicity is assessed according to the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 3.0http://ctep.cancer.gov/forms/CTCAEV3.pdf |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| 1. Women 18 years of age or older 2. Adenocarcinoma of the breast that is histologically or cytologically proven to show HER2 gene amplification positivity by fluorescence in situ hybridization (FISH) 3. Metastatic disease, using the American Joint Committee on Cancer staging criteria 4. No prior chemotherapy for metastatic disease. Prior chemotherapy in adjuvant or neo-adjuvant setting is allowed if completed at least 1 year earlier. Prior adjuvant or neo-adjuvant chemotherapy within 12 months is allowed, if completed > 4 weeks previously and if it did NOT include anthracyclines or taxanes or prior trastuzumab. Patients must not have received a cumulative dose of doxorubicin of greater than 240 mg/m2 or epirubicin of greater than 480 mg/m2. 5. Prior hormonal therapy is allowed in either the metastatic or adjuvant setting, but must be discontinued prior to first study drug administration. 6. At least one lesion that is measurable in one dimension (RECIST). Patients may have non-measurable disease as long as they have at least one measurable lesion. 7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix B) and an anticipated life expectancy of >6 months 8. Adequate bone marrow function: Absolute neutrophil count (ANC)> 2,000/mm3; Platelet count> 100,000/mm3; Hemoglobin >10 g/dL 9. Adequate liver and kidney function: Total bilirubin within normal limits for the institution; Aspartate aminotransferase (AST, SGOT)< 3 x ULN (or =< 5 ULN in presence of metastatic liver disease); Alanine aminotransferase (ALT, SGPT)< 3 x ULN ( or =<5 ULN in presence of metastatic liver disease); Serum creatinine < 2.0 mg/dL; Alkaline Phosphatase < 3 x ULN in the absence of bone metastases. If >3 ULN in the presence of metastatic liver disease, or attributable to bone metastases, patients will be eligible. 10. Left ventricular ejection fraction (LVEF) within institutional normal range measured by MUGA or echocardiogram with MUGA being the preferred method. Note: with either method, the results will be centrally reviewed in a blinded fashion. Eligibilty is based on site's initial reading. 11. Negative serum or urine b-hCG pregnancy test for women of childbearing potential within 7 days of study drug administration (i.e., women who are not surgically sterile or more than 2 years post-menopausal). 12. Adequate birth control measures by women of childbearing potential to prevent pregnancy during the study. 13. At least 4 weeks since major surgery, 3 weeks since radiotherapy, and discontinued hormone therapy (tamoxifen or aromatase inhibitors). 14. Written, signed and dated, informed consent. |
|
| E.4 | Principal exclusion criteria |
| 1. Prior chemotherapy or other systemic therapy other than hormonal therapy for metastatic disease 2. Active, unresolved infection 3. Prior adjuvant therapy with doxorubicin > 240 mg/m2 or epirubicin > 480 mg/m2 4. Patients who develop metastatic disease > 12 months after completing adjuvant trastuzumab (Herceptin), paclitaxel, docetaxel, or doxorubicin/epirubicin are considered to have had prior therapy for metastatic disease and are excluded from study participation. 5. Receiving concurrent hormonal therapy. 6. Prior radiation therapy ending less than three weeks before the start of study therapy 7. Prior radiation therapy to the mediastinal area > 3,500 cGy, or radiation to >25% of the bone marrow 8. Symptomatic brain metastases 9. Active cardiac disease. Any prior myocardial infarction. Current or history of documented congestive heart failure (CHF). Current use of digitalis glycosides or ACE inhibitors for CHF, Note: ACE inhibitors can be used for hypertension. Any prior history of arrhythmia or cardiac valvular disease requiring medications or considered clinically significant (e.g., under the care of a cardiologist). Current use of medications for treatment of arrhythmias or angina pectoris. Current uncontrolled hypertension (diastolic >100 mmHg or systolic > 200 mmHg). Clinically significant pericardial effusion 10. Prior malignancy within 5 years, except carcinoma in situ of the cervix or non-melanoma skin cancer 11. Women who are pregnant or breast feeding 12. Women of childbearing potential or sexual partner unwilling to employ adequate contraception 13. History of hypersensitivity reaction to anthracyclines, trastuzumab, benzyl alcohol, G-CSF, Cremophor, eggs, or egg products 14. Investigational agent(s) within 3 weeks of start of study therapy 15. Known HIV infection 16. Receiving any other standard or investigational treatment for cancer, or any other investigational agent for any indication 17. Any concurrent medical or psychological condition that would limit the ability of the patient to provide informed consent or to comply with the obligations of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy and Safety Endpoints:
Progression-Free Survival (PFS) in the Final Analysis and Objective Response Rate in the Interim Analysis
Progression Free Survival (PFS) is defined as the time from randomization until the date of disease progression or death due to any cause. For the primary analysis, PFS events will be the PFS events as defined by a blinded independent review board.
New York Heart Association Class III & IV congestive heart failure and cardiac death
The cardiac safety endpoint is defined as New York Heart Association Class III or Class IV congestive heart failure and cardiac death. For the primary analysis, cardiac safety events will be the events as defined by a blinded independent review board. |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | 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 | 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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