| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally recurrent or metastatic breast cancer after failure of multiple prior chemotherapy regimens |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | 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 |
| To compare the overall survival (OS) of patients treated with E7389 versus the Treatment of Physician’s Choice (including anti-tumor treatment of the investigator’s choice and palliative treatment) in patients with locally recurrent or metastatic breast cancer, who have received 2-5 prior chemotherapy regimens, which must have included an anthracycline and a taxane as prior therapy and at least 2 of which must have been given for locally recurrent or metastatic disease. Patients must also be refractory to their latest chemotherapy regimen, documented by progression on or within six (6) months of therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
• Progression Free Survival (PFS)
• Objective Tumor Response Rate as measured using RECIST criteria
• Duration of Response
• Safety Parameters (adverse events, laboratory parameters, concomitant medication, and study drug exposure)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female patients with histologically or cytologically confirmed carcinoma of the breast. Every effort should be made to make paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis.
2. Patients with locally recurrent or metastatic disease who have received at least two (and not more than five) prior chemotherapeutic regimens for breast cancer, at least two of which were administered for treatment of locally recurrent and/or metastatic disease. Prior therapy must by documented by the following criteria prior to entry onto study:
• Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a taxane (e.g., paclitaxel, docetaxel) in any combination or order. Treatment with any of these agents is not required if they are contraindicated for a certain patient.
• One or two of these regimens may have been administered as adjuvant and/or neoadjuvant therapy, but at least 2 must have been given for relapsed or metastatic disease
• Patients must have proved refractory to the most recent chemotherapy, documented by progression on or within six (6) months of therapy
• Patients with HER2/neu positive tumors may additionally have been treated with trastuzumab
• Patients may have additionally been treated with anti-hormonal therapy
3. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy ≤ Grade 2 and alopecia
4. Age ≥ 18 years
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
6. Life expectancy of ≥ 3 months
7. Adequate renal function as evidenced by serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula
8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 10*/L, hemoglobin ≥ 10.0 g/dL (a hemoglobin <10.0 g/dL is acceptable if it is corrected by growth factor or transfusion), and platelet count ≥ 100 x 10*/L
*=9
9. Adequate liver function as evidenced by bilirubin ≤ 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase
10. Patients willing and able to comply with the study protocol for the duration of the study
11. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice
|
|
| E.4 | Principal exclusion criteria |
1. Patients who have received any of the following treatments within the specified period before E7389 or TPC treatment start:
- chemotherapy, radiation, trastuzumab or hormonal therapy within three weeks
- any investigational drug within four weeks
2. Radiation therapy encompassing > 30% of marrow
3. Prior treatment with mitomycin C or nitrosourea
4. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen
5. Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (e.g. radiologic) and/or symptoms of brain metastases must be stable for at least 4 weeks.
6. Patients with meningeal carcinomatosis
7. Patients who are receiving anti-coagulant therapy with warfarin or related compounds, other than for line patency, and cannot be changed to heparin-based therapy, are not eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT) or international normalized ratio (INR) must be closely monitored.
8. Women who are pregnant or breast-feeding; women of childbearing potential with either a positive pregnancy test at screening or no pregnancy test; women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the Investigator. Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
9. Severe/uncontrolled intercurrent illness/infection
10. Significant cardiovascular impairment (history of congestive heart failure > NYHA grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia)
11. Patients with organ allografts requiring immunosuppression
12. Patients with known positive HIV status
13. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated ≥ 5 years previously with no subsequent evidence of recurrence
14. Patients with pre-existing neuropathy > Grade 2
15. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative
16. Patients who participated in a prior E7389 clinical trial
17. Patients with other significant disease or disorders that, in the Investigator’s opinion, would exclude the patient from the study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall Survival is defined as the time from the date of randomization until the date of death from any cause. For patients who do not die, overall survival will be censored at the last date the patient was known to be alive.
Secondary end point:
Progression-Free Survival (PFS) is defined as the time from randomization until disease progression or death due to any cause. For patients who do not have an event (i.e. those who are lost to follow-up or who have not progressed at the date of data cut-off), progression-free survival will be censored.
Tertiary end point:
• Objective tumor response rate (ORR) as measured using RECIST criteria in patients with measurable disease
• Duration of Response
• Safety parameters (adverse events, laboratory parameters, concomitant medication, ECG and study drug exposure)
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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 | No |
| 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 | 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
| |
| 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 | 3 |
| 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 | 3 |
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