| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Locally advanced or metastatic breast cancer | |
| 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 | 10055113 | |
| 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 compare the efficacy of E7389 versus capecitabine monotherapy, in terms of Overall Survival and Progression-Free Survival in patients with locally advanced or metastatic breast cancer | |
| E.2.2 | Secondary objectives of the trial | Secondary objectives are to assess:
• Quality of Life measured using the EORTC questionnaire
• Objective Tumor Response Rate as measured using RECIST criteria
• Duration of Response
• One, Two and Three year Survival
• Tumor Related Symptom Assessments measured by pain intensity (VAS), and analgesic consumption
• Safety Parameters (adverse events, laboratory parameters, concomitant medication, and study drug exposure)
To investigate pharmacokinetic/pharmacodynamic relationships in a population pharmacokinetic investigatrion in a minimum of 200 patients in the E7389 arm
| |
| 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 ensure that paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen are available for confirmation of diagnosis.
2. Patients with locally advanced or metastatic disease who have received up to three prior chemotherapy regimens and no more than two prior regimens for advanced and/or metastatic disease.
• Regimens must have included an anthracycline (e.g. doxorubicin, epirubicin) and a taxane (e.g. paclitaxel, docetaxel) either in combination or in separate regimens
• patients must have progressed during or after their last anticancer therapy, and this must be documented
• Patients with known HER2/neu over-expressing tumors may additionally have been treated with trastuzumab in centers where this treatment is available
• Patients with known estrogen and/or progesterone receptor-expressing tumors may have additionally been treated with estrogen-specific 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, 1 or 2
6. Life expectancy of ≥ 3 months
7. Adequate renal function as evidenced by serum creatinine < 1.5 mg/dL or calculated creatinine clearance > 50 mL/minute (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 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 transaminase (ALT), and aspartate transaminase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN), or in case of bone metastases, liver specific alkaline phosphatase ≤ 3 x ULN
10. Patients willing and able to complete the EORTC quality of life questionnaire (QLQ-C30 with breast cancer module QLQ-BR23) and Pain VAS
11. Patients willing and able to comply with the study protocol for the duration of the study
12. 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 more than three prior chemotherapy regimens for their disease, including adjuvant therapies, or patients who have received more than two prior chemotherapy regimens for advanced disease (other therapies are allowed e.g. anti-estrogens, trastuzumb and radiotherapy)
2. Patients who have received capecitabine as a prior therapy for their disease
3. Patients who have received chemotherapy, radiation, or biological therapy within two weeks, or hormonal therapy within one week before study treatment start, or any investigational drug within four weeks before study treatment start
4. Radiation therapy encompassing > 30% of marrow
5. Prior treatment with mitomycin C or nitrosourea
6. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen
7. 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 study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment; radiographic stability should be determined by comparing a contrast enhanced CT or MRI brain scan performed during screening to prior scan performed at least 4 weeks eralier.
8. Patients with meningeal carcinomatosis
9. 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) / international normalized ratio (INR) must be closely monitored.
10. 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 (considered to be two methods of contraception, one of which must be a barrier method) . Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
11. Severe/uncontrolled intercurrent illness/infection
12. 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)
13. Patients with organ allografts requiring immunosuppression
14. Patients with known positive HIV status
15. 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
16. Patients with neuropathy > Grade 2 at screening
17. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative
18. Patients who participated in a prior E7389 clinical trial
19. Patients with other significant disease or disorders that, in the Investigator’s opinion, would exclude the patient from the study | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Overall Survival is measured from the date of randomization until date of death from any cause or the last date the patient was known to be alive.
Progression-Free Survival is measured from the date of randomization to the date of recorded progression of the disease or the death of the patient from any cause. | |
| 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| 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 | 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 |
