E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic breast cancer |
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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 | 10055113 |
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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 evaluate the efficacy and safety of E7389 in patients with locally advanced or metastatic breast cancer who have received anthracycline, taxane, and capecitabine as prior therapy, and are refractory to their last chemotherapy regimen, documented by progression on or within six months of therapy. |
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E.2.2 | Secondary objectives of the trial |
To investigate the pharmacokinetic/ pharmacodynamic relationships in a population pharmacokinetic study.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
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 advanced or metastatic disease who have received at least two (and not more than five) prior chemotherapeutic regimens for breast cancer, at least one of which was administered for treatment of locally advanced or metastatic disease. Prior therapy must be documented by the following criteria prior to entry onto study: • Regimens must have included an anthracycline (eg, doxorubicin, epirubicin), a taxane (eg, paclitaxel, docetaxel) and capecitabine in any combination or order • One or two of these regimens may have been administered as adjuvant and/or neoadjuvant therapy • Patients with HER2/neu over-expressing tumors must additionally have been treated with trastuzumab • Patients with estrogen receptor-expressing tumors may have additionally been treated with estrogen-specific therapy • Prior hormonal therapy,biological therapy(eg,trastuzumab,bevacizumab)or immunotherapy are not to be counted as one of the 2 to 5 prior chemotherapy regimens allowed.However,hormonal therapy must be discontinued one week before administration of E7389,and biological therapy must be discontinued two weeks before E7389 administration • Patients who are being treated with bisphosphonates when they enter the study are allowed to continue the medication as long as the dosing does not change.In case a change in dosing is deemed necessary,the case needs to be discussed with the sponsor. 3. Progression on or within six months of the last regimen for advanced disease, documented by the following:
• The dates of treatment, doses, outcome of therapy and the reason for discontinuation of prior anthracycline, taxane, capecitabine, and trastuzumab therapy must be provided • Prior to entry onto the study, information ensuring that the last therapy fulfills eligibility criteria is required, which includes progression while receiving this last prior chemotherapy regimen, or within six months of receiving the last dose of that therapy • Chemotherapy medication administration sheets or other official medical/hospital records indicating type and dates of chemotherapy must be available for inspection, and one of the following as a reason for discontinuation of medication is required: radiographic evidence of progression, or doctor’s office or hospitalization notes documenting radiologic progression,clinically documented increase in tumor burden,and/or increase in tumor-specific markers 4. Patients with measurable disease by RECIST criteria, defined as at least one lesion that can be accurately measured in at least one diameter (at least 10 mm in LD by spiral CT scan), or at least 20 mm by standard techniques. If the only measurable lesion is a lymph node, it must measure at least 20 mm in LD. If a single lesion is identified as the target lesion, a biopsy or aspiration with cytological or histological confirmation of the diagnosis of breast carcinoma is required.
5. Resolution of all chemotherapy or radiation-related toxicities to less than Grade 2 severity, except for stable sensory neuropathy ≤ Grade 2 and alopecia.
6. Age ≥ 18 years.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 2.
8. Life expectancy of ≥ 3 months.
9. 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.
10. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥1.5 x 10 9/L, hemoglobin ≥ 10.0 g/dL (acceptable if it is corrected by therapeutic intervention or transfusional support), and platelet count ≥ 100 x 10 9/L.
11. Adequate liver function as evidenced by bilirubin ≤ 1.5 mg/dL and alkaline phosphatase, alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 3 times the upper limits of normal (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.
12. Willing and able to complete the EORTC quality of life assessment, Analgesic Diary, and Pain VAS.
13. Willing and able to comply with the study protocol for the duration of the study Eisai E7389-G000-211.
14. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.
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E.4 | Principal exclusion criteria |
1. Patients who have received chemotherapy, radiation, or biological therapy within two weeks, or hormonal therapy within one week, before E7389 treatment start.
2. Radiation therapy encompassing >30% of marrow (a lesion that has been irradiated cannot be used as a target lesion, unless it has progressed after the irradiation).
3. Prior treatment with mitomycin C or nitrosourea, or prior stem cell transplantation.
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,except if they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment with E 7389.Any signs(eg,radiologic) and/or symptoms from their brain metastases must be stable for at least 4 weeks
6. Patients with meningeal carcinomatosis.
7. Patients who require anti-coagulant therapy, other than line patency, with warfarin or related compounds,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 ration(INR) must be monitored closely.
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 child bearing potential unless (1) surgically sterile or (2) using adequate measures of contraception(two forms of contraception,at least one being a barrier method) 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, unstabel angina or myocardial infarction within the past six month, or seriuos cardiac arrhythmia).
11. Patients with organ allografts.
12. Patients with known 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 greater than or equal to 5 years previously with no subsequent evidence of recurrence.
14. Patients with pre-existing neuropathy > Grade 2
15. Hypersensitivity to halichondrin B and/or halicondrin B chemical derivative.
16. Patients who have previously been treated with E7389.
17. Patients with other significant diseases 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) |
Primary Efficacy Endpoint The primary efficacy endpoint is the objective tumor response (CR or PR) rate.
Secondary Efficacy Endpoint • Duration of response
Tertiary Efficacy Endpoints • Overall survival (median and 1-, 2-, and 5-year survival rates) • Progression free survival
Safety Endpoints include: • Adverse Events • Laboratory parameters • Concomitant medication • ECG • Study drug exposure
Clinical Benefits Endpoints Include • Quality of Life measured using the EORTC questionnaire • Tumor-Related Symptom Assessments measured by pain intensity (Visual Analog Scale), analgesic consumption, and ECOG performance status.
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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 | Yes |
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 | 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) | 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 | No |
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 | No |
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) | No |
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 |
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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
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The end of this study is defined as the final study visit of the last patient to be withdrawn from treatment.
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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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |