| 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.1.3 | 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. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate the pharmacokinetic/pharmacodynamic relationships in a population pharmacokinetic study.
A tertiary objective is to explore the potential relationships between clinical responses to E7389 and microtubule-related molecules: alpha- and beta-tubulin isotypes, tau, stathmin, and MAP4. Evaluation of genetic alterations or mutations as well as gene expression will be performed on paraffin embedded tissues or fresh, frozen biopsy specimens. |
|
| 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. A tissue sample from the diagnostic biopsy, paraffin block, cytological specimen, or slides obtained from these must be available for confirmation of diagnosis. To verify the diagnosis, patients need to have a counterstained,
glass-covered section of the fixed, paraffin-embedded sample of their primary tumor.
To analyze the gene expression pattern and screen for mutations in the genes encoding for tubulins and tubulin-regulating proteins in their tumors, patients need to have one of 3 types of samples (for full details please see protocol).
2. Patients with locally advanced or metastatic disease who have received at least two (and not more than four) prior therapeutic regimens for breast cancer, at least one of which was administered for treatment of locally advanced or metastatic disease. Prior therapy must by 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
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 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 clinical
progression
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 1.
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.
|
|
| E.4 | Principal exclusion criteria |
1. Patients who have received chemotherapy, radiation, or hormonal therapy within two weeks, or trastuzumab within three weeks, before E7389 treatment start.
2. Radiation therapy encompassing >10% 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 known presence of brain metastasis.
6. Patients with meningeal carcinomatosis.
7. Patients who require therapeutic anti-coagulant therapy with warfarin or related compounds; mini-dose warfarin for catheter related thrombosis prophylaxis is permitted.
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 n 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 month, or serious 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 participated in a prior E7389 clinical trial.
17. Patients with other significant diseases 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) |
The primary efficacy endpoint is the objective tumor response (CR or PR) rate.
A secondary efficacy endpoint is duration of response.
Tertiary efficacy endpoints include:
• 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 benefit 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.
|
|
| 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 | Yes |
| 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 |
|
| 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
|
The end of this study is defined as the final study visit of the last patient to be withdrawn from treatment.
|
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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