E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Progressive metastatic breast cancer previously treated in the following subpopulation of patients: Group A: Triple negative phenotype: Estrogen Receptor, Progesterone Receptor and HER-2 negative status (surrogate of basal-like type) Group B: HER-2 overexpressing tumors. Group C: Familial BRCA1 or BRCA2 mutation carriers |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055113 |
E.1.2 | Term | Breast cancer metastatic |
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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 |
Primary Objective: to determine the objective response rate by RECIST (Complete and Partial Response [CR + PR]) with trabectedin in patients with the following metastatic breast cancer subtypes: Group A: triple negative profile (ER-,PR-,HER-2-) Group B: human epidermal growth factor receptor-2 overexpressing tumors (HER-2+) Group C: familial BRCA1 or BRCA2 mutation carriers |
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E.2.2 | Secondary objectives of the trial |
To assess in each group: • Duration of response • Progression-free survival • Exploratory evaluation of changes in tumor volume (three dimensional analysis) and changes in tumoral radiological density • Safety profile in this patient population • Exploratory, hypothesis-generating pharmacogenomic analyses to correlate molecular parameters in patient samples with clinical outcomes (objective response and PFS) within and across patient strata. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient´s written informed consent before any clinical trial-specific procedure.
2. Woman 18 years-of-age or older. 3. Histologically proven diagnosis of progressive metastatic breast cancer either in documented:
• Group A: triple negative phenotype [Estrogen Receptor, Progesterone Receptor and HER-2 negative status (surrogate of basal-like type)]. Patients will be eligible if they had received prior therapy with an anthracycline and taxanes, including adjuvant or neoadjuvant therapy, but no more than three prior chemotherapy regimens for metastatic disease. NOTE: re-treatment with the same regimen or its components after a progression-free interval of 6 months or longer will be considered a second regimen. This arm is closed for recruitment.
• Group B: HER-2 overexpressing breast cancer. Patients will be eligible if they have progressive metastatic disease following treatment with trastuzumab-based regimens or other HER-2 targeted therapy containing regimens, but no more than three prior regimens that contain HER-2 directed therapy and chemotherapy for metastatic disease are allowed. NOTE: re-treatment with the same regimen or its components after a progression-free interval of 6 months or longer will be considered as second regimen.
• Group C: Familial BRCA1 or BRCA2 mutation carriers. Patients will be eligible if they have developed progressive metastatic disease after at least one prior chemotherapy regimen in the adjuvant or metastatic setting. There is no limit to the maximal number of prior therapies allowed
4. Measurable disease as defined by the radiological (CT-scan and MRI) Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines. If the only indicator lesion is in a previously irradiated area, the recurrence must be biopsy proven.
5. Patients with bone metastases currently receiving biphosphonates for palliation will be eligible if other sites of measurable disease are present.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
7. Hematologic variables: • Hemoglobin ≥9 g/dL • Absolute neutrophil count (ANC) ≥1,500/μL, and • Platelet count ≥100,000/μL.
8. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 30 mL/min
9. Creatinine phosphokinase (CPK) ≤ 2.5 ULN.
10. Hepatic function variables • Total bilirubin ≤ ULN. • Total alkaline phosphatase ≤ 2.5 ULN, or if > 2.5 ULN consider alkaline phosphatase liver fraction or GGT or 5’ nucleotidase must be ≤ ULN, if the elevation could be osseous in origin. • AST (serum aspartate transaminase [SGOT]) and ALT (serum alanine transaminase [SGPT]) must be ≤2.5 x ULN.
11. Albumin ≥ 25 g/l.
12. Complete recovered from the acute toxicity of any prior treatment. The presence of alopecia or NCI-CTC grade 1 symptomatic peripheral neuropathy is allowed.
13. Patients may have CNS metastases if stable (no evidence of progression) for at least 3 months after local therapy. |
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E.4 | Principal exclusion criteria |
1. Prior exposure to trabectedin.
2. Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone.
3. More than three prior chemotherapy regimens for metastatic disease for group A and B. NOTE:re-treatment with the same regimen or its components after a progression-free interval of 6 months or more is considered a second regimen.
4. Pregnant or lactating women or any women of childbearing potential who is not employing adequate contraception. Acceptable methods of contraception include; IUD, and double barrier (condom with a contraceptive sponge or contraceptive suppository). Use of hormonal contraception is not acceptable during this clinical trial.
5. Completion of prior therapy: less than 2 weeks from radiation therapy (radiated lesions may not serve as measurable disease) or last dose of hormonal therapy, less than 3 weeks from prior chemotherapy or biological therapy (all acute toxicities must be adequately recovered as per inclusion criteria # 12), less than 4 weeks with any investigational agent.
6. History of another neoplastic disease (except basal cell carcinoma or squamous cell carcinoma of the skin or cervical carcinoma in situ adequately treated) unless in remission for 5 years or longer.Group C patients can be enrolled with less than 5 years remission from another neoplastic disease; however, appropriate biopsy confirming current metastasic breast cancer is mandatory.
7. Patients with known leptomeningeal disease.
8. Other serious illnesses, such as: • Congestive heart failure or angina pectoris; myocardial infarction within 1 year before enrollment; uncontrolled arterial hypertension or arrhythmias • Psychiatric disorder that prevents compliance with protocol • Active viral hepatitis; or chronic liver disease • Active infection • Any other unstable medical conditions
9. Patients with a life expectancy < 3 months. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Confirmed objective tumor response (CR or PR) rate (RECIST) in each group. Each patient will be assigned one of the following categories: Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD)
Reasons for non-evaluability will be subdivided into the following categories: 1) ‘early toxicity’ (as reason for withdrawal without on-/end-oftreatment tumor assessment available) 2) ‘never treated’ (no on-/end-of-treatment tumor assessment available) 3) ‘other’ (e.g., no baseline tumor assessment, technical reasons, absence of on-/end-of-treatment tumor assessment for other reasons than ‘death’, ‘early toxicity’ or ‘never treated’, consent withdrawal before evaluation,)
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeated assessments that should be performed no less than 4 weeks after the criteria for response are first met. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | 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
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The predefined date of study termination (clinical cut-off) is set 30 days after the last visit of the last evaluable patient. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |