E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast cancer who have not received chemotherapy for metastatic breast cancer. |
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E.1.1.1 | Medical condition in easily understood language |
Patients recently diagnosed with breast cancer that has spread to other parts of the body (metastatic), for which systemic therapy is needed and have not yet received chemotherapy. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 of three different schedules of nab-Paclitaxel administration, as measured by progression-free survival (PFS), using the historical reference of PFS of docetaxel for first-line treatment of metastatic breast cancer. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate:
-Tolerability
- Feasibility
- Disease response according to RECIST criteria, including disease
control rate
- Overall survival
• To explore the changes in quality of life (QL) over time until treatment discontinuation.
• To investigate the prognostic role of putative markers (SPARC and caveolin) and assess any change in the expression of SPARC and caveolin between primary and the metastatic sites. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast cancer.
• Measurable or non-measurable, but radiologically evaluable, disease according to RECIST 1.1 criteria.
• Female aged 18 years or older.
• Life expectancy > 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Either ER-positive or ER-negative disease. Patients with ER-positive disease must be endocrine resistant, defined as having failed at least one prior endocrine therapy for breast cancer, or must be candidates for first-line chemotherapy.
• If previously treated with a taxane or anthracycline in the neoadjuvant or adjuvant setting, the period from end of treatment to disease recurrence must have been > 12 months (> 365 days).
• Radiation therapy, if given and regardless of site, must be completed at least 2 weeks prior to randomization.
• Normal hematologic status. Must meet all criteria: absolute neutrophil count ≥ 1500/mm3 (1.5 x 109/L), platelets ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL (≥ 90 g/L)).
• Normal renal function (serum creatinine ≤ 1.5 ULN or calculated creatinine clearance ≥ 50mL/min according to the Cockcroft and Gault formula).
• Normal liver function. Must meet all criteria: ALT (SGPT) and AST (SGOT) ≤ 3 × upper limit of normal (ULN) (without liver metastases; total bilirubin ≤ 1.5 mg/dL;. Exceptions: If the patient has liver metastases, ALT (SGPT) and AST (SGOT) must be ≤ 5 × ULN; total bilirubin ≤ 1.5 mg/dL. If the patient has Gilbert’s disease higher bilirubin is acceptable (≤ 3 mg/dL)
• Normal cardiac function defined as left ventricular ejection fraction within the institutional range of normal as measured by MUGA or echocardiogram.
• Women of child bearing potential must have documented negative pregnancy test within 2 weeks prior to randomization and agree to acceptable birth control during the duration of the trial therapy and for a period of 6 months following the last administration of study drug. If for any reason the administration of first dose of trial treatment is not within 2 weeks of the pregnancy test, a second pregnancy test should be performed within two weeks of day 1 of cycle 1.
• Written Informed Consent (IC) must be signed and dated by the patient and the Investigator prior to randomization.
• Completed baseline Quality of Life Form.
• The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
• Availability of an FFPE block from the primary tumor (breast lesion) for submission to central pathology review and for translational research.
• Written consent to pathology material submission, indicating the patient has been informed of and agrees to tissue material use, transfer and handling, must be signed and dated by the patient and the Investigator prior to randomization. |
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E.4 | Principal exclusion criteria |
• Any prior chemotherapy for metastatic breast cancer.
• Presence of CNS metastasis.
• Peripheral neuropathy grade 2 or higher (CTCAE version 4).
• Significant uncontrolled cardiac disease (i.e. unstable angina, recent myocardial infarction within prior 6 months), patients classified as having a New York Heart Association (NYHA) class III or IV congestive heart failure.
• Pregnant or lactating.
• Prior history of non-breast malignancy (except for adequately controlled basal cell carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the bladder).
• Any concurrent condition which in the Investigator’s opinion makes it inappropriate for the patient to participate in the trial or which would jeopardize compliance with the protocol.
• Contraindications or known hypersensitivity to the study medication or excipients.
• The use of any anti-cancer investigational agents within 30 days prior to expected start of trial treatment.
• Inability or unwillingness to abide by the study protocol or cooperate fully with the Investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS): time from randomization to documented progressive disease according to RECIST criteria or death, whichever occurs first. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy endpoint of PFS will be evaluated among each of the three treatment arms separately, in three independent tests, and compared to the historic PFS of first-line docetaxel. PFS distribution will also be summarized separately by different starting dose in induction (150mg/m2 and 125mg/m2).
The target number of events per group is 63. |
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E.5.2 | Secondary end point(s) |
• Tolerability: adverse events according to CTCAE v4
• Feasibility: completing treatment according to the protocol for at least 24 weeks
• Disease control: overall response or stable disease (or non-CR/non-PD for patients with non-measurable disease) or better (i.e., partial or complete response) according to RECIST criteria for a duration of ≥24 weeks
• Overall survival: time from randomization to death from any cause
• QL: primary endpoint physical well-being
• Prognostic markers: SPARC and caveolin expression |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The toxicities, feasibility, OS, disease control rate and other measures of disease response will be evaluated for each treatment arm separately and will also be summarized separately by different starting dose in induction (150mg/m2 and 125mg/m2).
The primary quality of life endpoint is physical well-being. The change in QL over time until treatment discontinuation for patients on each arm and on the different starting dose in induction (150mg/m2 and 125mg/m2)
will be explored using repeated measures modeling.
In translational research, on FFPE material from the primary tumor and metastatic sites separately, it will be evaluated whether SPARC and caveolin are prognostic markers for PFS in women with metastatic breast cancer using log-rank tests and Cox regression analysis. |
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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 | Yes |
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 | Yes |
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) | 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 | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 | No |
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 |
Belgium |
Hungary |
Ireland |
Italy |
Slovenia |
Spain |
Switzerland |
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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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Randomization of 258 patients during approximately 24 to 26 months, with an additional 16 to 18 months of follow up after the last patient is entered. The end of the trial therefore will be approximately 4 years after randomization of the first patient.
All patients will be followed up until approximately 18 months following the enrollment of the last Patient to reach the target number of events (maximum of 42 months, minimum of approximately 18 months). |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |