E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic HER2-negative breast cancer. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004244 |
E.1.2 | Term | Benign breast neoplasm NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The objective of this phase-III trial is to compare the efficacy and safety of sorafenib in combination with capecitabine versus capecitabine in combination with placebo in the treatment of subjects with locally advanced or metastatic HER2-negative breast cancer who are resistant to or have failed prior taxane and an anthracycline or for whom further anthracycline therapy is not indicated.
The primary efficacy endpoint is progression-free survival (PFS). |
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E.2.2 | Secondary objectives of the trial |
Secondary efficacy endpoints are overall survival (OS), time to progression (TTP), overall response rate (ORR) and duration of response (DoR). Patient reported outcomes (PROs) include an evaluation of breast cancer symptoms using the Functional Assessment of Cancer Therapy-Breast Symptom Index (8 item) (FBSI-8) questionnaire and health-related quality of life (HRQoL) using the EuroQoL 5 Dimension Questionnaire.
Safety evaluations comprise adverse event reporting and assessment of laboratory abnormalities.
In addition, this trial includes an exploratory analysis of biomarkers and estimation of capecitabine, 5-FU, and sorafenib exposures.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age is ≥18 years.
• Life expectancy is at least 12 weeks (3 months).
• Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of the breast. HER2 status should be determined by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or chromogenic in situ hybridization (CISH). If the subject’s HER2 status was determined using a test kit that is not approved by an appropriate regulatory authority (eg, US Food and Drug Administration) and/or was not tested using a validated assay, HER2 status will be confirmed, with the subject’s consent, using an approved test kit and/or validated assay. If such a subject does not consent to re-testing, the subject will not be eligible for the study.
•Subject has locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent (Stage IIIb or IIIc; American Joint Committee on Cancer [AJCC] Staging System, Sixth Edition).
•Subject has measurable or non-measurable (but clinically evaluable) disease (according to RECIST 1.1).
•All scans used to document disease were done ≤ 4 weeks before randomization.
•Subjects are resistant to or have failed a taxane and an anthracycline or for whom further anthracycline therapy is not indicated.
oPrior treatment must have included both a taxane (eg, paclitaxel or docetaxel) and an anthracycline (eg, doxorubicin or epirubicin).
oThese agents may have been given as either monotherapy or as part of a combination with another agent and may have been included in the same regimen.
oSequential neo-adjuvant or adjuvant regimens will count as a single regimen.
oThese agents may have been given in either the neo-adjuvant/adjuvant or the metastatic setting or both.
oResistance is defined as:
-tumor progression while on taxane or within 4 months of last taxane dose when given in the metastatic setting OR
•tumor progression while on anthracycline or within 3 months of last anthracycline dose when given in the metastatic setting OR
-recurrence within 12 months of the last taxane or anthracycline dose when given in the adjuvant or neo-adjuvant setting.
oSubjects for whom further anthracycline is not indicated; such subjects must have received cumulative doses of 400 mg/m2 to 550 mg/m2 of doxorubicin or doxorubicin equivalents (eg, epirubicin).
oNote: Subject must meet at least one of the following scenarios to be eligible for the study:
-Resistant to or have failed prior taxane and anthracycline (as defined above).
-Resistant to or have failed prior taxane and for whom further anthracycline therapy is not indicated (as defined above).
•Subject must have received no more than one chemotherapy regimen for metastatic disease.
oSubject must have received prior taxane and an anthracycline in the neo-adjuvant/adjuvant setting or metastatic setting.
•Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed.
•Prior neo-adjuvant or adjuvant chemotherapy is allowed.
•Subject must have discontinued prior chemotherapy, prior radiation therapy, or prior hormonal therapy for locally advanced or metastatic disease for greater than or equal to 4 weeks before randomization. Previously radiated areas must not be the only site of disease.
•Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
•Creatinine clearance greater than or equal to 50 ml/min (based on Cockcroft-Gault formula).
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E.4 | Principal exclusion criteria |
• Subject must NOT have
o active or clinically significant cardiac disease.
o thrombotic, embolic, venous, or arterial events within 6 months before randomization.
o pulmonary hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or above within 4 weeks before randomization.
o any other hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or above within 4 weeks before randomization.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable will be progression free survival, measured from the date of randomization to the date of first observed disease progression (radiological assessment according to RECIST 1.1 criteria for progression of non-measurable and measurable disease) or the date of death due to any cause (if death occurs before disease progression). |
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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 | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 100 |
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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For each participating EU country, the end of the trial according to the EU Clinical Trial Directive will be reached when the last visit (ie, end-of-treatment visit) for the last subject for all centers in the respective country has occurred. |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |