| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic HER2-negative breast cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer (locally advanced or metastatic breast cancer HER2-negative patients who are resistant to/failed prior taxane and anthracycline or where anthracycline therapy is not indicated) |
|
| 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 | 19.0 |
| 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 | 100000004864 |
|
| 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). |
|
| 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.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A Phase III Randomized, Double-blind, Placebo-controlled Trial Comparing Capecitabine Plus Sorafenib Versus Capecitabine Plus Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer, Amendment 5 (Site Specific, UK/Sweden)to Clinical Study Protocol No. BAY 43-9006 / 12444, Version 4.0, date 5. May 2011.
The primary objective:
Explore gene-expression profiling as a possible means of identifying gene signatures that could be predictive of therapeutic response, with focus on the combination of capecitabine and sorafenib versus capecitabine alone. Each subject will be analyzed longitudinally comparing Day-1 data with Day-14 data.
- The identification of therapy-predictive gene signatures would create the potential for the selection of responders versus non-responders prior to therapy.
- Look at biomarkers similar to those outlined in Section 7.4 of the main study protocol. |
|
| 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 an accredited laboratory by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or chromogenic in situ hybridization (CISH). Note: local accreditation is acceptable.
•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 radiologically evaluable) disease (according to RECIST 1.1).
•All computer tomography [CT] [with contrast] and magnetic resonance imaging [MRI]) used to document disease must have been done ≤ 4 weeks before randomization. Bone scans (if clinically indicated) must be done ≤ 12 weeks prior to randomization.
•Subject must have received up to two prior chemotherapy regimens (adjuvant/neo adjuvant treatments are considered one regimen), and no more than one prior regimen for advanced and/or metastatic disease. Chemotherapy regimens include both targeted and biologic therapy.
•Prior regimens must have included an anthracycline (eg, doxorubicin, epirubicin) and a taxane (eg, paclitaxel, docetaxel), either in combination or in separate regimens, in either the neo-adjuvant/adjuvant or the metastatic setting or both, as either monotherapy or as part of a combination with another agent. Sequential regimens will count as a single regimen; multiple neo-adjuvant / adjuvant regimens will count as a single regimen.
•Subject must meet at least one of the following scenarios to be eligible for the study (see Appendix 14.19 in the protocol for definitions of treatment resistance and failure):
-Resistant to or have failed prior taxane and anthracycline
OR
-Resistant to or have failed prior taxane AND for whom further anthracycline therapy is not indicated (eg, intolerance or cumulative doses of doxorubicin or doxorubicin equivalents [eg, epirubicin]).
NOTE: No minimum dose of prior anthracycline or anthracycline equivalents is required.
•Subjects who relapse beyond 12 months after the last taxane or anthracycline dose given in the adjuvant, neo-adjuvant, or metastatic setting are eligible. Further therapy with the agent(s) for a subsequent regimen must have been considered and ruled out for example due to: prior toxicity or intolerance, or based on the local standard of practice (see Appendix 14.19 in the protocol for definitions of treatment intolerance).
•Single agent experimental (not approved) chemotherapy is not allowed. Prior experimental chemotherapy treatment is allowed, provided it is given in combination with at least one drug approved for the treatment of breast cancer (excluding drugs that target VEGF or VEGFR, eg, bevacizumab, brivanib, sunitinib, vatalinib).
•Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed. Subjects who are refractory to hormonal therapy are allowed.
•Prior neo-adjuvant or adjuvant chemotherapy is allowed.
•Subject must have discontinued prior chemotherapy, including both targeted and biologic therapies, prior therapeutic radiation therapy, or prior hormonal therapy for locally advanced or metastatic disease ≥ 4 weeks (28 days) before randomization. Start of study treatment is allowed within less than 28 days of the prior therapy provided that 5 half-lives of the prior treatment drug(s) have elapsed before randomization. Previously radiated areas must not be the only site of disease, unless the site had subsequent evidence of progression. Palliative radiation to bone metastasis for pain control is permitted with provisions (see Section 6.9).
•ECOG performance status 0 or 1 (see Appendix 14.1 in the protocol).
•Creatinine clearance ≥ 50 ml/min (based on Cockcroft-Gault formula).
•Eligible subjects will be required to sign the ICF for participation in the main study as well as a specific ICF for participation in the sub-study. |
|
| E.4 | Principal exclusion criteria |
•HER2-positive breast cancer (IHC ≥ 3+, positive FISH, or positive CISH); equivocal or unknown HER2 status. Subjects with equivocal HER2 status may consent to having their HER2 status retested prior to enrollment by an accredited laboratory.
•Unknown hormone receptor status (estrogen and progesterone receptor).
•Subjects who have received no prior taxane and anthracycline for the treatment of breast cancer (either in adjuvant, neo-adjuvant or metastatic setting).
•Subjects with bilateral breast cancer or a history of two distinct breast cancers are excluded.
•Subjects with inflammatory breast carcinoma are excluded.
•Subject must NOT have
oactive or clinically significant cardiac disease.
othrombotic, embolic, venous, or arterial events within 6 months before randomization.
oany hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or above within 4 weeks before randomization.
•Radiation to any lesions ≤ 4 weeks prior to randomization. Palliative radiation to bone metastasis for pain control is permitted with provisions.
•Subjects with active brain metastases or leptomeningeal disease
|
|
| 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 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). |
|
| E.5.2 | Secondary end point(s) |
Overall survival (OS), time to progression (TTP), overall response rate (ORR), and duration of response rate
Patient reported outcomes (PRO) 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 (EQ-5D).
•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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Date of randomisation to date of death for OS and occurrence of event for TTP. For ORR will be evaluated during therapy and within 30 days post therapy. Duration of response will be measured as time from first objective response to disease progression or death.
Main analysis of the study will be performed when approximately 363 PFS events are observed. A second analysis will be done when approximately 405 deaths are observed. |
|
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| 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 | 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Peru |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
| 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. |
|
| 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 |
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