| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| 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 compare the investigator assessed progression-free survival (PFS) following treatment with single agent neratinib versus lapatinib plus capecitabine in subjects with erbB2 positive locally advanced or metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
- to compare overall survival, objective response rate, duration of response, and clinical benefit rate (complete response+ partial response+ stable disease ≥24 weeks)
- to compare the frequency of and time to symptomatic or progressive central nervous system lesions in both treatment arms
- to compare safety
- to compare the frequency of grade 3 or higher diarrhea (as graded by CTCAE V3)
- to compare the frequency of palmar-plantar erythrodysesthesia (as graded by CTCAE V3)
- to assess population pharmacokinetics of neratinib
- to compare patient reported breast cancer specific quality of life between treatment arms |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Women aged at least 18 years.
2. Histologically and/or cytologically confirmed diagnosis of breast cancer.
3. Locally advanced or metastatic breast cancer that is not amenable to curative surgery and/or radiation (stage IIIB, IIIC, or IV).
4. Documentation of erbB-2 gene amplification by fluorescence in situ hybridization (FISH, as defined by a ratio >2.2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer's kit instruction) or documentation of erbB-2 overexpression by immunohistochemistry (IHC, defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory or initial diagnostic results utilizing one of the sponsor-approved assays. If erbB-2 status was determined using a test other than a sponsor-approved assay as defined in attachment 1, testing and study eligibility must be obtained from the sponsor-identified central laboratory prior to randomization.
5. All subjects must have tumor tissue available for central review of erbB-2 expression levels by FISH testing performed by the sponsor-identified central laboratory.
6. Disease progression on or following a prior trastuzumab-containing treatment regimen (regimen should have been given for a duration of at least 6 weeks), alone or in combination with cytotoxic chemotherapy or hormonal therapy for metastatic or locally advanced disease. A 2 week washout period is required between trastuzumab treatment and first dose of the test article.
7. Prior treatment with a taxane in the neoadjuvant, adjuvant, locally advanced, and/or metastatic disease treatment settings.
8. At least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (specifically, ascites, pleural or pericardial effusion, osteoblastic bone metastases, and carcinomatous lymphangitis of the lung will not be considered measurable lesions). Subjects with skin lesions that are measurable by Computed Tomography (CT) scans or Magnetic Resonance Imaging (MRI) as the only site of measurable disease are allowed.
9. Eastern Cooperative Oncology Group (ECOG) status of 0,1 or 2 (not declining within 2 weeks prior to signing of informed consent).
10. Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple-gated acquisition (MUGA) or echocardiogram (ECHO).
11. Screening lab values within the following parameters:
• Absolute neutrophil count (ANC): ≥1.5 × 109/L (1,500/mm3)
• Platelet count: ≥100 ×109/L (100,000/mm3)
• Hemoglobin: ≥ 9.0 g/dL (90g/L)
• Serum creatinine: ≤1.5 × upper limit of normal (ULN)
• Total bilirubin: ≤1.5 × ULN (<3 ULN if Gilbert's disease)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤2.5 × ULN (< 5 × ULN if liver metastases are present).
12. Recovery (to grade 1 or baseline) from all clinically significant adverse effects related to prior therapies (excluding alopecia).
13. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control starting 2 weeks prior to the administration of the first dose of investigational product until 28 days after the last dose of investigational product. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who sexual partners are either sterile or using contraceptives. |
|
| E.4 | Principal exclusion criteria |
1. More than 2 prior trastuzumab-based regimens for metastatic or locally advanced disease.
2. Subjects with prior exposure to capecitabine, lapatinib, or other erbB-2 targeted treatments (with the exception of trastuzumab).
3. Prior treatment with anthracyclines with a cumulative dose of doxorubicin of > 400 mg/m2 or epirubicin dose > 800 mg/m2, or the equivalent dose for other anthracycline derivatives.
4. Subjects with bone as the only site of disease.
5. Active uncontrolled or symtomatic CNS metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Subjects with a history of CNS metastases or cord compression are allowable if CNS lesions metastases have been treated with radiation and/or surgical resection and are off anticonvulsivants and steroids for at least 4 weeks before the first dose of investigational product.
6. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn disease, malabsorption, or grade ≥2 diarrhea of any etiology at baseline).
7. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association [NYHA] functional classification of ≥3), unstable angina, or myocardial infarction.
8. Family history of long or short QT syndrome, Brugada syndrome or subjects with QT/QTc interval > 0.45 second or known history of QT/QTc prolongation or torsade de pointes (TdP).
9. Renal insufficiency defined as creatinine clearance < 50 mL/min (as calculated by Cockroft and Gault Method, and normalized to body surface area).
10. History of known hypersensitivity to lapatinib, capecitabine, 5-fluorouracil, or any of their excipients, or known dihydropyrimidine dehydrogenase deficiency.
11. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other cancer therapy within 2 weeks before administration of the first dose of test article.
12. Inability or unwillingness to swallow tablets or capsules.
13. Any other cancer within 5 years prior to screening with the exception of adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.
14. Pregnant, breast-feeding, or women of child bearing potential who are not using effective contraception during participation in the study and do not agree to do so for at least 28 days after final dose of study drug.
15. Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator’s judgment, make the subject inappropriate for this study. Examples include, but are not limited to, serious active infection (ie, requiring intravenous antibiotic or antiviral agent) or uncontrolled major seizure.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the comparison of the investigator assessed progression-free survival (PFS) following treatment with single agent neratinib versus lapatinib plus capecitabine in subjects with erbB-2-positive locally advanced or metastatic breast cancer. Progression-free survival is the time from the date of randomization to the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable tumor evaluation. |
|
| 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 | Yes |
| 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 | 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) | 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 | 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 | 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) | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 108 |
| 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 | 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
|
| The end of the study is the last visit of the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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