| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locall advanced or metastatic breast cancer |
|
| 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 | 14.1 |
| 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 |
|
| 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 ≥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 of the protocol, 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 investigational product.
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 modified Response Evaluation Criteria in Solid Tumors (RECIST 1.0) 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 × 10 to the power of 9/L (1,500/mm3)
• Platelet count: ≥100 ×10 to the power of 9/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 the 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).
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 investigational product.
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.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Objective Response Rate
Objective response rate is the proportion of subjects who achieve tumor response (complete or partial response) per RECIST 1.0.
Confirmation of Overall Response
The main goal of confirmation of objective response is to avoid an incorrect estimation of the response rate observed. In cases where confirmation of response is not feasible, it should be made clear when reporting the outcome of such studies that the responses are not confirmed.
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met.
In the case of SD, measurements must have met the SD criteria at least once at a minimum of 6 weeks following randomization.
Overall Survival
Overall survival is the time from the date of randomization until the date of death, censored at the last date known alive.
Duration of Response
Duration of response is measured from the time at which measurement criteria are met for CR or PR (whichever status is recorded first) until the first date on which recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since baseline.
Clinical Benefit Rate
Clinical benefit rate is the proportion of subjects who achieve a tumor response (CR or PR) or SD for at least 24 weeks.
Frequency of symptomatic or progressive CNS lesions
Incidence of subjects presenting with newly diagnosed symptomatic or progressive CNS lesions at the time of tumor progression.
Time to symptomatic or progressive CNS lesions
Time from the date of randomization until the date of appearance of newly diagnosed or progressive CNS lesions. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall survival at 12 months past 163rd event; ORR, DOR at time of 163rd event, CBR at 24 weeks; frequency of and time to symptomatic cns mets at time of 163rd event; safety (AE, SAE, diarrhea and PPE); PK at 22 days, PRO at time of 163rd event |
|
| 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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 79 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Bulgaria |
| Canada |
| Croatia |
| Czech Republic |
| Egypt |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Italy |
| Japan |
| Jordan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| Slovenia |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| Thailand |
| 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
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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