Her2 overexpressed, early stage breast cancer (adjuvant treatment stage) MedDRA version: 19.0 Level: LLT Classification code 10006173 Term: Breast adenocarcinoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: Neratinib
Product Code: HKI-272
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Neratinib
CAS Number: 698387-09-06
Current Sponsor code: HKI-272,WAY-179272-B
Concentration u
Sponsors
Puma Biotechnology, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Female subjects aged 18 years or older 2. Subjects must have histologically confirmed primary adenocarcinoma of the breast that is erbB-2 positive by one of the following assays, performed locally: Fluorescence in Situ Hybridization (FISH) or Silver in Situ Hybridization (SISH), or Chromogenic in Situ Hybridization (CISH), or Immunohistochemistry assay. 3. Archived diagnostic tumor sample must be available, and subject must agree to submission of sample for central erbB-2 testing. 4. Primary tumor ER/PgR status known before study entry. 5. Subjects must have completed a course of prior adjuvant trastuzumab. If less than 12 months of trastuzumab have been given, at least 8 prior doses of weekly trastuzumab, or at least 3 prior doses of trastuzumab given every 3 weeks must have been administered. Also, it must be specified that the subject is either not eligible or unable to receive further adjuvant trastuzumab, since the patient either completed the intended treatment course of adjuvant trastuzumab based on published data or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved. 6. If subjects had prior neoadjuvant therapy (chemotherapy with or without neoadjuvant trastuzumab, regardless of nodal status at initial diagnosis), they are eligible provided they had residual invasive cancer in the breast and/or axilla after completing neoadjuvant therapy. Subjects will be excluded if they achieved a pathologic complete response (pCR) in breast and axilla, or if they have only residual in situ disease in breast (DCIS) and pCR in axilla (if axillary status is known). 7. The last dose of trastuzumab must have been given > 2 weeks and =1 year (365 days) from randomization. 8. Have a diagnosis of stage 2 through stage 3c primary breast cancer with axillary node-positive disease according to the American Joint Committee on Cancer (sixth edition) staging criteria for breast cancer. Note that subjects who completed neoadjuvant therapy and have residual invasive disease only in the breast, with negative or unknown nodal status, are eligible. 9. Adequately treated primary breast cancer with surgery, as defined by prior mastectomy OR lumpectomy, with margins clear of invasive carcinoma and ductal carcinoma in situ. Subjects with positive sentinel node biopsies must have subsequent axillary dissection to be eligible. 10. Completed treatment with a neoadjuvant or adjuvant chemotherapy regimen containing an anthracycline and/or a taxane or any cyclophosphamide, methotrexate and 5 fluorouracil (CMF) regimen. 11. Clinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry, including - Bone scan; required only if alkaline phosphatase (ALP) is =2 x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is required if the results from the bone scan are questionable. - Computed tomography, MRI or ultrasound of the abdomen and chest; required only if aspartate transaminase (AST)/alanine transaminase (ALT) or ALP is =2 x ULN. - Chest radiograph. 12. Negative bilateral mammogram (or unilateral mammogram of the remaining breast if unilateral total mastectomy was performed) within 12 months (= 365 days) before randomisation. Mammogram is not indicated in case of bilateral total mastectomy. 13. Subjects with bilateral breast cancers are eligible only if t
Exclusion criteria
Exclusion criteria: 1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry. 2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer. 3. Any prior mediastinal irradiation except internal mammary node irradiation for the present breast cancer. 4. Metachronous invasive or metachronous DCIS breast cancer (ie, primary breast cancers diagnosed at different times [greater than 6 months apart from each other]). 5. Prior therapy with an ErbB-1 and/or ErbB-2 inhibitor other than trastuzumab. 6. Received any investigational agent within 14 days or 5 half-lives, whichever is longer, before administration of the first dose of investigational product. 7. Pregnant or breastfeeding women. 8. Subjects with second malignancy, other than adequately treated nonmelanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other nonmammary malignancies must have been disease free for at least 5 years. 9. Subjects with unstable angina, congestive heart failure (New York Heart Association class II, III, or IV), ) (including individuals who currently use digitalis, beta-blockers, or calcium channel blockers specifically for congestive heart failure), ventricular arrhythmia requiring medical therapy, or with a history of myocardial infarction within 12 months. 10. Subjects with active, unresolved infections. 11. Inability or unwillingness to swallow tablets. 12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn’s disease, ulcerative colitis, malabsorption, or grade =2 diarrhea of any etiology at baseline). 13. QTc interval >0.450 seconds or known history of QTc prolongation or torsades de pointes. 14. History of idiopathic ventricular tachycardia or ventricular fibrillation. 15. Subjects with a psychiatric illness that would prevent them from understanding the nature of the investigational therapy and complying with protocol requirements. 16. Any major concurrent illness or medical condition that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in and completion of the study. 17. On treatment or in follow-up of any other neoadjuvant or adjuvant breast cancer trial with DFS as an endpoint.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: to compare Disease Free Survival (DFS) of women with early-stage erbB-2 overexpressed/amplified node positive breast cancer following trastuzumab in the adjuvant setting, receiving neratinib against that of women receiving placebo. DFS is defined as the time from randomization to the first occurrence of the following DFS events: invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death from any cause, and invasive contralateral breast cancer. ;Secondary Objective: to compare the following endpoints of subjects receiving neratinib against those of subjects receiving placebo: - Disease Free Survival including Ductal Carcinoma In Situ (DFS-DCIS), defined as the time from randomization to the first occurrence of any DFS event or DCIS. - Time to Distant Recurrence (TTDR), defined as the time between randomization and the date of the first distant recurrence, or death from breast cancer. - Distant Disease Free Survival (DDFS), defined as the time from randomization to the first occurence of distant recurrence or death from any cause. - Incidence of central nervous system (CNS) recurrence, defined as the cumulative incidence of CNS recurrence at a site of first recurrence. - Overall Survival (OS), defined as the time from randomization until the date of death. - Short- and long-term safety (including incidence of grade 3/4 diarrhea). ;Primary end point(s): Comparison of Disease free survival (DFS) of women with early-stage erbB-2 overexpressed breast cancer following trastuzumab in the adjuvant setting, receiving neratinib against that of women receiving placebo. DFS is defined as the time from randomization to the first occurrence of the following DFS events: invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death from any cause, and invasive contralateral breast cancer. ;Timepoint(s) of evaluation of this end point: During treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): DFS-DCIS, incidence of CNS recurrence, OS, long and short term safety;Timepoint(s) of evaluation of this end point: During treatment, brief symptom guided physical exam will be done at months 0,3.6.9, full physical exam on month 12. targeted physical examinations during follow up every 4 months for 2 years from randomization until distance recurrence and with a mammogram every 12 months. | — |
Countries
Argentina, Australia, Bahamas, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Jordan, Korea, Republic of, Lebanon, Lithuania, Macedonia, the former Yugoslav Republic of, Malaysia, Malta, Mexico, Netherlands, New Zealand, Peru, Poland, Portugal, Romania, Saudi Arabia, Serbia, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactPersonal
Puma Biotechnology, Inc
Outcome results
None listed