A Randomized Double-blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women With Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer.

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2008-007345-31-GR
• Date of registration: 08/10/2009
• Prospective Registration: No
• Primary sponsor: Wyeth Research, Division of Wyeth Pharmaceuticals, Inc.
• Public title: A Randomized Double-blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women With Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer.
• Scientific title: A Randomized Double-blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women With Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer.
• Date of first enrolment: 08/09/2009
• Target sample size: 3850
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-007345-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Lithuania, Malta, Netherlands, Portugal, Slovakia, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Female subjects aged18 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. Subjects with primary tumor ER/PgR status known before study entry.

4. 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 and it must be specified that the subject is either not eligible or unable to receive further adjuvant trastuzumab. The last dose of trastuzumab must have been given >2 weeks and <2 years from randomization.

5. Subjects must have a diagnosis of stage 1 through stage 3c primary breast cancer according to the American Joint Committee on Cancer (sixth edition) staging criteria for breast cancer and meet one of the following criteria:
- Axillary node-positive disease OR node-negative disease with a tumor greater than or equal to 1.0 cm in greatest diameter.
- Node-negative disease is defined as negative sentinel node biopsy OR no positive lymph nodes found among 6 ancillary nodes examined on axillary node dissection OR status after axillary radiotherapy for sterilization if clinically evaluated as cN0.

6. Subjects with 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; negative sentinel node biopsies require no more axillary surgery for eligibility.

7. Subjects must have completed treatment with a neoadjuvant or adjuvant chemotherapy regimen containing either an anthracycline or a taxane or any cyclophosphamide, methotrexate and 5 fluorouracil (CMF) regimen.

8. Subjects with 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 or ultrasound of the abdomen; required only if aspartate transaminase (AST)/alanine transaminase (ALT) or ALP is =2 x ULN, unless the elevation is in the bone fraction.
- Chest radiograph.

9.Subjects with negative bilateral mammogram (or unilateral mammogram of the remaining breast if unilateral total mastectomy was performed) within 12 months before study entry. Mammogram is not indicated in case of bilateral total mastectomy.

10.Subjects with bilateral breast cancers are eligible only if their cancers are synchronous (ie, diagnosed at the same time [within 6 months of each other]). One or both tumors need to be erbB-2 positive. One could be negative.

11.Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

12. Subjects must have adequate organ function as defined by:
- Absolute neutrophil count: =1.5 × 109/L (1500/mm3).
- Platelet count: =100 × 109/L (100,000/mm3).
- Hemoglobin: =9.0
Exclusion criteria:
1. Subjects with clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease at the time of study entry.

2. Subjects currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer.

3. Subjects with any prior mediastinal irradiation except internal mammary node irradiation for the present breast cancer.

4. Subjects with metachronous invasive or DCIS breast cancer (ie, primary breast cancers diagnosed at different times [greater than 6 months apart from each other]).

5. Subjects with prior therapy with an ErbB-1 and/or ErbB-2 inhibitor other than trastuzumab.

6. Subjects who have 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 a concurrently active 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. Subjects with inability or unwillingness to swallow tablets.

12. Subjects with 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. Subjects with QTc interval >0.45 seconds or known history of QTc prolongation or torsades de pointes.

14. Subjects with 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. Subjects with 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. Subjects with known or suspected allergy to neratinib or other compounds related to these classes of medication.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Her2 overexpressed, early stage breast cancer (adjuvant treatment stage)
MedDRA version: 9.1 Level: LLT Classification code 10006173 Term: Breast adenocarcinoma

Intervention(s)

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: WAY-179272
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: to compare Disease Free Survival (DFS) of women with early-stage erbB-2 overexpressed/amplified 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.

Secondary ID(s)

NCT00878709

3144A2-3004

2008-007345-31-HU

Ethics review

Status: Approved
Approval date:
Contact: