Phase II Randomized Trial Evaluating Neoadjuvant Therapy With Neratinib or Trastuzumab Followed by Postoperative Trastuzumab in Women With Locally Advanced HER2-positive Breast Cancer

2014-08-27 03:18:10 | BioPortfolio


FB-7 is a Phase II, multi-center randomized study of neratinib in combination with weekly paclitaxel followed by doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for women with HER2-positive locally advanced breast cancer. Patients in the control arm will receive neoadjuvant trastuzumab in combination with weekly paclitaxel followed by AC. The primary aim of the study is to determine the pathologic complete response (pCR) rate in breast and axillary nodes following the neoadjuvant therapy regimens. The secondary aims include determination of the pCR rate in breast only, clinical complete response (cCR) rate, two-year recurrence-free interval, two-year overall survival, toxicity of the neoadjuvant regimens, and exploration of molecular and genetic correlates of response.


Sequential AC followed by a taxane initiated concurrently with trastuzumab has become a standard of care in the United States for operable HER2-positive breast cancer following initial surgery.

Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein, was developed to block HER2 signaling pathways and has been shown to substantially improve the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers.

However, some patients develop recurrence and succumb to the disease following trastuzumab-based adjuvant therapy. Evaluation of additional approaches that target this pathway have shown promising results in trastuzumab-resistant breast cancer.

Neratinib (HKI-272), an orally administered small molecule, is an irreversible inhibitor of pan ErbB receptor tyrosine kinases, which distinguishes this small molecule from lapatinib. Because of the high degree of homology between kinase domains of EGFR and HER2, neratinib inhibits both EGFR and HER2 function. Neratinib is designed to block kinase activity by binding to the ATP site of the enzymes. In BT474 cell lines, HKI-272 effectively repressed phosphorylation of MAPK and Akt signal transduction pathways, whereas trastuzumab failed to completely inhibit HER2 receptor phosphorylation or downstream signaling events. In tumor xenografts which overexpress HER2, neratinib has been observed to repress tumor growth in a dose-dependent manner.

A comparison of overall response rates with lapatinib and neratinib in comparable patients, albeit in separate Phase II studies, suggest favorable efficacy of neratinib as monotherapy in trastuzumab-refractory patients (response rate of 5.1% vs. 26%) and in trastuzumab-naïve patients (response rate of 24% vs. 56%). Taken together, the data support the rationale that a small molecule TKI may be more efficacious than trastuzumab in the neoadjuvant setting, and that neratinib may be more active than lapatinib.

Patients will be randomized to one of two neoadjuvant therapy regimens. Patients in Arm A will receive 4 cycles of paclitaxel 80 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle. Trastuzumab will begin concurrently with paclitaxel and will be given weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC will be administered every 21 days for 4 cycles. Patients in Arm B will receive 4 cycles of paclitaxel 80 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg will be taken orally once daily beginning on day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Standard AC administered every 21 days for 4 cycles will be administered following paclitaxel/neratinib therapy.

In both arms, clinical response will be assessed by palpation between the chemotherapy regimens and prior to surgery. Following recovery from surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) will be administered every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy). Patients will receive adjuvant radiation therapy and endocrine therapy as clinically indicated.

Submission of tumor and blood samples for FB-7 correlative science studies will be a study requirement for all patients. A core biopsy procedure to procure three fresh tumor samples will be performed before randomization (after the patient has signed the consent form and has been screened for eligibility). Also, a tumor block from the diagnostic core biopsy sample and a tumor block from gross residual disease greater than or equal to 1.0 cm, if found in the surgical specimen, will be required. In addition to tumor sample submissions, a blood sample collected after randomization (before the start of study therapy) will also be required for the correlative science studies.

Patients will be randomized to the control arm (Arm A) and to the investigational arm (Arm B) in a 1:2 ratio. The sample size will be up to 120 patients with about 80 patients in Arm B to provide 76 evaluable patients and about half that number in Arm A. Accrual is expected to occur over 18 months.

Study Design

Allocation: Randomized, Control: Active Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment


Breast Cancer


Paclitaxel, Trastuzumab, Neratinib, Trastuzumab (post surgery), Doxorubicin, Cyclophosphamide


Not yet recruiting


National Surgical Adjuvant Breast and Bowel Project (NSABP)

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:18:10-0400

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Medical and Biotech [MESH] Definitions

A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.

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