A study before surgery evaluating Regimens with Weekly Paclitaxel plus Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer.

Phase 1

Conditions: ocally advanced HER2-positive breast cancer
MedDRA version: 16.1Level: PTClassification code 10065430Term: HER-2 positive breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 16.1Level: LLTClassification code 10072740Term: Locally advanced breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-004391-35-PT

Lead Sponsor: Puma Biotechnology Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Female

Target Recruitment: 126

Inclusion Criteria

1. The patient must have consented to participate and must have signed and dated an appropriate IRB/IEC-approved consent form to enter the study, for the optional procurement of tumor samples by a core biopsy procedure prior to randomization, and for submission of tumor and blood samples required for the FB-7 correlative science studies (see Section 7.1).
2. Patients must be female.
3. Patients must be = 18 years old.
4. The European Cooperative Oncology Group (ECOG) performance status must be 0 or 1.
5. Patients must have the ability to swallow oral medication.
6. The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or by limited incisional biopsy.
7. Patients must have estrogen receptor (ER) analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then progesterone receptor (PgR) analysis must also be performed. Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.
8. Breast cancer must be determined to be HER2-positive prior to randomization. Assays using FISH or CISH require gene amplification. Assays using IHC require a strongly positive (3+) staining score.
9. Clinical staging, based on the assessment by physical exam, must be AJCC stage IIB, IIIA, IIIB, or IIIC:
- cT2 and cN1;
- cT3 and cN0 or cN1;
- Any cT and cN2 or cN3; or
- cT4.
10. The patient must have a mass in the breast or axilla measuring = 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in which case measurable disease by physical exam is not required.
11. At the time of randomization, blood counts performed within 4 weeks prior to randomization must meet the following criteria:
- Absolute neutrophil count (ANC) must be = 1200/mm3;
- Platelet count must be = 100,000/mm3;
- Hemoglobin must be = 10 g/dL;
12. The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to randomization must be met:
- total bilirubin must be = upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin; and
- alkaline phosphatase must be = 2.5 x ULN for the lab; and
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be = 1.5 x ULN for the lab.
13. Patients with alkaline phosphatase > ULN but = 2.5 x ULN are eligible for inclusion in the study if liver imaging (Computerized Tomography [CT], Magnetic Resonance Imaging [MRI], Positron Emission Tomography [PET], or PET-CT scan) performed within 4 weeks prior to randomization does not demonstrate metastatic disease and the requirements in Section 4.2.12 are met.
14. Patients with either unexplained skeletal pain or alkaline phosphatase that is ULN but = 2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 4 weeks prior to randomization does not demonstrate metastatic disease. Patients with suspicious findings on bone scan or PET scan are eligible if suspicious findings are determined to be benign by x-ray, MRI, or biopsy.
15. Serum creatinine performed within 4 weeks prior to randomization must be = 1.5 x ULN for the lab.
16. The LVEF assessment by 2-D echocardiogram or MUGA scan performed within 90 days prior to randomization must be = 50% regardless of the facility's lower limit of normal (LLN). Note: Since the pre-entry

Exclusion Criteria

1. Fine needle aspiration (FNA) alone to diagnose the primary breast cancer.
2. Excisional biopsy or lumpectomy performed prior to randomization.
3. Surgical axillary staging procedure prior to randomization. Procedures that are permitted prior to study entry include: 1) FNA or core biopsy of an axillary node for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel node (SN) biopsy for patients with clinically negative axillary nodes.
4. Definitive clinical or radiologic evidence of metastatic disease. Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.
5. History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral ductal carcinoma in situ (DCIS) treated with radiation therapy (RT). Patients with a history of lobular carcinoma in situ (LCIS) are eligible.
6. Contralateral invasive breast cancer at any time. Patients with contralateral DCIS or LCIS are eligible.
7. History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization.
8. Known metastatic disease from any malignancy (solid tumor or hematologic).
9. Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or neratinib for any malignancy.
10. Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.
11. Continued endocrine therapy such as raloxifene or tamoxifen (or other selective estrogen receptor modulator [SERM]) or an aromatase inhibitor. Patients are eligible if these medications are discontinued prior to randomization.
12. Any continued sex hormonal therapy, e.g., birth control pills and ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization.
13. Active hepatitis B or hepatitis C with abnormal liver function tests.
14. Intrinsic lung disease resulting in dyspnea.
15. Active infection or chronic infection requiring chronic suppressive antibiotics.
16. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
17. Persistent = grade 2 diarrhea regardless of etiology.
18. Sensory or motor neuropathy = grade 2, as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0).
19. Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication.
20. Chronic daily treatment with corticosteroids with a dose of = 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
21. Uncontrolled hypertension defined as a systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medications. Patients with hypertension that is well-controlled on medication are eligible.
22. Cardiac disease (history of and/or active disease) that would preclude the use of any of the drugs included in the treatment regimen. This includes but is not confined to:
Active cardiac disease:
- symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention;
- ventricular arrhythmias except for

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the pathologic complete response rate in breast and axillary lymph nodes (pCR breast and nodes) for patients with HER2-positive locally advanced breast cancer (LABC) following neoadjuvant therapy.;Secondary Objective: To determine the pathologic complete response (pCR) rate in breast in patients with locally advanced breast cancer (LABC);<br>To determine the clinical complete response (cCR) rate in patients with LABC who present with palpable disease;<br>To determine 2-year recurrence-free interval (RFI);<br>To determine 2-year overall survival (OS);<br>To determine toxicities of the FB-7 regimens.<br>;Primary end point(s): Pathologic complete response rate (pCR) in breast and nodes.;Timepoint(s) of evaluation of this end point: At the time of surgery, approximately 7 months from randomization.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Pathologic complete response (pCR) in breast;<br>Clinical complete response (cCR) assessed by physical exam at the completion of paclitaxel (before AC);<br>cCR assessed by physical exam at the completion of AC (before surgery);<br>Events for analysis of recurrence-free interval (RFI) include inoperable progressive disease and local, regional, and distant recurrence during the 2 years from randomization;<br>Time from randomization until death from any cause;<br>Reported toxicities, including cardiotoxicity, as defined by Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0).;Timepoint(s) of evaluation of this end point: 2 years from randomization;<br>Time from randomization until death from any cause.

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