A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy 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
The goal of this clinical research study is to learn how breast cancer tumors such as yours are affected by a drug called neratinib in combination with paclitaxel, or in combination with paclitaxel and trastuzumab, as compared with standard treatment of trastuzumab and paclitaxel given as breast cancer treatments before surgery. The safety of these drugs will also be studied. A second goal of the study is to learn if adding neratinib to standard treatments for HER2-positive breast cancer will prevent breast cancer from returning. Researchers will look at whether adding neratinib to standard treatments will help women with HER2-positive breast cancer live longer. Researchers also want to learn more about the possible side effects that might result from the combination of drugs used in this study.
Disease Group: Breast
Treatment Agent: Cyclophosphamide
Treatment Location: Both at MD Anderson & Other Sites
Primary aim and endpoint Aim: To determine the pathologic complete response rate in breast and axillary lymph nodes (pCR breast and nodes) for patients with HER2-positive LABC following neoadjuvant therapy Endpoint: pCR breast and nodes Secondary aims and endpoints 1. Pathologic complete response in breast (pCR breast) Aim: To determine the pCR rate in breast in patients with LABC Endpoint: pCR breast 2. Clinical complete response (cCR) Aim: To determine the cCR rate in patients with LABC who present with palpable disease Endpoint: cCR assessed by physical exam at the completion of paclitaxel (before AC) Endpoint: cCR assessed by physical exam at the completion of AC (before surgery) 3.Recurrence-free interval (RFI) Aim: To determine 2-year RFI Endpoint: Events for analysis of RFI include inoperable progressive disease and local, regional, and distant recurrence during the 2 years from randomization. 4. Overall survival (OS) Aim: To determine 2-year OS Endpoint: Time from randomization until death from any cause 5. Toxicity Aim: To determine toxicities of the FB-7 regimens Endpoint: Reported toxicities, including cardiotoxicity, as defined by CTCAE v3.0 6. Correlative science studies Aim: To explore molecular and genetic correlates of response
IRB Review and Approval Date: 06/13/2011
Recruitment Status: Closed
Projected Accrual: 126
1) The patient must have consented to participate and must have signed
and dated an appropriate IRB-approved consent form that conforms to
federal and institutional guidelines for the study treatment, for the
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
2) Patients must be female.
3) Patients must be >/= 18 years old.
4) The 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 ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then 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 Fluorescence In Situ Hybridization (FISH) or Cytokine-inducible SH2-containing protein (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: 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 </= 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 AST and 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 (CT, MRI, PET, or PET-CT scan) performed within 4 weeks prior to randomization does not demonstrate metastatic disease and the requirements in #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 LLN. Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments to determine if targeted therapy can be administered, it is critical that this baseline study be an accurate assessment of the patient's LVEF. If the baseline LVEF is >/=70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and to consider repeating the study if the accuracy is uncertain.
1) 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 SN biopsy for patients with clinically negative axillary nodes.
4) Definitive clinical or radiologic evidence of metastatic disease. (Note: 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 DCIS treated with RT. (Patients with a history of 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 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 NCI 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 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 benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromise in cardiac function; and symptomatic pericarditis. History of cardiac disease: myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function; history of documented CHF; and documented cardiomyopathy.
23) Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
24) Pregnancy or lactation at the time of randomization. (Note: Pregnancy testing should be performed within 14 days prior to randomization according to institutional standards for women of childbearing potential.)
25) The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.
26) Use of any investigational agent within 4 weeks prior to randomization