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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by NSABP Foundation Inc
Sponsor:
Collaborator:
Puma Biotechnology, Inc.
Information provided by (Responsible Party):
NSABP Foundation Inc
ClinicalTrials.gov Identifier:
NCT01008150
First received: November 3, 2009
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

FB-7 is a Phase II, multi-center randomized study of neratinib in combination with weekly paclitaxel with or without trastuzumab 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.


Condition Intervention Phase
Breast Cancer
Drug: Paclitaxel
Drug: Trastuzumab
Drug: Neratinib
Drug: Doxorubicin
Drug: Cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by NSABP Foundation Inc:

Primary Outcome Measures:
  • Pathologic Complete Response in breast and axillary lymph nodes. As measured by no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes after neoadjuvant chemotherapy [ Time Frame: At time of surgery ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pathologic complete response in breast. As measured by no histologic evidence of invasive tumor cells in the surgical breast specimen [ Time Frame: At time of surgery ] [ Designated as safety issue: No ]
  • Clinical complete response. As measured by physical exam; resolution of all target and non-target lesions identified at baseline and no new lesions or other signs of disease progression [ Time Frame: After last dose of paclitaxel, after AC before surgery ] [ Designated as safety issue: No ]
  • Recurrence-free interval [ Time Frame: Time from randomization until 2 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Time from randomization until death from any cause ] [ Designated as safety issue: No ]
  • Toxicity [ Time Frame: Time from randomization until 2 years ] [ Designated as safety issue: Yes ]
  • Correlative science studies [ Time Frame: Before randomization and after surgery ] [ Designated as safety issue: No ]

Estimated Enrollment: 126
Study Start Date: October 2010
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1: paclitaxel + trastuzumab then A C
4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Trastuzumab concurrently with paclitaxel weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)
Drug: Paclitaxel
Other Name: Taxol
Drug: Trastuzumab
Other Name: Herceptin
Drug: Doxorubicin
Other Names:
  • Adriamycin
  • A
Drug: Cyclophosphamide
Other Name: C
Experimental: Arm 2: paclitaxel + neratinib then A C
4 cycles of paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Neratinib 240 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)
Drug: Paclitaxel
Other Name: Taxol
Drug: Neratinib Drug: Doxorubicin
Other Names:
  • Adriamycin
  • A
Drug: Cyclophosphamide
Other Name: C
Experimental: Arm 3: paclitaxel + trastuzumab + neratinib then A C
4 cycles of paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Trastuzumab concurrently with paclitaxel, weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200 mg orally once daily beginning on Day 1 of paclitaxel and continuing through Day 28 of the final cycle of paclitaxel. Following paclitaxel/trastuzumab/neratinib therapy, standard AC every 21 days for 4 cycles. Following surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy)
Drug: Paclitaxel
Other Name: Taxol
Drug: Trastuzumab
Other Name: Herceptin
Drug: Neratinib Drug: Doxorubicin
Other Names:
  • Adriamycin
  • A
Drug: Cyclophosphamide
Other Name: C

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast cancer.
  • Submission of a block from the diagnostic biopsy sample and from the surgical sample, if gross residual disease greater than or equal to 1.0 cm was removed at the time of surgery, is required for all patients
  • Patients of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy and for at least 6 months after the last dose of study therapy.
  • The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.
  • Patients must have the ability to swallow oral medication.
  • The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or by limited incisional biopsy.
  • Patients must have 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.)
  • 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.
  • Clinical staging, based on the assessment by physical exam, must be American Joint Committee on Cancer (AJCC) stage IIB, IIIA, IIIB, or IIIC: cT2 and cN1; cT3 and cN0 or cN1; Any cT and cN2 or cN3; or cT4
  • The patient must have a mass in the breast or axilla measuring greater than or equal to 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in which case measurable disease by physical exam is not required.
  • 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 greater than or equal to 1200/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin must be greater than or equal to 10 g/dL
  • The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to randomization must be met: total bilirubin must be less than or equal to upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and aspartate aminotransferase (AST) and ALT must be less than or equal to 1.5 x ULN for the lab.
  • Patients with alkaline phosphatase greater than ULN but less than or equal to 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 for adequate hepatic function are met.
  • Patients with either unexplained skeletal pain or alkaline phosphatase that is greater than ULN but less than or equal to 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.
  • Serum creatinine performed within 4 weeks prior to randomization must be less than or equal to 1.5 x ULN for the lab.
  • The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or multiple gated acquisition(MUGA) scan performed within 90 days prior to randomization must be greater than or equal to 50% regardless of the facility's LLN.

Exclusion Criteria:

  • fine-needle aspiration (FNA) alone to diagnose the primary breast cancer.
  • Excisional biopsy or lumpectomy performed prior to randomization.
  • 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.)
  • 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.)
  • 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 LCIS are eligible.)
  • Contralateral invasive breast cancer at any time. (Patients with contralateral DCIS or lobular carcinoma in situ (LCIS) are eligible.)
  • 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.
  • Known metastatic disease from any malignancy (solid tumor or hematologic).
  • Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or neratinib for any malignancy.
  • Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.
  • 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.)
  • 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.
  • Active hepatitis B or hepatitis C with abnormal liver function tests.
  • Intrinsic lung disease resulting in dyspnea.
  • Active infection or chronic infection requiring chronic suppressive antibiotics.
  • Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function.
  • Persistent greater than or equal to grade 2 diarrhea regardless of etiology.
  • Sensory or motor neuropathy greater than or equal to grade 2, as defined by the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0.
  • Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication.
  • Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
  • Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with hypertension that is well-controlled on medication are eligible.)
  • 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 congestive heart failure (CHF); and documented cardiomyopathy.
  • Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
  • Pregnancy or lactation at the time of randomization.
  • 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.
  • Use of any investigational agent within 4 weeks prior to randomization.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01008150

Contacts
Contact: Diana Gosik, RN, BS 412-339-5333 diana.gosik@nsabp.org

  Show 42 Study Locations
Sponsors and Collaborators
NSABP Foundation Inc
Puma Biotechnology, Inc.
Investigators
Principal Investigator: Norman Wolmark, MD NSABP Foundation Inc
  More Information

No publications provided

Responsible Party: NSABP Foundation Inc
ClinicalTrials.gov Identifier: NCT01008150     History of Changes
Other Study ID Numbers: NSABP FB-7
Study First Received: November 3, 2009
Last Updated: June 19, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
United States: Institutional Review Board
Canada: Ethics Review Committee
Spain: Ministerio de Sanidad, Servicios Sociales e Igualdad
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Italy: The Italian Medicines Agency
Portugal: INFARMED, National Authority of Medicines and Health Products, IP

Keywords provided by NSABP Foundation Inc:
breast cancer
neoadjuvant
neratinib
paclitaxel
trastuzumab
doxorubicin
cyclophosphamide

Additional relevant MeSH terms:
Trastuzumab
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Liposomal doxorubicin
Cyclophosphamide
Doxorubicin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014