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
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.
The study started as a two-arm design with randomization to the control arm (Arm 1) and to
the investigational arm (Arm 2) in a 1:2 ratio. With the addition of a second investigation
arm, (Arm 3), the study becomes a three-arm design with a 1:1:1 allocation ratio (about
equal numbers of patients randomized to Arms 1, 2, and 3). The sample size will be up to
126 patients with about 42 evaluable patients in each arm. Patients who enter the trial but
are not treated for any reason will be replaced. Accrual is expected to occur over 18
months. Patients will be randomized to one of three neoadjuvant therapy regimens: Patients
in Arm 1 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 2 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; Patients in Arm 3 will receive 4 cycles of paclitaxel 80 mg/m2 administered Days 1,
8, and 15 of a 28 day cycle with trastuzumab, beginning concurrently with paclitaxel, given
weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Neratinib 200
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 will be administered every 21 days for
4 cycles following paclitaxel/trastuzumab/neratinib therapy.
In all 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.
Interventional
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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
At time of surgery
No
Norman Wolmark, MD
Principal Investigator
NSABP Foundation Inc.
United States: Food and Drug Administration
NSABP FB-7
NCT01008150
October 2010
June 2017
Name | Location |
---|---|
MD Anderson Cancer Center | Houston, Texas 77030-4096 |
CCOP - Colorado Cancer Research Program, Inc. | Denver, Colorado 80209-5031 |
CCOP - Metro-Minnesota | Saint Louis Park, Minnesota 55416 |
St. Vincent Hospital and Health Care Center | Indianapolis, Indiana 46260 |
Loma Linda University Medical Center | Loma Linda, California 92354 |
CCOP - Dayton | Kettering, Ohio 45429 |
York Hospital | York, Pennsylvania 17315 |
Hartford Hospital | Hartford, Connecticut 06102-5037 |
Cancer Institute of New Jersey | New Brunswick, New Jersey 08901 |
Baptist Cancer Institute - Jacksonville | Jacksonville, Florida 32207 |
Virginia Commonwealth University Massey Cancer Center | Richmond, Virginia 23298-0037 |
Allegheny Cancer Center at Allegheny General Hospital | Pittsburgh, Pennsylvania 15212 |
Spartanburg Regional Healthcare System | Spartanburg, South Carolina 29303 |
University of Pittsburgh | Pittsburgh, Pennsylvania 15261 |
University of Kentucky Medical Center | Lexington, Kentucky 40536-0093 |
Wake Forest University School of Medicine | Winston-Salem, North Carolina 27157-1023 |
Edward Cancer Center | Naperville, Illinois 60540 |
Kootenai Cancer Center | Post Falls, Idaho 83854 |
NSABP Foundation, Inc. | Pittsburgh, Pennsylvania 15212 |
Kaiser Permanente-San Diego | San Diego, California 92120 |
Edward Cancer Center Plainfield | Plainfield, Illinois 60585 |
University of Missouri-Ellis Fischel | Columbia, Missouri 65203 |
West Virginia University Hospitals Inc. | Morgantown, West Virginia 26506-9162 |
Yorkville Family Practice | Yorkville, Illinois 60560 |
Case Western Reserve University/University Hospitals of Cleveland | Cleveland, Ohio 44106 |
University Hospital and Medical Center - SUNY Stony Brook | Stonybrook, New York 11794 |
CCOP Carolinas HealthCare System | Charlotte, North Carolina 28232-2861 |
Roper Hosp & Med Asso (Care Alliance Health) | Charleston, South Carolina 29401 |