Ignite Creation Date:
2024-05-05 @ 9:59 PM
Last Modification Date:
2024-10-26 @ 10:12 AM
Study NCT ID:
NCT01008150
Status:
COMPLETED
Last Update Posted:
2021-10-25
First Post:
2009-11-03
Brief Title:
Phase II Randomized Trial Evaluating Neoadjuvant Therapy With Neratinib andor Trastuzumab Followed by Postoperative Trastuzumab in Women With Locally Advanced HER2-positive Breast Cancer
Sponsor:
NSABP Foundation Inc
Organization:
NSABP Foundation Inc
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2021-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
Detailed Description:
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 51 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 12 ratio With the addition of a second investigation arm Arm 3 the study becomes a three-arm design with a 111 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 mgm2 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 mgkg loading dose then 2 mgkg weekly Following paclitaxeltrastuzumab standard AC will be administered every 21 days for 4 cycles Patients in Arm 2 will receive 4 cycles of paclitaxel 80 mgm2 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 paclitaxelneratinib therapy Patients in Arm 3 will receive 4 cycles of paclitaxel 80 mgm2 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 mgkg loading dose then 2 mgkg 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 paclitaxeltrastuzumabneratinib 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 mgkg loading dose then 6 mgkg 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
At the time of local IRB approval of amendment 6 submission of fresh tumor samples for FB-7 correlative science studies will be optional for all patients For patients who agree 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 Submission of a tumor block from the diagnostic core biopsy sample and a tumor block from gross residual disease greater than or equal to 10 cm if found in the surgical specimen will be required In addition a blood sample collected after randomization before the start of study therapy will also be required for the correlative science studies
Beginning with Amendment 8 Arm 1 and Arm 2 were closed to accrual in the US subsequent to FDA approval of pertuzumab when given in combination with trastuzumab for neoadjuvant therapy in breast cancer Pertuzumab and trastuzumab are both targeted therapy drugs US patients enrolled in the study will not be randomized but will be placed into the combined targeted therapy group Arm 3 NR only Randomization and study therapy for patients entered via institutions outside of the US remains unchanged
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 51 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 12 ratio With the addition of a second investigation arm Arm 3 the study becomes a three-arm design with a 111 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 mgm2 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 mgkg loading dose then 2 mgkg weekly Following paclitaxeltrastuzumab standard AC will be administered every 21 days for 4 cycles Patients in Arm 2 will receive 4 cycles of paclitaxel 80 mgm2 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 paclitaxelneratinib therapy Patients in Arm 3 will receive 4 cycles of paclitaxel 80 mgm2 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 mgkg loading dose then 2 mgkg 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 paclitaxeltrastuzumabneratinib 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 mgkg loading dose then 6 mgkg 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
At the time of local IRB approval of amendment 6 submission of fresh tumor samples for FB-7 correlative science studies will be optional for all patients For patients who agree 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 Submission of a tumor block from the diagnostic core biopsy sample and a tumor block from gross residual disease greater than or equal to 10 cm if found in the surgical specimen will be required In addition a blood sample collected after randomization before the start of study therapy will also be required for the correlative science studies
Beginning with Amendment 8 Arm 1 and Arm 2 were closed to accrual in the US subsequent to FDA approval of pertuzumab when given in combination with trastuzumab for neoadjuvant therapy in breast cancer Pertuzumab and trastuzumab are both targeted therapy drugs US patients enrolled in the study will not be randomized but will be placed into the combined targeted therapy group Arm 3 NR only Randomization and study therapy for patients entered via institutions outside of the US remains unchanged
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None