Ignite Creation Date:
2024-05-06 @ 1:39 AM
Last Modification Date:
2024-10-26 @ 11:07 AM
Study NCT ID:
NCT01864746
Status:
COMPLETED
Last Update Posted:
2023-12-12
First Post:
2013-05-14
Brief Title:
A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery
Sponsor:
German Breast Group
Organization:
German Breast Group
Study Overview
Official Title:
Phase III Study Evaluating Palbociclib PD-0332991 a Cyclin-Dependent Kinase CDK 46 Inhibitor in Patients With Hormone-receptor-positive HER2-normal Primary Breast Cancer With High Relapse Risk After Neoadjuvant Chemotherapy PENELOPEB
Status:
COMPLETED
Status Verified Date:
2023-11
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:
PENELOPE-B
Brief Summary:
The PENELOPEB study is designed to demonstrate that in the background of standard anti-hormonal therapy palbociclib provides superior invasive disease-free survival iDFS compared to placebo in pre- and postmenopausal women with HR-positiveHER2-normal early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane- containing chemotherapy Considering the high risk of recurrence in patients after neoadjuvant chemotherapy and a high CPS-EG score palbociclib appears to be an attractive option with a favourable safety profile for these patients
Detailed Description:
Introduction
Patients with hormone receptor-positive HR human epidermal growth factor receptor 2-negative HER2- primary breast cancer who receive chemotherapy as part of their primary treatment are at higher risk of relapse About a third of the patients with residual invasive disease after neoadjuvant chemotherapy NACT will relapse despite adjuvant endocrine therapy ET The risk of relapse can be assessed more accurately using the clinical pathological staging-estrogen receptor grading CPS-EG scoring system This involves the tumor stage before treatment start and at surgery the estrogen receptor ER status and the pathologic grading A higher score indicates a higher risk of relapse Patients with a score of three and higher had a disease-free survival of 70 at 5 years despite receiving ET When combined with the group having a CPS-EG score of two and involved lymph nodes the disease-free survival increased to 77 This group comprises about 25 of all patients with residual disease after NACT
Therapeutic inhibition of cyclin-dependent kinase 4 and 6 CDK46 by palbociclib combined with ET demonstrated clinically relevant efficacy in metastatic HR and HER2- breast cancer irrespective of biomarker selection After the pivotal PALOMA-1 trial which led to accelerated approval of palbociclib in February 2015 further phase III trials demonstrated that the use of CDK46 inhibitors in pre- and postmenopausal patients with hormone-sensitive or resistant cancers in first-line and pretreated metastatic breast cancer improves progression-free and overall survival OS
Thus we hypothesized that palbociclib may also be active in patients with residual disease after NACT who are at high risk of relapse Based on the data from PALOMA-1 we designed the PENELOPE-B trial assessing the efficacy of one year palbociclib vs placebo added to any ET in HR and HER2- breast cancer patients with residual disease and high risk after NACT based on the CPS-EG score
Patient Selection and Study Design
PENELOPE-B is a prospective multicenter multinational randomized double-blind placebo controlled phase III study investigating the addition of palbociclib for one year to standard adjuvant ET for patients with high-risk residual disease according to the CPS-EG score after NACT for early HR and HER2- breast cancer
The trial was sponsored by GBG Forschungs GmbH in collaboration with NSABP Foundation plus I-SPY and CCTR ABCSG AGO-B ANBCSG BIG Geicam ICR-CTSU JBCSG and KCSG Pfizer Inc funded the trial and provided drug The trial was conducted according to ICH-GCP guidelines and the Declaration of Helsinki The clinical trial Protocol online only was approved by the respective health authorities and ethics committees or institutional review boards All patients provided written informed consent for trial participation data transfer and biomaterial collection The trial was overseen by the International Steering Committee and the GBG Boards and supervised by an Independent Data Monitoring Committee IDMC
Eligible patients were randomly assigned in a 11 manner in permuted blocks of alternating size 46 stratified by risk status CPS-EG sore 3 v 2ypN nodal involvement after surgery ypN0-1 v ypN2-3 Ki-67 15 v 15 age 50 v 50 years and global region of participating site Asian v non-Asian
Treatment
Patients received either palbociclib 125 mg orally once daily for 21 days followed by 1 week off treatment for a total duration of 13 4-week cycles or matching placebo in addition to standard adjuvant ET at the discretion of the investigator given for at least 5 years Dose interruptions reductions or delays according to predefined toxicity management were acceptable in the case of significant treatment-related toxicity
Objectives and End Points
The primary objective of the study was to compare the invasive disease-free survival iDFS defined as the time in months between random assignment and first event ipsilateral invasive in-breast or locoregional recurrence distant recurrence invasive contralateral breast cancer second primary invasive cancer nonbreast or death because of any cause for palbociclib versus placebo Secondary end points included iDFS excluding second primary invasive nonbreast cancers distant disease-free survival OS locoregional relapse-free interval LRRFI safety which was reported as adverse events AEs irrespective of relatedness to study treatment based on National Cancer Institute Common Toxicity Criteria v40 and compliance
All time-to-event end points were analyzed in the intent-to-treat population comprising all randomly assigned patients Compliance and safety were analyzed in the safety analysis set including all randomly assigned patients who took study medication at least once For the patients randomly assigned to placebo who received palbociclib at least once during the trial the treatment group allocation for safety and compliance analyses was the palbociclib arm
Sample Size and Interim Analyses
In the initial sample size computation 233 iDFS events were required to detect a hazard ratio for palbociclibplacebo of 067 from 72 to 80 3-year iDFS rate corresponding to a clinically relevant risk reduction of 33 for invasive disease with a power of 85 using a two-sided stratified log-rank test and an overall two-sided significance level of 005 Eight hundred patients were planned to be enrolled To accelerate recruitment after 68 patients had been enrolled the population was expanded to patients with a CPS-EG score of two and ypN who were also identified as high-risk patients but with a generally lower risk than the patients with CPS-EG three Thereafter the target hazard ratio for palbociclibplacebo was updated to 0685 from 77 to 836 3-year iDFS rate and the iDFS events were increased to 255 and sample size to 1100 patients
The study had an adaptive design with two interim efficacy analyses to monitor futility to test for overwhelming efficacy and to allow for sample size re-estimation Safety was assessed at both interim analyses OBrien and Fleming type stopping boundaries based on the Lan-DeMets spending function were used in the interim analyses
Statistical Analysis
Final analysis of the primary end point iDFS was planned after 290 iDFS events with a nominal significance level of 00463 two-sided To address the concern of possible inflation of the type I error because of the sample size increase statistical significance was determined using a weighted statistic of the stratified log-rank test stratified by risk status nodal involvement after surgery Ki-67 age but not global region of participating site as prespecified in the Protocol based on the method of Cui Hung and Wang CHW with CHW interim monitoring implemented in EAST version 65 Cytel Inc The 95 repeated CI was reported taking into account the adaptive sample size re-estimation and group sequential nature of the design
For all other tests the alpha was set to 005 two-sided Adjustment for multiple testing in the other tests was not planned The Kaplan-Meier method was used to estimate the survival probability at specific time points together with a two-sided 95 CI Univariable Cox-proportional hazards models stratified by the same factors as in the primary analysis were used for time-to-event end points except LRRFI to report hazard ratios with 95 CI LRRFI was analyzed using the cumulative incidence function for rates at specific time points with stratified Grays test for comparison and stratified univariate Fine-Gray model to report hazard ratio for treatment Fishers exact test was used to compare frequencies of AEs between arms
All statistical analyses were performed using SAS Version 94 with SAS Enterprise Guide Version 71 on Microsoft Windows 10 Enterprise Data cutoff date was August 24 2020
Patients with hormone receptor-positive HR human epidermal growth factor receptor 2-negative HER2- primary breast cancer who receive chemotherapy as part of their primary treatment are at higher risk of relapse About a third of the patients with residual invasive disease after neoadjuvant chemotherapy NACT will relapse despite adjuvant endocrine therapy ET The risk of relapse can be assessed more accurately using the clinical pathological staging-estrogen receptor grading CPS-EG scoring system This involves the tumor stage before treatment start and at surgery the estrogen receptor ER status and the pathologic grading A higher score indicates a higher risk of relapse Patients with a score of three and higher had a disease-free survival of 70 at 5 years despite receiving ET When combined with the group having a CPS-EG score of two and involved lymph nodes the disease-free survival increased to 77 This group comprises about 25 of all patients with residual disease after NACT
Therapeutic inhibition of cyclin-dependent kinase 4 and 6 CDK46 by palbociclib combined with ET demonstrated clinically relevant efficacy in metastatic HR and HER2- breast cancer irrespective of biomarker selection After the pivotal PALOMA-1 trial which led to accelerated approval of palbociclib in February 2015 further phase III trials demonstrated that the use of CDK46 inhibitors in pre- and postmenopausal patients with hormone-sensitive or resistant cancers in first-line and pretreated metastatic breast cancer improves progression-free and overall survival OS
Thus we hypothesized that palbociclib may also be active in patients with residual disease after NACT who are at high risk of relapse Based on the data from PALOMA-1 we designed the PENELOPE-B trial assessing the efficacy of one year palbociclib vs placebo added to any ET in HR and HER2- breast cancer patients with residual disease and high risk after NACT based on the CPS-EG score
Patient Selection and Study Design
PENELOPE-B is a prospective multicenter multinational randomized double-blind placebo controlled phase III study investigating the addition of palbociclib for one year to standard adjuvant ET for patients with high-risk residual disease according to the CPS-EG score after NACT for early HR and HER2- breast cancer
The trial was sponsored by GBG Forschungs GmbH in collaboration with NSABP Foundation plus I-SPY and CCTR ABCSG AGO-B ANBCSG BIG Geicam ICR-CTSU JBCSG and KCSG Pfizer Inc funded the trial and provided drug The trial was conducted according to ICH-GCP guidelines and the Declaration of Helsinki The clinical trial Protocol online only was approved by the respective health authorities and ethics committees or institutional review boards All patients provided written informed consent for trial participation data transfer and biomaterial collection The trial was overseen by the International Steering Committee and the GBG Boards and supervised by an Independent Data Monitoring Committee IDMC
Eligible patients were randomly assigned in a 11 manner in permuted blocks of alternating size 46 stratified by risk status CPS-EG sore 3 v 2ypN nodal involvement after surgery ypN0-1 v ypN2-3 Ki-67 15 v 15 age 50 v 50 years and global region of participating site Asian v non-Asian
Treatment
Patients received either palbociclib 125 mg orally once daily for 21 days followed by 1 week off treatment for a total duration of 13 4-week cycles or matching placebo in addition to standard adjuvant ET at the discretion of the investigator given for at least 5 years Dose interruptions reductions or delays according to predefined toxicity management were acceptable in the case of significant treatment-related toxicity
Objectives and End Points
The primary objective of the study was to compare the invasive disease-free survival iDFS defined as the time in months between random assignment and first event ipsilateral invasive in-breast or locoregional recurrence distant recurrence invasive contralateral breast cancer second primary invasive cancer nonbreast or death because of any cause for palbociclib versus placebo Secondary end points included iDFS excluding second primary invasive nonbreast cancers distant disease-free survival OS locoregional relapse-free interval LRRFI safety which was reported as adverse events AEs irrespective of relatedness to study treatment based on National Cancer Institute Common Toxicity Criteria v40 and compliance
All time-to-event end points were analyzed in the intent-to-treat population comprising all randomly assigned patients Compliance and safety were analyzed in the safety analysis set including all randomly assigned patients who took study medication at least once For the patients randomly assigned to placebo who received palbociclib at least once during the trial the treatment group allocation for safety and compliance analyses was the palbociclib arm
Sample Size and Interim Analyses
In the initial sample size computation 233 iDFS events were required to detect a hazard ratio for palbociclibplacebo of 067 from 72 to 80 3-year iDFS rate corresponding to a clinically relevant risk reduction of 33 for invasive disease with a power of 85 using a two-sided stratified log-rank test and an overall two-sided significance level of 005 Eight hundred patients were planned to be enrolled To accelerate recruitment after 68 patients had been enrolled the population was expanded to patients with a CPS-EG score of two and ypN who were also identified as high-risk patients but with a generally lower risk than the patients with CPS-EG three Thereafter the target hazard ratio for palbociclibplacebo was updated to 0685 from 77 to 836 3-year iDFS rate and the iDFS events were increased to 255 and sample size to 1100 patients
The study had an adaptive design with two interim efficacy analyses to monitor futility to test for overwhelming efficacy and to allow for sample size re-estimation Safety was assessed at both interim analyses OBrien and Fleming type stopping boundaries based on the Lan-DeMets spending function were used in the interim analyses
Statistical Analysis
Final analysis of the primary end point iDFS was planned after 290 iDFS events with a nominal significance level of 00463 two-sided To address the concern of possible inflation of the type I error because of the sample size increase statistical significance was determined using a weighted statistic of the stratified log-rank test stratified by risk status nodal involvement after surgery Ki-67 age but not global region of participating site as prespecified in the Protocol based on the method of Cui Hung and Wang CHW with CHW interim monitoring implemented in EAST version 65 Cytel Inc The 95 repeated CI was reported taking into account the adaptive sample size re-estimation and group sequential nature of the design
For all other tests the alpha was set to 005 two-sided Adjustment for multiple testing in the other tests was not planned The Kaplan-Meier method was used to estimate the survival probability at specific time points together with a two-sided 95 CI Univariable Cox-proportional hazards models stratified by the same factors as in the primary analysis were used for time-to-event end points except LRRFI to report hazard ratios with 95 CI LRRFI was analyzed using the cumulative incidence function for rates at specific time points with stratified Grays test for comparison and stratified univariate Fine-Gray model to report hazard ratio for treatment Fishers exact test was used to compare frequencies of AEs between arms
All statistical analyses were performed using SAS Version 94 with SAS Enterprise Guide Version 71 on Microsoft Windows 10 Enterprise Data cutoff date was August 24 2020
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2013-001040-62 | EUDRACT_NUMBER | None | None |