Clinical Trial Results:
A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of Enzalutamide with Trastuzumab in Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer
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Summary
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EudraCT number |
2013-000093-29 |
Trial protocol |
BE GB ES IT |
Global end of trial date |
30 Jan 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Dec 2024
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First version publication date |
22 Dec 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
9785-CL-1121
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02091960 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Astellas Pharma Global Development, Inc
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Sponsor organisation address |
1 Astellas Way, Northbrook, IL, United States, 60062
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Public contact |
Clinical transparency, Astellas Pharma Global Development, Inc, astellas.resultsdisclosure@astellas.com
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Scientific contact |
Clinical transparency, Astellas Pharma Global Development, Inc, astellas.resultsdisclosure@astellas.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Jan 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jan 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to evaluate the efficacy of enzalutamide with trastuzumab in evaluable participants with human epidermal growth factor receptor 2 positive (HER2+) and androgen receptor positive (AR+) metastatic or locally advanced breast cancer, as measured by Clinical Benefit Rate (CBR).
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Sep 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 14
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Country: Number of subjects enrolled |
Canada: 9
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Country: Number of subjects enrolled |
Italy: 11
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
United Kingdom: 18
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Country: Number of subjects enrolled |
United States: 44
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Worldwide total number of subjects |
103
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EEA total number of subjects |
32
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
75
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From 65 to 84 years |
28
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 35 clinical sites in Belgium, Canada, Italy, Spain, the United Kingdom and the United States. | ||||||||||||||
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Pre-assignment
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Screening details |
This study enrolled women with HER2+ and AR+ metastatic or locally advanced breast cancer who progressed on anti-HER2 therapy in the metastatic or advanced setting. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Period
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Enzalutamide + Trastuzumab | ||||||||||||||
Arm description |
Participants received 160 (milligrams) mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Trastuzumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion, Solution for injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Participants received 6 mg/kg trastuzumab intravenously/subcutaneously once every 21 days.
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Investigational medicinal product name |
Enzalutamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received 160 mg enzalutamide orally once daily.
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Baseline characteristics reporting groups
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Reporting group title |
Enzalutamide + Trastuzumab
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Reporting group description |
Participants received 160 (milligrams) mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Enzalutamide + Trastuzumab
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Reporting group description |
Participants received 160 (milligrams) mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met. | ||
Subject analysis set title |
Efficacy Evaluable Set (EES)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The EES was a subset of the FAS (Full analysis set) defined as all enrolled participants who had centrally assessed AR+ breast cancer (defined as >10% of tumor cells with nuclear expression), received at least one dose of study drug, and had at least one available post baseline tumor assessment.
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Subject analysis set title |
Safety Analysis Set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The SAF consisted of all participants who had received at least 1 or partial dose of study drug.
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End point title |
Clinical Benefit Rate (CBR) [1] | ||||||||
End point description |
CBR was defined as percentage of evaluable participants with best objective response of confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or prolonged stable disease (≥ 24 weeks). CR was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all < 10 mm in short axis. PR was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions, with persistence of non-target lesions and no new lesions. Stable disease (SD) was defined as < 30% decrease and < 20% increase in size of target lesions, persistence of non-target lesions, and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after date that PR or CR was first observed. SD required confirmation with equivalent or improved assessment no less than 8 weeks after enrollment. Participants in EES with available data were analyzed.
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End point type |
Primary
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End point timeframe |
Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Per protocol, statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Response Rate at Week 24 | ||||||||
End point description |
Overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all < 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. Participants in the EES population with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
24 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Progression | ||||||||
End point description |
Time to progression was defined as the time from the first date of enzalutamide treatment until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, who progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression. Participants in the EES population with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
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| No statistical analyses for this end point | |||||||||
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End point title |
Best Overall Response Rate | ||||||||
End point description |
Best overall response was the best response across all time points, based on investigator assessments. Best overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) at any time during the study per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all < 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. Participants in the EES population with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression-free Survival | ||||||||
End point description |
Progression-free survival was defined as the time from the date of first dose of enzalutamide until the date of disease progression per RECIST 1.1, or death from any cause on study, whichever occurred first. Participants who initiated another antitumor therapy before documented progressive disease (PD) or death, or who progressed or died after missing 2 or more consecutive radiological assessments were censored at the date of the last radiological assessment showing no progression. Progressive disease was defined as a ≥ 20% increase in the size of target lesions and at least a 5 mm increase in size of target lesions from smallest size on study, or unequivocal progression of non-target lesions, or any new lesions. Participants in the EES population with available data were analyzed.
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End point type |
Secondary
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End point timeframe |
From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response | ||||||||
End point description |
Duration of response was defined as the time from the date of first documentation of response (CR or PR) until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression. Participants in the EES population with best overall response of CR or PR were analyzed. 99999 = the data could not be analyzed due to low number of events.
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End point type |
Secondary
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End point timeframe |
Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Response | ||||||||
End point description |
Time to response was defined as the time from the first date of enzalutamide treatment to initial CR or PR and was calculated for participants with a CR or PR. Participants in the EES population with best overall response of CR or PR were analyzed.
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End point type |
Secondary
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End point timeframe |
From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants with Treatment Emergent Adverse Events (TEAEs) | ||||||||||||||||||||||||||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered study drug/who underwent study procedures and did not necessarily have a causal relationship with treatment. Abnormalities identified during medical tests were defined as an AE if they induced clinical signs/symptoms, required active intervention, interruption or discontinuation of study medication, or were clinically significant to investigator. An AE was defined as serious if any of the following resulted: Death, was life-threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/ birth defect, inpatient hospitalization/prolongation of hospitalization or other medically important event. TEAE was defined as an AE observed during the treatment emergent period, which is from first dose date of study drug to 30 days after last dose date or start of subsequent treatment or date of death, whichever is first. SAF.
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End point type |
Secondary
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End point timeframe |
From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever is first (Up to 3031 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever is first (Up to 3031 days).
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Adverse event reporting additional description |
The Safety Analysis Set (SAF) consisted of all participants who had received at least 1 or partial dose of study drug.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
v23.0
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Reporting groups
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Reporting group title |
Enzalutamide + Trastuzumab
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Reporting group description |
Participants received 160 mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Oct 2014 |
Changes included: • Updated the primary objective to clarify that CBR is evaluable participants with CR, PR at any point or stable disease ≥ 24 weeks. • Removed OS (long-term follow-up post study drug termination). • Updated timeline for prestudy radiographic bone assessment requirement at 6 mo prior to enrollment (day 1). • Updated prior line requirements to provide clarity regarding prior lines of therapy, the definition of disease progression, and the use of trastuzumab in the adjuvant setting in Inclusion Criterion 7. • Aligned protocol visits with trastuzumab infusion visits. All protocol-required visits are now in increments of 3 weeks (i.e., 6, 9, 12) in order to line-up with the trastuzumab infusion visits conducted every 3 weeks. • Clarified language allowing fresh tissue biopsy to be done only in cases of known local AR+ status per local report but insufficient tissue sample available to send for central confirmation. • Updated pregnancy language to remove hormonal contraceptive agents (oral, injected or implanted hormones) as a possible form of contraception. The pregnancy language was updated per the Astellas standard protocol template. • Updated the duration requirement for contraception and breastfeeding. Inclusion Criterion 12 extended the contraceptive use and breastfeeding restriction requirement from 3 to 6 months after study drug discontinuation. |
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06 Oct 2014 |
Changes also included: • Updated exclusion language to prevent enrollment of patients with potential renal insufficiency. Exclusion Criterion 4 includes creatinine clearance in addition to the creatinine level to restrict entry of patients with renal insufficiency. • Updated trastuzumab dose noted per locally available formulation. Subcutaneous added as available route of administration. • Clarified allowed estrogen use. Vaginal estrogen creams were allowed while on study. • Updated scope of efficacy endpoint. Removed initiation of new antitumor therapy from efficacy endpoint. • Updated pharmacokinetic data in Introduction section. • Updated statistical sections to reflect clarifications made to primary efficacy definition, clarification in various analyses sets and removal of OS. • Added myocardial perfusion scintigraphy (MPS) as allowable procedure for screening and subsequent visits in lieu of an echocardiogram (ECHO) or multigated acquisition (MUGA) scan. • Updated physical examination and added a 7-day window within screening visit for the physical examination to be done prior to signing of the informed consent form. • Removed vital sign requirement that temperature should be measured orally. • Removed the pharmacodynamic blood draw for circulating hormones and protein marker collection at the screening visit. |
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10 Jun 2015 |
Changes included: • Removed requirement for participants to have HER2 positive breast cancer that is ER negative and PgR negative. • Updated Inclusion Criterion 7 to remove the cap on the required number of prior lines of therapy the participants can receive, to clarify the definition of a prior line of therapy, to allow discontinuation of the most recent regimen for any toxicity except cardiotoxicity and to allow nonapproved anti-HER2 agents in the most recent regimen. • Updated Inclusion Criterion 6 to allow participants with non-measurable, evaluable disease per RECIST 1.1 to be eligible for enrollment in the study. In addition, the Schedule of Assessments was modified to clarify when patients with non-measurable, evaluable disease must have efficacy assessments completed. • Updated Inclusion Criterion 7 and Exclusion Criterion 16 to allow patients that had received pertuzumab as the most recent line of therapy. • Updated the protocol text and Inclusion Criterion 10 to change the preferred source of archival tissue from a primary tumor to the most recent biopsy available. • Updated Exclusion Criterion 16 to exclude participants who, in the investigator’s opinion, may benefit from hormonal therapy during the study. |
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09 Aug 2018 |
Changes included: • Removed assessment of circulating endocrine and other protein markers and pharmacokinetic samples. • Updated to include the definition of urgent safety measures and procedures for reporting them. |
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30 Nov 2020 |
Changes included: • The instruction that participants who discontinued study drug for a reason other than disease progression will continue to have tumor assessments performed was removed from the protocol. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
