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Safety Study of Enzalutamide (MDV3100) in Patients With Incurable Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01597193
Recruitment Status : Completed
First Posted : May 11, 2012
Results First Posted : May 8, 2019
Last Update Posted : May 8, 2019
Sponsor:
Collaborators:
Astellas Pharma Inc
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE May 9, 2012
First Posted Date  ICMJE May 11, 2012
Results First Submitted Date  ICMJE June 4, 2018
Results First Posted Date  ICMJE May 8, 2019
Last Update Posted Date May 8, 2019
Actual Study Start Date  ICMJE April 30, 2012
Actual Primary Completion Date December 15, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
  • Dose-Escalation Phase: Percentage of Participants With Dose-limiting Toxicity (DLTs) [ Time Frame: Baseline up to Day 35 ]
    DLTs were defined as any of following events related to the study drug: Any adverse event (AE) consistent with a seizure of any grade; Grade greater than equal to (>=) 3 fatigue, diarrhea, nausea, or vomiting that did not improve to Grade 1 within 14 days of initiating standard of care therapy; any Grade >=3 hematologic toxicity with the following modifications: 1) Grade >=3 platelet count associated with bleeding, 2) Grade >=3 absolute neutrophil count that persists for 7 or more days or that was associated with fevers (febrile neutropenia); Grade >=3 any other non-hematological toxicity that was determined to be related to study drug.
  • Percentage of Participants With Adverse Events of Grade 3 or Higher Severity by National Cancer Institute Common Toxicity Criteria For Adverse Events (NCI CTCAE) (Version 4.03) [ Time Frame: Day 1 up to 30 days after the last dose of study drug or before initiation of a new systemic antitumor treatment, whichever occurred first (up to 3.5 years) ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on NCI CTCAE Version 4.03 and defined as Grade 3 AEs = severe or medically significant events but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self-care activities of daily living; Grade 4 AEs = life-threatening, urgent intervention indicated; Grade 5 AEs = death related to adverse event.
  • Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to 30 days after the last dose of study drug or before initiation of a new systemic antitumor treatment, whichever occurred first (up to 3.5 years) ]
    An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
  • Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events [ Time Frame: Day 1 up to 30 days after the last dose of study drug or before initiation of a new systemic antitumor treatment, whichever occurred first (up to 3.5 years) ]
    An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly.
  • Percentage of Participants Who Require Dose Reductions Due to Adverse Events [ Time Frame: Day 1 up to 30 days after the last dose of study drug or before initiation of a new systemic antitumor treatment, whichever occurred first (up to 3.5 years) ]
    An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly.
  • Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Day 1 up to 30 days after the last dose of study drug or before initiation of a new systemic antitumor treatment, whichever occurred first (up to 3.5 years) ]
    Absolute systolic blood pressure (SBP) greater than (>) 180 millimeter of mercury (mm Hg) and an increase of >40 mm Hg from baseline; absolute SBP less than (<) 90 mm Hg and an decrease of >30 mm Hg from baseline. Absolute diastolic blood pressure (DBP) >105 mm Hg and an increase of >30 mm Hg from baseline; absolute DBP <50 mm Hg and an increase of >20 mm Hg from baseline. Absolute heart rate >120 beats per minute (bpm) and an increase of >30 bpm from baseline; absolute heart rate <50 bpm and decrease of >20 bpm from baseline. Participants with any of these abnormalities were reported for this outcome in each arm.
  • Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1 ]
    Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
  • Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1 ]
    Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
  • Dose-Escalation Phase: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC24h) of Enzalutamide and Its Metabolites After Single Dose [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose on Day 1 ]
    Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
  • Dose-Escalation Phase: Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC72h) of Enzalutamide After Single Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48 and 72 hours post dose on Day 1 ]
  • Dose-Escalation Phase: Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Enzalutamide After Single Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1 ]
    AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf).
  • Dose-Escalation Phase: Terminal Elimination Half-Life (t1/2) of Enzalutamide After Single Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1 ]
    Terminal elimination half-life is the time measured for the plasma concentration of Enzalutamide to decrease by one-half of its initial concentration.
  • Dose Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Single Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1 ]
    Apparent oral clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
  • Dose Escalation Phase: Apparent Volume of Distribution (Vz/F) of Enzalutamide After Single Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
  • Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50 ]
    Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
  • Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50 ]
    Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
  • Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50 ]
    Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours. Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
  • Dose-Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Multiple Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50 ]
    Apparent oral clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
  • Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50 ]
    Peak-to-trough ratio was calculated by dividing Cmax with Cmin of Enzalutamide and its Metabolites. Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide. Cmax was maximum plasma concentration during the dosing interval and Cmin was minimum observed plasma concentration during the dosing interval.
  • Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing [ Time Frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 1 and 50 ]
    Accumulation Ratio was defined as the ratio of AUC24 of Day 50 to AUC24 of Day 1, where AUC24 was area under the plasma concentration-time curve from time zero to 24 hours post-dose. Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
Original Primary Outcome Measures  ICMJE
 (submitted: May 9, 2012)
To evaluate the safety, tolerability of daily enzalutamide [ Time Frame: 12 months ]
The parameters describing the safety and tolerability of MDV3100 will include:
  • The percentage of patients with DLTs;
  • The percentage of patients with adverse events by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) (version 4.03) grade and associated dose of MDV3100;
  • The percentage of patients with serious adverse events;
  • The percentage of patients who discontinue MDV3100 due to adverse events or serious adverse events;
  • The percentage of patients who require dose modifications (reductions or cessation) of MDV3100.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide [ Time Frame: pre-dose on Day 57 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2012)
To characterize the pharmacokinetic properties of enzalutamide [ Time Frame: 12 months ]
Individual and mean plasma concentration time data after single and multiple-dose administration will be tabulated and displayed by dose level and analyzed by noncompartmental methods to obtain the following key parameters: Cmax, tmax, AUC, t1/2, CL/F, V/F, peak-to-trough, dose proportionality, and accumulation.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of Enzalutamide (MDV3100) in Patients With Incurable Breast Cancer
Official Title  ICMJE A PHASE 1 OPEN-LABEL, DOSE ESCALATION STUDY EVALUATING THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF ENZALUTAMIDE (FORMERLY MDV3100) IN PATIENTS WITH INCURABLE BREAST CANCER
Brief Summary The purpose of this study is to determine the safety, tolerability and pharmacokinetics of enzalutamide alone and in combination with anastrozole, or exemestane, or fulvestrant in patients with incurable breast cancer.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: enzalutamide
    80 mg (2 capsules) or 160 mg (4 capsules) taken orally daily.
    Other Name: MDV3100, Xtandi
  • Drug: anastrozole
    1 mg/day
    Other Name: Arimidex
  • Drug: exemestane
    The exemestane dose is 25mg daily.
    Other Name: Aromasin
  • Drug: fulvestrant
    500 mg every 28 days
    Other Name: Faslodex
  • Drug: enzalutamide
    160 mg (4 capsules) taken orally daily.
    Other Names:
    • MDV3100
    • Xtandi
  • Drug: exemestane
    The exemestane dose is 50 mg daily.
    Other Name: Aromasin
Study Arms  ICMJE
  • Experimental: enzalutamide (80-mg with increase to 160 mg)
    enzalutamide be provided as two or four 40-mg capsules by mouth daily
    Intervention: Drug: enzalutamide
  • Experimental: enzalutamide and anastrozole
    enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with anastrozole (1 mg) administered as one 1-mg tablet by mouth once daily.
    Interventions:
    • Drug: anastrozole
    • Drug: enzalutamide
  • Experimental: enzalutamide and exemestane 25 mg
    enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with exemestane administered as one 25-mg tablet daily
    Interventions:
    • Drug: exemestane
    • Drug: enzalutamide
  • Experimental: enzalutamide and exemestane 50 mg
    enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with exemestane administered as two 25-mg tablets daily
    Interventions:
    • Drug: enzalutamide
    • Drug: exemestane
  • Experimental: enzalutamide and fulvestrant
    enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with fulvestrant (500 mg) administered as two 250-mg intramuscular injections every 28 days
    Interventions:
    • Drug: fulvestrant
    • Drug: enzalutamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 26, 2015)
101
Original Estimated Enrollment  ICMJE
 (submitted: May 9, 2012)
27
Actual Study Completion Date  ICMJE January 22, 2018
Actual Primary Completion Date December 15, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed breast cancer with accompanying pathology report;
  • Submit unstained representative tumor specimen, either as a paraffin block (preferred) or ≥ 10 unstained slides
  • Received at least 2 lines of systemic therapy in the advanced setting (for enzalutamide alone arm only);
  • Eastern Cooperative Oncology Group performance (ECOG) status of 0 or 1;
  • Estimated life expectancy of at least 3 months

Exclusion Criteria:

  • Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment;
  • Pregnant or lactating;
  • Known or suspected brain metastasis or leptomeningeal disease;
  • History of another malignancy within the previous 5 years other than curatively treated in situ carcinomas;
  • For patients who are enrolled to receive enzalutamide plus anastrozole or exemestane or fulvestrant must not have received tamoxifen or any medication known to be a potent CYP3A4 inducer or inhibitor.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01597193
Other Study ID Numbers  ICMJE MDV3100-08
C3431006 ( Other Identifier: Alias Study Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE
  • Astellas Pharma Inc
  • Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Investigators  ICMJE
Study Director: Pfizer Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP