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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

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: enzalutamide Drug: anastrozole Drug: exemestane Drug: fulvestrant Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 101 participants
Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A PHASE 1 OPEN-LABEL, DOSE ESCALATION STUDY EVALUATING THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF ENZALUTAMIDE (FORMERLY MDV3100) IN PATIENTS WITH INCURABLE BREAST CANCER
Actual Study Start Date : April 30, 2012
Actual Primary Completion Date : December 15, 2015
Actual Study Completion Date : January 22, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: enzalutamide (80-mg with increase to 160 mg)
enzalutamide be provided as two or four 40-mg capsules by mouth daily
Drug: enzalutamide
80 mg (2 capsules) or 160 mg (4 capsules) taken orally daily.
Other Name: MDV3100, Xtandi

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.
Drug: anastrozole
1 mg/day
Other Name: Arimidex

Drug: enzalutamide
160 mg (4 capsules) taken orally daily.
Other Names:
  • MDV3100
  • Xtandi

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
Drug: exemestane
The exemestane dose is 25mg daily.
Other Name: Aromasin

Drug: enzalutamide
160 mg (4 capsules) taken orally daily.
Other Names:
  • MDV3100
  • Xtandi

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
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

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
Drug: fulvestrant
500 mg every 28 days
Other Name: Faslodex

Drug: enzalutamide
160 mg (4 capsules) taken orally daily.
Other Names:
  • MDV3100
  • Xtandi




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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 ]
  11. 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).

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.


Secondary Outcome Measures :
  1. Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide [ Time Frame: pre-dose on Day 57 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01597193


Locations
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United States, Colorado
ATTN-Research Pharmacist
Aurora, Colorado, United States, 80045
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
University of Colorado Hospital, Anschutz Outpatient Pavilion
Aurora, Colorado, United States, 80045
United States, Connecticut
Connecticut Multispecialty Group
Enfield, Connecticut, United States, 06082
United States, Florida
Florida Cancer Specialists
Sarasota, Florida, United States, 34232
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Mississippi
The West Clinic, PC
Corinth, Mississippi, United States, 38834
The West Clinic
Southaven, Mississippi, United States, 38671
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10022
Memorial Sloan Kettering Cancer Center - IDS Pharmacy
New York, New York, United States, 10065
Memorial Sloan Kettering Cancer Center - OPD Pharmacy
New York, New York, United States, 10065
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Tennessee
The West Clinic
Germantown, Tennessee, United States, 38138
The West Clinic
Memphis, Tennessee, United States, 38104
The West Clinic
Memphis, Tennessee, United States, 38120
Tennessee Oncology, PLLC.
Nashville, Tennessee, United States, 37203
The Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Pfizer
Astellas Pharma Inc
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Investigators
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Study Director: Pfizer Pfizer CT.gov Call Center Pfizer

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01597193    
Other Study ID Numbers: MDV3100-08
C3431006 ( Other Identifier: Alias Study Number )
First Posted: May 11, 2012    Key Record Dates
Results First Posted: May 8, 2019
Last Update Posted: May 8, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
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.
Keywords provided by Pfizer:
enzalutamide
MDV3100
breast cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Anastrozole
Exemestane
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action