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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
101
80 mg (2 capsules) or 160 mg (4 capsules) taken orally daily.
1 mg/day
The exemestane dose is 25mg daily.
ATTN-Research Pharmacist
Aurora, Colorado, United States
University of Colorado Cancer Center
Aurora, Colorado, United States
Dose-Escalation Phase: Percentage of Participants With Dose-limiting Toxicity (DLTs)
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.
Time frame: Baseline up to Day 35
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)
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.
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)
Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs)
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.
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500 mg every 28 days
160 mg (4 capsules) taken orally daily.
The exemestane dose is 50 mg daily.
University of Colorado Hospital, Anschutz Outpatient Pavilion
Aurora, Colorado, United States
Connecticut Multispecialty Group
Enfield, Connecticut, United States
Florida Cancer Specialists
Sarasota, Florida, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
The West Clinic, PC
Corinth, Mississippi, United States
The West Clinic
Southaven, Mississippi, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Memorial Sloan Kettering Cancer Center - IDS Pharmacy
New York, New York, United States
...and 7 more locations
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)
Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events
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.
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)
Percentage of Participants Who Require Dose Reductions Due to Adverse Events
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.
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)
Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs
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.
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)
Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose
Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing
Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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
Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
Time frame: pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose on Day 1
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
AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf).
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
Dose-Escalation Phase: Terminal Elimination Half-Life (t1/2) of Enzalutamide After Single Dosing
Terminal elimination half-life is the time measured for the plasma concentration of Enzalutamide to decrease by one-half of its initial concentration.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
Dose Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Single Dosing
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.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
Dose Escalation Phase: Apparent Volume of Distribution (Vz/F) of Enzalutamide After Single Dosing
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.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing
Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing
Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing
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.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
Dose-Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Multiple Dosing
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.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing
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.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing
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.
Time frame: pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 1 and 50
Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide
Time frame: pre-dose on Day 57