Breast Cancer
Conditions
Keywords
enzalutamide, MDV3100, 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.
Interventions
DRUGenzalutamide
80 mg (2 capsules) or 160 mg (4 capsules) taken orally daily.
DRUGanastrozole
1 mg/day
DRUGexemestane
The exemestane dose is 25mg daily.
DRUGfulvestrant
500 mg every 28 days
Sponsors
Astellas Pharma Inc
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Pfizer
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | 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. |
| Dose-Escalation Phase: Percentage of Participants With Dose-limiting Toxicity (DLTs) | 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) | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame |
|---|---|
| Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide | pre-dose on Day 57 |
Countries
United States
Participant flow
Pre-assignment details
Stage 1: Included participants with incurable breast cancer. Stage 2: Included participants with hormone receptor-positive incurable breast cancer.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation: Enzalutamide 80 mg Participants received enzalutamide 80 mg (two 40 mg) capsules, orally, once daily until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 7 |
| Dose Escalation: Enzalutamide 160 mg Participants received enzalutamide 160 mg (four 40 mg) capsules, orally, once daily until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 8 |
| Dose Expansion: Enzalutamide 160 mg Participants received enzalutamide 160 mg (four 40 mg) capsules, orally, once daily until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by the sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 14 |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg Participants received enzalutamide 160 mg (four 40 mg) capsule in combination with the anastrozole 1 mg tablet, orally, once daily until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 20 |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg Participants received enzalutamide 160 mg (four 40 mg) capsule in combination with the exemestane 25 mg tablet, orally, once daily until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 16 |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg Participants received enzalutamide 160 mg (four 40 mg) capsule in combination with the exemestane 50 mg tablet, orally, once daily until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 23 |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg Participants received enzalutamide 160 mg (four 40 mg) capsule once daily in combination with the fulvestrant 500 mg intramuscular injection, once every 28 days until documented disease progression, initiation of a new antitumor treatment, an intolerable adverse event (including any seizure), noncompliance, withdrawal of consent, discontinuation by the sponsor, or investigator. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor or investigational therapy, whichever occurred first. | 11 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Stage 1: Dose Escalation (141 Days) | Disease progression | 7 | 8 | 0 | 0 | 0 | 0 | 0 |
| Stage 2: Dose Expansion (1067 Days) | Adverse Event | 0 | 0 | 0 | 1 | 2 | 3 | 0 |
| Stage 2: Dose Expansion (1067 Days) | Disease progression | 0 | 0 | 14 | 18 | 14 | 18 | 11 |
| Stage 2: Dose Expansion (1067 Days) | Other | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 2: Dose Expansion (1067 Days) | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Escalation: Enzalutamide 80 mg | Dose Escalation: Enzalutamide 160 mg | Dose Expansion: Enzalutamide 160 mg | Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg |
|---|---|---|---|---|---|---|---|---|
| Age, Customized Between 65 to 74 years | 29 Participants | 1 Participants | 3 Participants | 2 Participants | 5 Participants | 2 Participants | 12 Participants | 4 Participants |
| Age, Customized Greater than or equal to (>=) 75 years | 7 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Age, Customized Less than (<) 65 years | 63 Participants | 6 Participants | 5 Participants | 11 Participants | 12 Participants | 13 Participants | 10 Participants | 6 Participants |
| Sex: Female, Male Female | 99 Participants | 7 Participants | 8 Participants | 14 Participants | 20 Participants | 16 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 8 | 1 / 14 | 0 / 20 | 0 / 16 | 0 / 23 | 0 / 11 |
| other Total, other adverse events | 7 / 7 | 8 / 8 | 14 / 14 | 20 / 20 | 15 / 16 | 21 / 23 | 11 / 11 |
| serious Total, serious adverse events | 2 / 7 | 1 / 8 | 2 / 14 | 1 / 20 | 5 / 16 | 3 / 23 | 2 / 11 |
Outcome results
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 17.9 ratio | Standard Deviation 2.69 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 47.6 ratio | Standard Deviation 21.4 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 157 ratio | Standard Deviation 48.2 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 9.39 ratio | Standard Deviation 3.75 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 68.0 ratio | Standard Deviation 35.8 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Accumulation Ratio of AUC24 of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 77.8 ratio | Standard Deviation 35.7 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Multiple Dosing | 0.390 liter per hour | Standard Deviation 0.0491 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Multiple Dosing | 0.507 liter per hour | Standard Deviation 0.0906 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Single Dosing | 0.426 liter per hour | Standard Deviation 0.16 |
| Dose Escalation: Enzalutamide 160 mg | Dose Escalation Phase: Apparent Oral Clearance (CL/F) of Enzalutamide After Single Dosing | 0.382 liter per hour | Standard Deviation 0.115 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose Escalation Phase: Apparent Volume of Distribution (Vz/F) of Enzalutamide After Single Dosing | 151 liter | Standard Deviation 73.6 |
| Dose Escalation: Enzalutamide 160 mg | Dose Escalation Phase: Apparent Volume of Distribution (Vz/F) of Enzalutamide After Single Dosing | 94.5 liter | Standard Deviation 13.7 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 207 milligram*hour per milliliter | Standard Deviation 24.3 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 33.0 milligram*hour per milliliter | Standard Deviation 13 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 140 milligram*hour per milliliter | Standard Deviation 6.08 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 325 milligram*hour per milliliter | Standard Deviation 61.6 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 120 milligram*hour per milliliter | Standard Deviation 56 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 317 milligram*hour per milliliter | Standard Deviation 89.4 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | 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 | Enzalutamide | 17.3 micrograms*hour per milliliter | Standard Deviation 8.32 |
| Dose Escalation: Enzalutamide 80 mg | 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 | M1 | 0.632 micrograms*hour per milliliter | Standard Deviation 0.385 |
| Dose Escalation: Enzalutamide 80 mg | 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 | M2 | 1.13 micrograms*hour per milliliter | Standard Deviation 0.916 |
| Dose Escalation: Enzalutamide 160 mg | 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 | Enzalutamide | 41.6 micrograms*hour per milliliter | Standard Deviation 8.19 |
| Dose Escalation: Enzalutamide 160 mg | 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 | M1 | 1.20 micrograms*hour per milliliter | Standard Deviation 0.648 |
| Dose Escalation: Enzalutamide 160 mg | 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 | M2 | 2.76 micrograms*hour per milliliter | Standard Deviation 1 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC72h) of Enzalutamide After Single Dosing | 43.0 micrograms*hour per milliliter | Standard Deviation 21.4 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Area Under the Plasma Concentration-time Curve From Time Zero to 72 Hours (AUC72h) of Enzalutamide After Single Dosing | 107 micrograms*hour per milliliter | Standard Deviation 15.6 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Enzalutamide After Single Dosing | 208 micrograms*hour per milliliter | Standard Deviation 66 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Enzalutamide After Single Dosing | 478 micrograms*hour per milliliter | Standard Deviation 232 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 11.6 micrograms per milliliter | Standard Deviation 1.95 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 1.77 micrograms per milliliter | Standard Deviation 0.521 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 6.42 micrograms per milliliter | Standard Deviation 0.132 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 15.3 micrograms per milliliter | Standard Deviation 2.62 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 6.24 micrograms per milliliter | Standard Deviation 2.28 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 14.1 micrograms per milliliter | Standard Deviation 3.66 |
Primary
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
Population: Pharmacokinetic (PK) analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose | Enzalutamide | 1.90 micrograms per milliliter | Standard Deviation 0.757 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose | M1 | 0.0375 micrograms per milliliter | Standard Deviation 0.0286 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose | M2 | 0.0879 micrograms per milliliter | Standard Deviation 0.0718 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose | Enzalutamide | 4.01 micrograms per milliliter | Standard Deviation 2.09 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose | M1 | 0.0707 micrograms per milliliter | Standard Deviation 0.0379 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Maximum Plasma Concentration (Cmax) of Enzalutamide and Its Metabolites After Single Dose | M2 | 0.184 micrograms per milliliter | Standard Deviation 0.0689 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 1.39 ratio | Standard Deviation 0.4 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 1.32 ratio | Standard Deviation 0.407 |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 0.999 ratio | Standard Deviation 0.0012 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 1.14 ratio | Standard Deviation 0.174 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 1.42 ratio | Standard Deviation 0.388 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Peak-to-Trough Ratio of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 1.00 ratio | Standard Deviation 0.042 |
Primary
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
Population: Safety analysis population included all enrolled participants who received at least 1 dose of Enzalutamide. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Percentage of Participants With Dose-limiting Toxicity (DLTs) | 16.7 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Percentage of Participants With Dose-limiting Toxicity (DLTs) | 0.0 percentage of participants |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Terminal Elimination Half-Life (t1/2) of Enzalutamide After Single Dosing | 280 hours | Standard Deviation 170 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Terminal Elimination Half-Life (t1/2) of Enzalutamide After Single Dosing | 198 hours | Standard Deviation 105 |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 0.500 hours |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 5.70 hours |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 24.0 hours |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing | Enzalutamide | 1.00 hours |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M1 | 2.29 hours |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Multiple Dosing | M2 | 0.58 hours |
Primary
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
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing | Enzalutamide | 0.500 hours |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing | M1 | 24.1 hours |
| Dose Escalation: Enzalutamide 80 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing | M2 | 23.9 hours |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing | Enzalutamide | 1.00 hours |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing | M1 | 23.1 hours |
| Dose Escalation: Enzalutamide 160 mg | Dose-Escalation Phase: Time to Reach Maximum Plasma Concentration (Tmax) of Enzalutamide and Its Metabolites After Single Dosing | M2 | 23.7 hours |
Primary
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)
Population: Safety analysis population included all enrolled participants who received at least 1 dose of Enzalutamide.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 0.0 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 0.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 7.1 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 5.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 12.5 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 13.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg | Percentage of Participants Who Discontinued the Study Drug Due to Adverse Events or Serious Adverse Events | 0.0 percentage of participants |
Primary
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)
Population: Safety analysis population included all enrolled participants who received at least 1 dose of Enzalutamide.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 0.0 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 0.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 0.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 20.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 12.5 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 8.7 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg | Percentage of Participants Who Require Dose Reductions Due to Adverse Events | 18.2 percentage of participants |
Primary
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)
Population: Safety analysis population included all enrolled participants who received at least 1 dose of Enzalutamide.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | 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) | 57.1 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | 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) | 12.5 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg | 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) | 21.4 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | 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) | 30.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | 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) | 37.5 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | 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) | 39.1 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg | 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) | 36.4 percentage of participants |
Primary
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)
Population: Safety analysis population included all enrolled participants who received at least 1 dose of Enzalutamide.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 1 percentage of participants |
| Dose Escalation: Enzalutamide 80 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 0 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 0 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 2 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 1 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 1 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 1 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 2 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Heart rate | 0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg | Percentage of Participants With Potentially Clinically Significant Change From Baseline in Vital Signs | Blood pressure | 1 percentage of participants |
Primary
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.
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)
Population: Safety analysis population included all enrolled participants who received at least 1 dose of Enzalutamide.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 28.6 percentage of participants |
| Dose Escalation: Enzalutamide 160 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 12.5 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 14.3 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 5.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 31.3 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 50 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 13.0 percentage of participants |
| Dose Expansion: Enzalutamide 160 mg + Fulvestrant 500 mg | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 18.2 percentage of participants |
Secondary
Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide
Time frame: pre-dose on Day 57
Population: PK analysis population included all participants who had at least 1 dose of Enzalutamide and had sufficient PK data to calculate at least 1 of the PK parameters of interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Enzalutamide 80 mg | Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide | 13.40 micrograms per milliliter | Standard Deviation 2.51 |
| Dose Escalation: Enzalutamide 160 mg | Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide | 14.33 micrograms per milliliter | Standard Deviation 3.99 |
| Dose Expansion: Enzalutamide 160 mg | Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide | 13.52 micrograms per milliliter | Standard Deviation 2.62 |
| Dose Expansion: Enzalutamide 160 mg + Anastrozole 1 mg | Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide | 12.41 micrograms per milliliter | Standard Deviation 3.76 |
| Dose Expansion: Enzalutamide 160 mg + Exemestane 25 mg | Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide | 11.62 micrograms per milliliter | Standard Deviation 4.69 |