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

Study Overview
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Brief Summary
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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.

Official Title
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A PHASE 1 OPEN-LABEL, DOSE ESCALATION STUDY EVALUATING THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF ENZALUTAMIDE (FORMERLY MDV3100) IN PATIENTS WITH INCURABLE BREAST CANCER

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: enzalutamide
* Drug: anastrozole
* Drug: exemestane
* Drug: fulvestrant
* Drug: enzalutamide
* Drug: exemestane


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: enzalutamide (80-mg with increase to 160 mg)<br>enzalutamide be provided as two or four 40-mg capsules by mouth daily | Drug: enzalutamide<br>* 80 mg (2 capsules) or 160 mg (4 capsules) taken orally daily.<br>* Other names: MDV3100, Xtandi;|
| Experimental: enzalutamide and anastrozole<br>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<br>* 1 mg/day<br>* Other names: Arimidex;Drug: enzalutamide<br>* 160 mg (4 capsules) taken orally daily.<br>* Other names: Xtandi;|
| Experimental: enzalutamide and exemestane 25 mg<br>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<br>* The exemestane dose is 25mg daily.<br>* Other names: Aromasin;Drug: enzalutamide<br>* 160 mg (4 capsules) taken orally daily.<br>* Other names: Xtandi;|
| Experimental: enzalutamide and exemestane 50 mg<br>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<br>* 160 mg (4 capsules) taken orally daily.<br>* Other names: Xtandi;Drug: exemestane<br>* The exemestane dose is 50 mg daily.<br>* Other names: Aromasin;|
| Experimental: enzalutamide and fulvestrant<br>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<br>* 500 mg every 28 days<br>* Other names: Faslodex;Drug: enzalutamide<br>* 160 mg (4 capsules) taken orally daily.<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 |  | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 1 and 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide |  | pre-dose on Day 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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enzalutamide, MDV3100, breast cancer