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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01597193
• Other study ID #: MDV3100-08
• Secondary ID: C3431006
• Status: Completed
• Phase: Phase 1
• Start date: April 30, 2012
• Est. completion date: January 22, 2018

Study information

• Verified date: May 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: January 22, 2018
• Est. primary completion date: December 15, 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• enzalutamide
80 mg (2 capsules) or 160 mg (4 capsules) taken orally daily.
• anastrozole
1 mg/day
• exemestane
The exemestane dose is 25mg daily.
• fulvestrant
500 mg every 28 days
• enzalutamide
160 mg (4 capsules) taken orally daily.
• exemestane
The exemestane dose is 50 mg daily.

Locations

Country	Name	City	State
United States	ATTN-Research Pharmacist	Aurora	Colorado
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	University of Colorado Hospital, Anschutz Outpatient Pavilion	Aurora	Colorado
United States	The West Clinic, PC	Corinth	Mississippi
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Connecticut Multispecialty Group	Enfield	Connecticut
United States	The West Clinic	Germantown	Tennessee
United States	The West Clinic	Memphis	Tennessee
United States	The West Clinic	Memphis	Tennessee
United States	Tennessee Oncology, PLLC.	Nashville	Tennessee
United States	The Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
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	Memorial Sloan Kettering Cancer Center - OPD Pharmacy	New York	New York
United States	Florida Cancer Specialists	Sarasota	Florida
United States	The West Clinic	Southaven	Mississippi

Sponsors (3)

Lead Sponsor	Collaborator
Pfizer	Astellas Pharma Inc, Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline up to Day 35
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.	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)
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.	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)
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.	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)
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.	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)
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.	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)
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.	pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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.	pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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.	pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose on Day 1
Primary	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
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).	pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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.	pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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.	pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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.	pre-dose, 0.5, 1, 2, 4, 6, 24, 48, 72 and 96 hours post dose on Day 1
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.	pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
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.	pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
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.	pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
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.	pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
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.	pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 50
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.	pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post-dose on Day 1 and 50
Secondary	Dose-Expansion Phase: Trough Plasma Concentration for Enzalutamide		pre-dose on Day 57