A Study to Determine Safety and Tolerability of Enzalutamide (MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients

• ClinicalTrials.gov Identifier: NCT01650194
• Recruitment Status: Completed
• First Posted: July 26, 2012
• Results First Posted: February 5, 2019
• Last Update Posted: February 5, 2019
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborator: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description

Brief Summary:

The purpose of this study was to explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Subjects diagnosed with cancer of the prostate that was getting worse and spreading to the bone despite receiving hormone treatment were enrolled and received study treatment until disease progression.

Condition or disease	Intervention/treatment	Phase
Metastatic Castration-Resistant Prostate Cancer	Drug: enzalutamide; Drug: abiraterone acetate; Drug: prednisone	Phase 2

Detailed Description:

For the study duration, all subjects maintained androgen deprivation with a gonadotropin releasing hormone (GnRH) agonist or antagonist or orchiectomy. Study drug was administered until disease progression. Disease progression was defined as a composite endpoint consisting of either clinical deterioration, radiographic progression or prostate-specific antigen (PSA) progression according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study Determining Safety and Tolerability of Enzalutamide (Formerly MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients
• Actual Study Start Date: July 9, 2012
• Actual Primary Completion Date: January 4, 2018
• Actual Study Completion Date: January 4, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Enzalutamide + Abiraterone + Prednisone; Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.	Drug: enzalutamide; Participants received 160 mg of enzalutamide orally once daily (4 capsules, 40 mg each).; Other Name: MDV3100; Drug: abiraterone acetate; Participants received 1000 mg of abiraterone acetate orally once daily (4 tablets, 250 mg each).; Drug: prednisone; Participants received 5 mg of prednisone orally twice daily (2 tablets, 5 mg each).

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events (AEs) [ Time Frame: From the first dose of study drug administration up 30 days following the last dose of study drug date, with a median duration of treatment of 10.1 months. ]
   A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03).

Secondary Outcome Measures :

1. Change From Baseline in Testosterone Concentration in Bone Marrow Aspirate [ Time Frame: Baseline and Week 9 ]
   Testosterone concentration in bone marrow aspirate was measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry.
2. Change From Baseline in Dihydrotestosterone (DHT) Concentration in Bone Marrow Aspirate [ Time Frame: Baseline and Week 9 ]
   DHT concentration in bone marrow aspirate was to be measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry. DHT bone data were not collected.
3. Change From Baseline in Cortisol in Bone Marrow Aspirate [ Time Frame: Baseline and Week 9 ]
   Cortisol in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
4. Change From Baseline in Androstenedione in Bone Marrow Aspirate [ Time Frame: Baseline and Week 9 ]
   Androstenedione in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
5. Change From Baseline in Progesterone in Bone Marrow Aspirate [ Time Frame: Baseline and Week 9 ]
   Progesterone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
6. Change From Baseline in Pregnenolone in Bone Marrow Aspirate [ Time Frame: Baseline and Week 9 ]
   Pregnenolone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
7. Change From Baseline in Testosterone Concentration in Blood [ Time Frame: Baseline and Week 9 ]
   Testosterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
8. Change From Baseline in DHT Concentration in Blood [ Time Frame: Baseline and Week 9 ]
   DHT concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. The endpoint could not be analyzed since no participants had DHT levels over the lower limit of quantification (LLOQ).
9. Change From Baseline in Cortisol Concentration in Blood [ Time Frame: Baseline and Week 9 ]
   Cortisol concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
10. Change From Baseline in Androstenedione Concentration in Blood [ Time Frame: Baseline and Week 9 ]
    Androstenedione concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
11. Change From Baseline in Progesterone Concentration in Blood [ Time Frame: Baseline and Week 9 ]
    Progesterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
12. Change From Baseline in Pregnenolone Concentration in Blood [ Time Frame: Baseline and Week 9 ]
    Pregnenolone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
13. Change From Baseline to End-of-Treatment (EoT) in Prostate-Specific Antigen (PSA) Levels [ Time Frame: Baseline and EoT; the median duration of treatment was 10.1 months. ]
    Prostate-specific antigen progression by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) was defined as a PSA increase ≥25% and ≥2 ng/ml above the post-baseline nadir, and which was confirmed by the first subsequent value of 3 or more weeks later.
14. Progression Free Survival (PFS) [ Time Frame: Up to 1849 days ]
    PFS was measured as the time from the date of first dose of any drug of the study combination treatment until the first evidence of documented progression (a composite endpoint consisting of radiographic progression or PSA progression by PCWG2 or clinical deterioration) or death in the absence of progression (whichever came first) or the date last known to be progression free. The Kaplan-Meier (KM) 95% CI was based on Brookmeyer and Crowley robust non-parametric method.
15. Percentage of Participants With Objective Response for Soft Tissue Lesions According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) [ Time Frame: Up to 1849 days ]
    Objective response was based on RECIST version 1.1 for soft tissue lesion on Magnetic resonance imaging (MRI) / Computerized tomography (CT) and the PCWG2 guidelines for bone lesions on bone scans and was defined as partial response (PR) or complete response (CR) based on the investigators' assessments of target, non-target and new lesions while on study treatment. The 95% for objective response rate was based on exact binomial 95% confidence interval (Clopper-Pearson).
16. Bone Scan Response at EoT [ Time Frame: EoT; the median duration of treatment was 10.1 months. ]
    PD: ≥1 of 3 criteria: PSA progression: ≥2 rising PSA levels, interval of ≥1 week between each determination. Soft tissue disease progression: RECIST 1.1. Bone disease progression: PCWG2 criteria (≥2 or new lesions on bone scan compared with prior scan). Target lesion CR: disappearance of all target lesions, PR as ≥30% decrease in sum of longest diameter (LD) of target lesions, referencing baseline sum LD, SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referencing smallest sum LD since treatment start, PD ≥20% increase in sum of LD of target lesions, referencing smallest sum LD recorded since treatment start or appearance of ≥1 new lesions. Non-target lesions CR: disappearance of all non-target lesions and normalization of tumor marker level, SD: persistence of ≥1 non-target lesions and/or maintenance of tumor marker level above normal limits, PD: appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions.
17. Change From Baseline to EoT in Bone Specific Alkaline Phosphatase [ Time Frame: Baseline and EoT; the median duration of treatment was 10.1 months. ]
    Bone metabolism marker bone specific alkaline phosphatase levels were derived from blood samples collected.
18. Change From Baseline in Urine N-Telopeptide [ Time Frame: Baseline and Week 9 ]
    Bone metabolism marker urine N-telopeptide levels were derived from urine samples collected.

Other Outcome Measures:

1. Androgen Receptor Signaling Assessed by Expression and Localization of Androgen Receptor (AR), CYP17 Expression, Splice Variants, and Pathways Linked With Non-classical AR Signaling and Bone Development [ Time Frame: Baseline and Week 9 ]
   The endpoint was considered exploratory and no analysis was planned.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
• Presence of metastatic disease to the bone
• Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration)
• Subject receiving bisphosphonate or denosumab therapy must have been on stable doses for at least 4 weeks prior to Day 1

• Progressive disease defined as one or more of the following three criteria (Note: subjects who received an antiandrogen must demonstrate disease progression following discontinuation of antiandrogen):

  • PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 ng/mL
  • Soft tissue disease progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  • Bone disease progression defined by PCWG2 criteria (two or more new lesions on bone scan compared with prior scan)
• Subject previously treated with chemotherapy must have no more than two prior chemotherapy regimens for the treatment of metastatic prostate cancer
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Agree to use a double-barrier method of contraception which involves the use of a condom in combination with one of the following: contraceptive sponge, diaphragm, or cervical ring with spermicidal gel or foam, if having sex with a woman of child-bearing potential during the length of the study and for one week after abiraterone is discontinued and for at least three months after enzalutamide is discontinued
• Subject agrees not to participate in another interventional study while on treatment

Exclusion Criteria:

• Known or suspected metastases in the brain
• Absolute neutrophil count < 1,000/μL, platelet count < 75,000/μL, and hemoglobin < 9 g/dL (NOTE: subject may not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at the Screening visit)
• Total bilirubin (TBL), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal
• Creatinine (Cr) > 2 mg/dL
• Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-α reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy within 4 weeks of Day 1 visit
• Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks) of Day 1 visit, or radionuclide therapy within 8 weeks of Day 1
• Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
• Structurally unstable bone lesions suggesting impending fracture
• History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 visit)

• Clinically significant cardiovascular disease including:

  • Myocardial infarction within 6 months of Screening visit;
  • Uncontrolled angina within 3 months of Screening visit;
  • Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the Screening visit results in a left ventricular ejection fraction that is ≥ 45%
  • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes)
  • Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the Electrocardiogram (ECG) > 470 msec.
  • History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
  • Hypotension (systolic blood pressure < 86 mmHg or bradycardia with a heart rate of <50 beats per minute on the ECG., unless pharmaceutically induced and thus reversible (i.e. beta blockers).
  • Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg
• Prior use of ketoconazole, abiraterone acetate or enzalutamide, or participation in a previous clinical trial of ketoconazole, abiraterone acetate or enzalutamide

• History of significant bleeding disorder unrelated to cancer, including:

  • Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
  • Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) of Screening visit
  • History of GI bleeding within 6 months of Screening visit
• Active or symptomatic viral hepatitis or chronic liver disease
• Known history of pituitary or adrenal dysfunction

Contacts and Locations

Locations

United States, Texas

Site US2492 MD Anderson Cancer Ctr

Houston, Texas, United States, 77030

Sponsors and Collaborators

Astellas Pharma Global Development, Inc.

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Investigators

• Study Director: Associate Medical Director; Astellas Pharma Global Development

  Study Documents (Full-Text)

Documents provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):

Study Protocol  [PDF] June 18, 2014

Statistical Analysis Plan  [PDF] January 4, 2016

More Information

Additional Information:

Link to results on the Astellas Clinical Study Results website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Assi R, Temraz S, Shamseddine A, Mukherji D. New Compounds Targeting the Androgen Receptor for Treatment of Advanced Prostate Cancer. Curr Drug Targets. 2016;17(3):290-302. Review.

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT01650194
• Other Study ID Numbers: 9785-CL-0011
• First Posted: July 26, 2012
• Results First Posted: February 5, 2019
• Last Update Posted: February 5, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• URL: https://www.clinicalstudydatarequest.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):

abiraterone acetate; prednisone; enzalutamide; cancer; prostate; MDV3100

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Prednisone; Abiraterone Acetate; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors