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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01650194
Recruitment Status : Completed
First Posted : July 26, 2012
Last Update Posted : March 2, 2018
Medivation, Inc.
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:
The purpose of this study is to explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Subjects diagnosed with cancer of the prostate that is getting worse and spread to the bone despite receiving hormone treatment will be enrolled and receive 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 will maintain androgen deprivation with a gonadotropin releasing hormone (GnRH) agonist or antagonist or orchiectomy. Study drug will be administered until disease progression. Disease progression is 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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
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

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Enzalutamide combined with abiraterone acetate plus prednisone
Enzalutamide daily, abiraterone acetate daily, prednisone twice daily
Drug: enzalutamide
Other Name: MDV3100

Drug: abiraterone acetate

Drug: prednisone

Primary Outcome Measures :
  1. Nature, frequency and severity of adverse events [ Time Frame: Until documented disease progression (up to 24 months) ]
  2. Safety assessed by laboratory tests, vital signs, 12 lead electrocardiograms (ECGs) and physical examinations [ Time Frame: Until documented disease progression (up to 24 months) ]

Secondary 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 ]
  2. Androgens including testosterone and dihydrotestosterone (DHT) concentrations in bone marrow aspirate and blood [ Time Frame: Baseline and Week 9 ]
  3. Androgen pre-cursors including cortisol, androstenedione, pregnenolone, progesterone [ Time Frame: Baseline and Week 9 ]
  4. Prostate-specific antigen (PSA) levels) [ Time Frame: 24 months ]
  5. Progression free survival (PFS) [ Time Frame: 24 months ]
    Defined as the time interval from the date of starting treatment until the date of documented progression or death in absence of progression.

  6. Objective response according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) [ Time Frame: 24 months ]
    Partial or complete response

  7. Bone scan results [ Time Frame: Week 13, Week 25 and every subsequent 12 weeks (up to 24 months) ]
  8. Bone specific alkaline phosphatase [ Time Frame: 24 months ]
    Marker of bone metabolism

  9. Urine N-telopeptides [ Time Frame: Baseline and Week 9 ]
    Marker of bone metabolism

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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01650194

United States, Texas
Site US2492 MD Anderson Cancer Ctr
Houston, Texas, United States, 77030
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Medivation, Inc.
Study Director: Associate Medical Director Astellas Pharma Global Development

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Astellas Pharma Global Development, Inc. Identifier: NCT01650194     History of Changes
Other Study ID Numbers: 9785-CL-0011
First Posted: July 26, 2012    Key Record Dates
Last Update Posted: March 2, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Abiraterone Acetate
Anti-Inflammatory Agents
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