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Enzalutamide and Mifepristone in Treating Patients With Metastatic Hormone Resistant Prostate Cancer

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ClinicalTrials.gov Identifier: NCT02012296
Recruitment Status : Recruiting
First Posted : December 16, 2013
Last Update Posted : December 10, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Chicago

Brief Summary:
This partially randomized phase I/II trial studies the side effects and best dose of enzalutamide and mifepristone when given together and to see how well they work in treating patients with metastatic hormone resistant prostate cancer. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as enzalutamide and mifepristone, may lessen the amount of androgens made by the body. It is not yet known whether enzalutamide is more effective with or without mifepristone in treating patients with prostate cancer.

Condition or disease Intervention/treatment Phase
Hormone-resistant Prostate Cancer Recurrent Prostate Cancer Stage IV Prostate Cancer Drug: enzalutamide Drug: mifepristone Other: laboratory biomarker analysis Other: pharmacological study Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To establish the safe and pharmacologically active doses of mifepristone and enzalutamide to use in combination. (Phase I) II. To determine if mifepristone in combination with enzalutamide prolongs time to prostate-specific antigen (PSA) progression compared to enzalutamide alone in patients with metastatic castration resistant prostate cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the effect of mifepristone on endocrine biomarkers such as serum cortisol and thyrotropin.

II. To determine the effect of mifepristone on enzalutamide clearance and steady state enzalutamide exposure.

III. To determine if mifepristone affects PSA response rate when added to enzalutamide.

IV. To determine if mifepristone when added to mifepristone prolongs radiographic and clinical progression free survival according to standard working group criteria.

V. To explore the role of glucocorticoid receptor (GR) and androgen receptor (AR) protein expression within circulating tumor cells as a pharmacodynamic biomarker for mifepristone and enzalutamide in castration resistant prostate cancer (CRPC).

VI. To explore the expression of GR and down-stream AR/GR targets in metastatic tumor specimen prior to combination drug administration and at clinical progression.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

PHASE I: Patients receive enzalutamide orally (PO) on days 1-57 and mifepristone PO on days 29-57. Treatment continues in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive enzalutamide PO for 12 weeks per standard of care. Patients are then randomized to 1 of 2 treatment arms.

ARM I: Patients receive enzalutamide PO per standard of care.

ARM II: Patients receive enzalutamide PO and mifepristone PO.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Enzalutamide Plus the Glucocorticoid Receptor Antagonist Mifepristone for Patients With Metastatic Castration Resistant Prostate Cancer (CRPC)
Study Start Date : December 2013
Estimated Primary Completion Date : December 1, 2019
Estimated Study Completion Date : December 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Treatment (enzalutamide)
Patients receive enzalutamide PO per standard of care.
Drug: enzalutamide
Given PO
Other Names:
  • MDV3100
  • selective androgen receptor modulator MDV3100
  • XTANDI

Other: laboratory biomarker analysis
Correlative studies

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Experimental: Treatment (enzalutamide, mifepristone)
Patients receive enzalutamide PO and mifepristone PO.
Drug: enzalutamide
Given PO
Other Names:
  • MDV3100
  • selective androgen receptor modulator MDV3100
  • XTANDI

Drug: mifepristone
Given PO
Other Names:
  • Mifegyne
  • Mifeprex
  • RU-38486

Other: laboratory biomarker analysis
Correlative studies

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies




Primary Outcome Measures :
  1. Recommended phase II dose defined as the highest mifepristone dose in combination with enzalutamide such that < 33% experience dose-limiting toxicity graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to 28 days ]
    Adverse events will be summarized by grade and type and compared between groups using chi-square or Fisher's exact tests.

  2. PSA progression-free survival (PFS) defined as a PSA (confirmed 2 weeks later) that is >= 1.25 times (25% increase) the PSA at randomization (week 12) (Phase II) [ Time Frame: Up to 1 year ]
    Kaplan-Meier curves will be generated and the two treatment arms compared using a logrank test. Median time to event in each group will be estimated along with 90% confidence intervals using the method of Brookmeyer and Crowley. Cox proportional hazards regression models will be fit to assess and adjust for the effects of baseline covariates.


Secondary Outcome Measures :
  1. Overall survival (Phase II) [ Time Frame: Up to 1 year ]
    Kaplan-Meier curves will be generated and the two treatment arms compared using a logrank test. Median time to event in each group will be estimated along with 90% confidence intervals using the method of Brookmeyer and Crowley. Cox proportional hazards regression models will be fit to assess and adjust for the effects of baseline covariates.

  2. Radiographic PFS (Phase II) [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]
    The stratified log-rank will be used to compare the two treatment arms with respect to PFS. The Kaplan-Meier approach will be used to estimate PFS distribution and the proportional hazards model will be used to assess the importance of treatment arm in predicting PFS.

  3. Pharmacokinetic (PK) parameters of enzalutamide and mifepristone [ Time Frame: Baseline; at days 29, 36, 43, 50, and 57 of Phase I; and on days 1 and 28 of Phase II ]
    PK parameters will be summarized using standard descriptive methods (means, standard deviations, medians and ranges).

  4. AR expression within circulating tumor cells (CTCs) [ Time Frame: Up to 30 days after completion of study treatment ]
    The median/range, mean/standard deviation of expression (relative fluorescence) for AR will be summarized for each patient (intra-patient variability) and for the entire population (inter-patient variability). The components of variability will be estimated using analysis of variance. In addition percent nuclear/cytoplasmic/both cellular localization will be calculated.

  5. GR expression within CTCs [ Time Frame: Up to 30 days after completion of study treatment ]
    The median/range, mean/standard deviation of expression (relative fluorescence) for GR will be summarized for each patient (intra patient variability) and for the entire population (inter-patient variability). The components of variability will be estimated using analysis of variance. In addition percent nuclear/cytoplasmic/both cellular localization will be calculated.



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

Inclusion Criteria:

  • Histologically or cytologically confirmed prostate cancer
  • Evidence of castrate testosterone level < 50 ng/dL (or surgical castration)
  • For Phase I portion of the study: evidence of disease progression:

    • 2 or more new lesions on bone scan or
    • Progressive disease on computed tomography (CT)/magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or
    • Rising PSA: PSA evidence for progressive prostate cancer consists of a minimum PSA level of at least 2 ng/ml, which has subsequently risen on at least 2 successive occasions, at least 2 weeks apart
  • For Phase II portion of the study:

    • Subjects must be on enzalutamide for metastatic CRPC and within the first 12 weeks of enzalutamide at 160mg/day
    • Record of subject's enzalutamide start date and baseline PSA (within 28 days of starting) before starting enzalutamide available
  • Subjects must have documented clinically stable disease or better during the screening period of the study as defined by all of the following:

    • PSA =<1.25 times the PSA at start of enzalutamide
    • Lack of radiographic progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Prostate Cancer Working Group Criteria
    • Clinically stable as confirmed by treating physician
  • Any prior therapy for castrate disease is acceptable except prior specific cytochrome P450 family 17 (CYP17) antagonists (e.g. abiraterone acetate, orteronel) or prior second generation AR antagonists (e.g. enzalutamide or ARN509) which are excluded other than enzalutamide as specified for phase II portion; a minimum washout of 28 days for any other anticancer therapy prior to first dose of study drug is required (only applicable for phase I)
  • Any other radiotherapy or radionuclide require 28-day washout prior to first dose of study drug
  • Denosumab or zoledronic acid are allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Total bilirubin =< 1.5 x the upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart), or any herbal product known to decrease PSA levels (e.g., saw palmetto and PC-SPES), or any systemic corticosteroid within 2 weeks prior to first dose of study drug
  • Inability to swallow capsules or known gastrointestinal malabsorption
  • History of other malignancies, with the exception of: adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 solid tumor malignancies who are without evidence of disease, or other solid tumors curatively treated with no evidence of disease for >= 5 years from enrollment
  • Blood pressure that is not controlled despite > 2 oral agents (systolic blood pressure [SBP] > 160 and diastolic blood pressure [DBP] > 90 documented during the screening period with no subsequent blood pressure readings < 160/100)
  • History of seizure disorder or active use of anticonvulsants
  • Corrected QT interval (QTc) on electrocardiogram (EKG) > 450 msec
  • Serious intercurrent infections or non-malignant medical illnesses that are uncontrolled
  • Active psychiatric illness/social situations that would limit compliance with protocol requirements
  • New York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)
  • Concurrent therapy with strong inhibitors or inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) due to concerning possible drug-drug interactions

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 ClinicalTrials.gov identifier (NCT number): NCT02012296


Locations
United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637-1470
Contact: Kelly O'Connor    773-702-4653    koconnor@medicine.bsd.uchicago.edu   
Principal Investigator: Russell Z. Szmulewitz         
Cancer Care Specialists of Central Illinois (Decatur) /Decatur Memorial Hospital Recruiting
Decatur, Illinois, United States, 62526
Contact: James Wade, MD    217-876-6600      
NorthShore University Health System Recruiting
Evanston, Illinois, United States, 60201
Contact: Daniel Shevrin, MD    224-364-7100    dshevrin@northshore.org   
United States, Michigan
Wayne State University Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Elisabeth Heath, MD    313-576-8624    heathe@karmanos.org   
Sponsors and Collaborators
University of Chicago
National Cancer Institute (NCI)
Investigators
Principal Investigator: Russell Szmulewitz University of Chicago Comprehensive Cancer Center

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT02012296     History of Changes
Other Study ID Numbers: IRB13-0979
NCI-2013-02151 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDMRP-PC121149
IRB13-0979 ( Other Identifier: University of Chicago )
P30CA014599 ( U.S. NIH Grant/Contract )
First Posted: December 16, 2013    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: March 2018

Additional relevant MeSH terms:
Mifepristone
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Abortifacient Agents, Steroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptives, Oral, Synthetic
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Contraceptives, Postcoital, Synthetic
Contraceptives, Postcoital
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Luteolytic Agents
Menstruation-Inducing Agents