Clinical Trials /

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

NCT02012296

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enzalutamide and Mifepristone in Treating Patients With Metastatic Hormone Resistant Prostate Cancer
  • Official Title: A Phase I/II Trial of Enzalutamide Plus the Glucocorticoid Receptor Antagonist Mifepristone for Patients With Metastatic Castration Resistant Prostate Cancer (CRPC)

Clinical Trial IDs

  • ORG STUDY ID: IRB13-0979
  • SECONDARY ID: NCI-2013-02151
  • SECONDARY ID: CDMRP-PC121149
  • SECONDARY ID: IRB13-0979
  • SECONDARY ID: P30CA014599
  • NCT ID: NCT02012296

Conditions

  • Hormone-resistant Prostate Cancer
  • Recurrent Prostate Cancer
  • Stage IV Prostate Cancer

Interventions

DrugSynonymsArms
enzalutamideMDV3100, selective androgen receptor modulator MDV3100, XTANDITreatment (enzalutamide)
mifepristoneMifegyne, Mifeprex, RU-38486Treatment (enzalutamide, mifepristone)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (enzalutamide)Active ComparatorPatients receive enzalutamide PO per standard of care.
  • enzalutamide
Treatment (enzalutamide, mifepristone)ExperimentalPatients receive enzalutamide PO and mifepristone PO.
  • enzalutamide
  • mifepristone

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Adverse events will be summarized by grade and type and compared between groups using chi-square or Fisher's exact tests.

Secondary Outcome Measures

Measure:Overall survival (Phase II)
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:PK parameters will be summarized using standard descriptive methods (means, standard deviations, medians and ranges).
Measure:AR expression within circulating tumor cells (CTCs)
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.
Measure:GR expression within CTCs
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Last Updated

December 6, 2018