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

• ClinicalTrials.gov Identifier: NCT02012296
• Recruitment Status: Completed
• First Posted: December 16, 2013
• Results First Posted: July 13, 2022
• Last Update Posted: July 13, 2022
• Sponsor: University of Chicago
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Chicago

Study Description

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: We report here the phase 2 results
• 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)
• Actual Study Start Date: December 13, 2013
• Actual Primary Completion Date: June 10, 2019
• Actual Study Completion Date: August 1, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. PSA Progression-free Survival [ Time Frame: Up to 3 years, measured from randomization ]
   PSA progression was defined as a PSA that is ≥1.25 times (25% increase) the PSA at randomization (week 12) and an absolute 5 ng/ml increase. PSA progression-free survival is PSA progression or death from any cause.

Secondary Outcome Measures :

1. Radiographic PFS [ Time Frame: Up to 3 years, measured from randomization ]
   Radiographic progression or death from any cause.
2. Number of Participants With Positive AR Expression Within Circulating Tumor Cells (CTCs) [ Time Frame: Week 12 (randomization) ]
   Positive/negative classification with positive defined as a cytokeratin cell for whom there was an androgen receptor > 0
3. Number of Participants With Positive GR Expression Within Circulating Tumor Cells (CTCs) [ Time Frame: Week 12 (randomization) ]
   Positive/negative classification with positive defined as a cytokeratin cell for whom there was an glucocorticoid receptor > 0
4. Testosterone [ Time Frame: 12 to 16 weeks ]
   Change from week 12 to week 16
5. Thyroid Stimulating Hormone [ Time Frame: 12 to 16 weeks ]
   Change in log(TSH) from week 12 to week 16
6. Cortisol [ Time Frame: 12 to 16 weeks ]
   Change in log(Cortisol) from week 12 to week 16

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 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

Contacts and Locations

Locations

United States, Illinois

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States, 60637-1470

Cancer Care Specialists of Central Illinois (Decatur) /Decatur Memorial Hospital

Decatur, Illinois, United States, 62526

NorthShore University Health System

Evanston, Illinois, United States, 60201

United States, Michigan

Wayne State University Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

Sponsors and Collaborators

University of Chicago

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Russell Szmulewitz; University of Chicago Comprehensive Cancer Center

  Study Documents (Full-Text)

Documents provided by University of Chicago:

Study Protocol and Statistical Analysis Plan  [PDF] July 10, 2014

More Information

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT02012296
• 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
• Results First Posted: July 13, 2022
• Last Update Posted: July 13, 2022
• Last Verified: June 2022

Additional relevant MeSH terms:

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