Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer
Conditions
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.
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.
Interventions
DRUGenzalutamide
Given PO
DRUGmifepristone
Given PO
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
We report here the phase 2 results
Eligibility
Sex/Gender
MALE
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PSA Progression-free Survival | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Positive AR Expression Within Circulating Tumor Cells (CTCs) | Week 12 (randomization) | Positive/negative classification with positive defined as a cytokeratin cell for whom there was an androgen receptor \> 0 |
| Number of Participants With Positive GR Expression Within Circulating Tumor Cells (CTCs) | Week 12 (randomization) | Positive/negative classification with positive defined as a cytokeratin cell for whom there was an glucocorticoid receptor \> 0 |
| Radiographic PFS | Up to 3 years, measured from randomization | Radiographic progression or death from any cause. |
| Thyroid Stimulating Hormone | 12 to 16 weeks | Change in log(TSH) from week 12 to week 16 |
| Cortisol | 12 to 16 weeks | Change in log(Cortisol) from week 12 to week 16 |
| Testosterone | 12 to 16 weeks | Change from week 12 to week 16 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Enzalutamide) Patients receive enzalutamide 160 mg daily during a 12-week lead-in followed by enzalutamide 160 mg daily per standard of care.
enzalutamide: Given PO | 33 |
| Treatment (Enzalutamide, Mifepristone) Patients receive enzalutamide 160 mg daily during a 12-week lead-in followed by enzalutamide 120 mg daily plus mifepristone 300 mg daily.
enzalutamide: Given PO
mifepristone: Given PO | 33 |
| Not Randomized Patients received enzalutamide 160 mg daily during a 12-week lead-in. | 22 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Early study closure | 0 | 0 | 5 |
| Overall Study | Lack of Efficacy | 0 | 0 | 15 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment (Enzalutamide) | Total | Not Randomized | Treatment (Enzalutamide, Mifepristone) |
|---|---|---|---|---|
| Age, Continuous | 71 years | 70 years | 68 years | 71 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 19 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 62 Participants | 16 Participants | 26 Participants |
| Region of Enrollment United States | 33 participants | 66 participants | 22 participants | 33 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 33 Participants | 88 Participants | 22 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 1 / 33 | 0 / 22 |
| other Total, other adverse events | 33 / 33 | 30 / 33 | 20 / 22 |
| serious Total, serious adverse events | 3 / 33 | 6 / 33 | 3 / 22 |
Outcome results
Primary
PSA Progression-free Survival
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.
Time frame: Up to 3 years, measured from randomization
Population: Patients not randomized were not evaluated for PSA progression-free survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzalutamide) | PSA Progression-free Survival | 20.8 Months |
| Treatment (Enzalutamide, Mifepristone) | PSA Progression-free Survival | 16.5 Months |
p-value: 0.83Log Rank
Secondary
Cortisol
Change in log(Cortisol) from week 12 to week 16
Time frame: 12 to 16 weeks
Population: 12 patients in the enzalutamide arm and 1 patient in the enzalutamide plus mifepristone arm had missing data. Patients not randomized were not evaluated for changes in cortisol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Enzalutamide) | Cortisol | 0.072 log(ug/dL) | Standard Error 0.126 |
| Treatment (Enzalutamide, Mifepristone) | Cortisol | 0.733 log(ug/dL) | Standard Error 0.102 |
p-value: 0.0002t-test, 2 sided
Secondary
Number of Participants With Positive AR Expression Within Circulating Tumor Cells (CTCs)
Positive/negative classification with positive defined as a cytokeratin cell for whom there was an androgen receptor \> 0
Time frame: Week 12 (randomization)
Population: Number of patients with circulating tumor cells.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Enzalutamide) | Number of Participants With Positive AR Expression Within Circulating Tumor Cells (CTCs) | 16 Participants |
| Treatment (Enzalutamide, Mifepristone) | Number of Participants With Positive AR Expression Within Circulating Tumor Cells (CTCs) | 8 Participants |
| Not Randomized | Number of Participants With Positive AR Expression Within Circulating Tumor Cells (CTCs) | 5 Participants |
Secondary
Number of Participants With Positive GR Expression Within Circulating Tumor Cells (CTCs)
Positive/negative classification with positive defined as a cytokeratin cell for whom there was an glucocorticoid receptor \> 0
Time frame: Week 12 (randomization)
Population: Patients with circulating tumor cells (CTCs).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Enzalutamide) | Number of Participants With Positive GR Expression Within Circulating Tumor Cells (CTCs) | 17 Participants |
| Treatment (Enzalutamide, Mifepristone) | Number of Participants With Positive GR Expression Within Circulating Tumor Cells (CTCs) | 8 Participants |
| Not Randomized | Number of Participants With Positive GR Expression Within Circulating Tumor Cells (CTCs) | 5 Participants |
Secondary
Radiographic PFS
Radiographic progression or death from any cause.
Time frame: Up to 3 years, measured from randomization
Population: Patients not randomized were not evaluated for radiographic progression-free survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzalutamide) | Radiographic PFS | NA Months |
| Treatment (Enzalutamide, Mifepristone) | Radiographic PFS | 16.5 Months |
p-value: 0.21Log Rank
Secondary
Testosterone
Change from week 12 to week 16
Time frame: 12 to 16 weeks
Population: 6 patients in the enzalutamide arm and 7 patients in the enzalutamide plus mifepristone arm had missing data. Patients not randomized were not evaluated for changes in testosterone.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Enzalutamide) | Testosterone | 0.6 ng/dL | Standard Error 1.2 |
| Treatment (Enzalutamide, Mifepristone) | Testosterone | 21.0 ng/dL | Standard Error 6 |
p-value: 0.0012t-test, 2 sided
Secondary
Thyroid Stimulating Hormone
Change in log(TSH) from week 12 to week 16
Time frame: 12 to 16 weeks
Population: 13 patients in the enzalutamide arm and 2 patients in the enzalutamide plus mifepristone arm had missing data. Patients not randomized were not evaluated for changes in TSH.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Enzalutamide) | Thyroid Stimulating Hormone | -0.121 log(mcU/mL) | Standard Error 0.037 |
| Treatment (Enzalutamide, Mifepristone) | Thyroid Stimulating Hormone | 0.306 log(mcU/mL) | Standard Error 0.097 |
p-value: <0.0001t-test, 2 sided