Localized Prostate Carcinoma, Prostate Adenocarcinoma, Stage II Prostate Cancer AJCC v8, Stage I Prostate Cancer AJCC v8
Conditions
Brief summary
Apalutamide is an anti-androgen that blocks the effect of testosterone on prostate cancer growth. This phase IIa trial is designed to determine whether very low doses of apalutamide, given for 3 to 4 weeks before prostate surgery to men with prostate cancer confined to the prostate gland, reduces plasma levels of PSA (a biomarker of apalutamide's ability to block testosterone). If low dose apalutamide lowers PSA levels in this setting, further study of this agent in men with localized prostate cancer who wish to delay definitive therapy with surgery or radiation may be warranted.
Detailed description
PRIMARY OBJECTIVE: I. To determine the effects of low dose apalutamide on circulating levels of prostate specific antigen (PSA). SECONDARY OBJECTIVES: I. To determine the effect of low dose apalutamide on: Ia. Reversibility of testosterone levels 7-14 days post intervention; Ib. Post-intervention plasma trough apalutamide concentration; Ic. Health-related quality of life. EXPLORATORY OBJECTIVE: I. To determine the effects of apalutamide on intra-prostatic immune cell infiltration and Gleason score and the effects of tobacco/alcohol use on the study endpoints. OUTLINE: Patients receive apalutamide orally (PO) on study. Patients also undergo collection of blood samples throughout the study. After completion of the trial intervention, patients are followed up at 7-10 days and at 60 days.
Interventions
DRUGApalutamide
Given PO
PROCEDUREBiospecimen Collection
Undergo collection of blood samples
OTHERQuality-of-Life Assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed organ-confined adenocarcinoma of the prostate (PCa) suitable for prostatectomy * Gleason score =\< (4+4), however no Gleason pattern 5 * Current serum PSA =\< 20 ng/ml * Age \> 18 years * Karnofsky \>= 70% * Leukocytes \>= 3,000/uL * Absolute neutrophil count \>= 1,500/uL * Platelets \>= 100,000/uL * Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (note: in subjects with Gilbert's syndrome, if total bilirubin is \> 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =\< 1.5 x ULN, subject may be eligible) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \< 2.5 x institutional ULN * Creatinine \< 2 x institutional ULN * Thyroid stimulating hormone (TSH) within the institutional normal range * Willing to use adequate contraception (barrier method; abstinence; subject has had a vasectomy; or partner is using effective birth control or is postmenopausal) for the duration of study participation * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Prior or ongoing hormonal treatment for prostate cancer including, but not limited to orchiectomy, antiandrogens, abiraterone, ketoconazole, or estrogens, or luteinizing hormone-releasing hormone (LHRH) agonists/antagonists. Men on stable doses of 5-alpha reductase inhibitors (e.g., finasteride, dutasteride) are eligible as long as there is no planned dose change while on study * Patients who have prostate cancer with distant metastases * Presence of neuroendocrine differentiation in the prostate biopsies * Serum testosterone (blood collected between 7-10 AM for men \< 45 years of age and prior to 2 PM for men \>= 45 years of age) \< 200 ng/dL * Have a history of prior malignancies other than prostate cancer within the past 2 years, excluding non-melanoma skin cancer * Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to registration * History of seizure or known condition that may pre-dispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to registration, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect) * Use of drugs known to lower the seizure threshold, including: atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone), bupropion, lithium, meperidine, pethidine, phenothiazine antipsychotics (e.g. chlorpromazine, mesoridazine, thioridazine), and tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine) * Concurrent use of drugs in category X drug interactions with apalutamide * Participants may not be receiving any other investigational agents * History of allergic reactions attributed to compounds of similar chemical composition of apalutamide * Uncontrolled intermittent illnesses or medical conditions which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. Such illnesses/conditions may include, but are not limited to, hypertension, ongoing or active infection, or psychiatric illness/social situations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Prostate Specific Antigen (PSA) Levels | Baseline to end-of-intervention (mean 4.8 weeks; up to 9 weeks) | The proportion of participants with \>= 25% decline in PSA levels (from baseline to end-of-intervention) will be reported along with the 97.5% credible interval for the response rate based on the posterior distribution of the response rate derived from a non-informative prior for the response rate, which is consistent with the Bayesian approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reversibility of Testosterone Levels | End-of-intervention to post-operation (mean 2.7 days; up to 7 days) | Mean change in testosterone from end-of-intervention to post-operation |
| Post-intervention Plasma Trough Apalutamide Concentrations | End-of-intervention (mean 4.8 weeks; up to 9 weeks) | Correlation between plasma apalutamide and percent change of PSA levels |
| Health-related Quality of Life (HRQOL) | Baseline to end of intervention (mean 4.8 weeks; up to 9 weeks) | Expanded Prostate Cancer Index Composite for Clinical Practice \[EPIC-CP\]. Higher scores indicate worse outcome (more symptoms). The minimum and maximum values for the total score are 0 to 60. A negative change indicates that the score decreased and therefore is a better outcome (reduced symptoms). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJuan Chipollini
University of Arizona Cancer Center - Prevention Research Clinic
Participant flow
Recruitment details
All potential subjects were initially recruited into Cohort 1. Once it was determined that the dose would be de-escalated for the next phase of the trial, subsequent potential subjects were recruited into Cohort 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 60 mg apalutamide, 3x per week | 15 |
| Cohort 2 60 mg apalutamide, 1x per week | 17 |
| Total | 32 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 2 |
|---|---|---|---|
| Age, Continuous | 70.1 years | 68.1 years | 65.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 30 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Prostate specific antigen (PSA) | 6.3 ng/mL | 6.4 ng/mL | 7.9 ng/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 32 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 17 |
| other Total, other adverse events | 11 / 15 | 13 / 17 |
| serious Total, serious adverse events | 0 / 15 | 1 / 17 |
Outcome results
Primary
Change in Prostate Specific Antigen (PSA) Levels
The proportion of participants with \>= 25% decline in PSA levels (from baseline to end-of-intervention) will be reported along with the 97.5% credible interval for the response rate based on the posterior distribution of the response rate derived from a non-informative prior for the response rate, which is consistent with the Bayesian approach.
Time frame: Baseline to end-of-intervention (mean 4.8 weeks; up to 9 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Change in Prostate Specific Antigen (PSA) Levels | 10 Participants |
| Cohort 2 | Change in Prostate Specific Antigen (PSA) Levels | 7 Participants |
Comparison: Posterior probability of observing a response rate ≥ 50%
Comparison: Posterior probability of observing a response rate ≥ 25%
Secondary
Health-related Quality of Life (HRQOL)
Expanded Prostate Cancer Index Composite for Clinical Practice \[EPIC-CP\]. Higher scores indicate worse outcome (more symptoms). The minimum and maximum values for the total score are 0 to 60. A negative change indicates that the score decreased and therefore is a better outcome (reduced symptoms).
Time frame: Baseline to end of intervention (mean 4.8 weeks; up to 9 weeks)
Population: Missing data for overall score for one subject in each cohort
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Health-related Quality of Life (HRQOL) | 0.6 change in overall score | Standard Deviation 5.3 |
| Cohort 2 | Health-related Quality of Life (HRQOL) | -2.5 change in overall score | Standard Deviation 6.9 |
p-value: 0.658paired t-test
p-value: 0.167paired t-test
Secondary
Post-intervention Plasma Trough Apalutamide Concentrations
Correlation between plasma apalutamide and percent change of PSA levels
Time frame: End-of-intervention (mean 4.8 weeks; up to 9 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Post-intervention Plasma Trough Apalutamide Concentrations | 796.3 ng/mL | Standard Deviation 250.5 |
| Cohort 2 | Post-intervention Plasma Trough Apalutamide Concentrations | 212.4 ng/mL | Standard Deviation 90 |
Comparison: Correlation with % change PSA at end-of-interventionp-value: 1Pearson correlation
Comparison: Correlation with % change PSA at end-of-interventionp-value: 1Pearson correlation
Secondary
Reversibility of Testosterone Levels
Mean change in testosterone from end-of-intervention to post-operation
Time frame: End-of-intervention to post-operation (mean 2.7 days; up to 7 days)
Population: Missing testosterone data for one subject in Cohort 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Reversibility of Testosterone Levels | -136.1 ng/dL | Standard Deviation 195 |
| Cohort 2 | Reversibility of Testosterone Levels | -80.5 ng/dL | Standard Deviation 198.8 |
p-value: 0.034paired t-test
p-value: 0.252paired t-test
Other Pre-specified
Effects of Tobacco/Alcohol Use
Will be assessed by examining the associations between tobacco and alcohol consumption and the effects of apalutamide on the study endpoints.
Time frame: Baseline, every 7-10 during study, within 3 days prior to surgery, and 7-14 days after surgery
Other Pre-specified
Gleason Score of Pre- and Post-intervention Tumor(s) With Matched Location
Changes (from most recent biopsy to prostatectomy) in the Gleason score of pre- and post-intervention tumor(s) with matched location will be assessed for each dose group. Linear mixed effects model with a random intercept accounting for within-subject dependence will be performed to compare the change in Gleason score of pre- and post-intervention tumor(s) with matched location since a participant can have more than one tumor. A 95% Cl will be reported for each of the two dose groups.
Time frame: Up to 7-14 days after prostate surgery
Other Pre-specified
Intra-prostatic Immune Cell Infiltration
CD8+, CD4+, and CD56+ positive cells in the prostate tissues will be assessed by immunohistochemistry. Changes (from most recent biopsy to prostatectomy) in these immune cells will be assessed for each dose group. Changes in immune cel infiltration will also be assessed in a subgroup of participants where materials are available from pre- and post-intervention tumors) with matched location. Changes (from most recent biopsy to prostatectomy) in these immune cells will be assessed for each dose group by paired t test. A 95% Cl will be reported for each of the two dose groups.
Time frame: Up to 7-14 days after prostate surgery