Testing the Effects of Low Dose Apalutamide on Prostate-Specific Antigen (PSA) Levels in Men Scheduled for Removal of the Prostate Gland
Study Details
Study Description
Brief Summary
This phase IIa trial investigates how well apalutamide before surgery works in treating patients with prostate cancer that is confined to the prostate gland. Testosterone can cause the growth of prostate cancer cells. Apalutamide blocks the use of testosterone by the tumor cells. Giving low dose apalutamide before prostate surgery may lead to lowered PSA levels in men with prostate cancer that is confined to the prostate gland.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- 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:
- 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:
The first 40 patients taking part in this trial receive apalutamide orally (PO) three times a week (TIW) for 4-8 weeks prior to before prostate surgery in the absence of disease progression or unacceptable toxicity. Based on PSA levels of the first 40 patients, the next group of 40 patients receive apalutamide either once a week (QW) or once daily (QD) for 4-8 weeks prior to before prostate surgery in the absence of disease progression or unacceptable toxicity. Patients may receive apalutamide for up to 4 to 12 weeks before prostate surgery (in the event surgery is delayed).
After completion of study treatment, patients are followed up at 7-14 days after prostate surgery.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (apalutamide) The first 40 patients taking part in this trial receive apalutamide PO QD TIW (on Monday, Wednesday, and Friday) for 4-8 weeks prior to before prostate surgery in the absence of disease progression or unacceptable toxicity. Based on PSA levels of the first 40 patients, the next group of 40 patients receive apalutamide either QW or QD for 4-8 weeks prior to before prostate surgery in the absence of disease progression or unacceptable toxicity. Patients may receive apalutamide for up to 4 to 12 weeks before prostate surgery (in the event surgery is delayed). |
Drug: Apalutamide
Given PO
Other Names:
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in prostate specific antigen (PSA) levels [Baseline up to end of treatment]
The proportion of participants with >= 25% decline in PSA levels (from baseline to end-of-intervention) will be determined for each dose cohort. Paired t test will be performed on the changes in PSA to evaluate the effects of low dose apalutamide for each dose group. The dose level of the second dose group can be higher than the first dose group (i.e. does escalation). Therefore, we conservatively use Bonferroni correction to control for multiple comparisons for the primary endpoint analysis since a gate-keeping procedure based on the test result of the first dose group will be inappropriate when does escalation occurs.
Secondary Outcome Measures
- Reversibility of testosterone levels [Baseline, and at 7-14 days post-intervention (post-operative)]
The post-operative testosterone levels will be compared with the levels at baseline and end-of-intervention within each dose cohort. Paired t test will be performed on the changes in testosterone to evaluate the effects of low dose apalutamide for each dose group. A 95% CI will be reported for each of the two dose groups.
- Post-intervention plasma trough apalutamide concentrations [Up to 7-14 days after prostate surgery]
Post-intervention plasma trough apalutamide concentrations will be quantified by a sensitive and specific liquid chromatography mass spectrometry assay. The correlation between plasma trough apalutamide and the change of PSA levels will be assessed. Pearson correlation coefficient will be derived to evaluate the correlation between the plasma trough apalutamide levels and the change of PSA levels. A 95% CI will be reported for each of the two dose groups.
- Health-related quality of life (HRQOL) [Baseline, until end of intervention]
HRQOL will be assessed by a validated questionnaire (Expanded Prostate Cancer Index Composite for Clinical Practice [EPIC-CP]) to allow for efficient and accurate measurement of urinary incontinence, urinary irritation, bowel, sexual, and hormonal HRQOL in prostate cancer patients. Changes (from baseline to end-of-intervention) in the overall score and subscore for each measure will be assessed for each dose group. Changes in EPIC-CP (from baseline to end-of-intervention) in the overall score and sub-score for each measure will be derived and paired t test will be performed to evaluate the change for each dose group. A 95% CI will be reported for each of the two dose groups.
Other Outcome Measures
- Gleason score of pre- and post-intervention tumor(s) with matched location [Up to 7-14 days after prostate surgery]
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 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% CI will be reported for each of the two dose groups.
- Intra-prostatic immune cell infiltration [Up to 7-14 days after prostate surgery]
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 cell infiltration will also be assessed in a subgroup of participants where materials are available from pre- and post-intervention tumor(s) 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% CI will be reported for each of the two dose groups.
- Effects of tobacco/alcohol use [Baseline, every 7-10 during study, within 3 days prior to surgery, and 7-14 days after surgery]
Will be assessed by examining the associations between tobacco and alcohol consumption and the effects of apalutamide on the study endpoints.
Eligibility Criteria
Criteria
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
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Karnofsky >= 70%
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Leukocytes >= 3,000/uL
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Absolute neutrophil count >= 1,500/uL
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Platelets >= 100,000/uL
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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
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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
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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
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Patients who have prostate cancer with distant metastases
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Presence of neuroendocrine differentiation in the prostate biopsies
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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
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Have a history of prior malignancies other than prostate cancer within the past 2 years, excluding non-melanoma skin cancer
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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
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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)
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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)
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Concurrent use of drugs in category X drug interactions with apalutamide
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Participants may not be receiving any other investigational agents
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History of allergic reactions attributed to compounds of similar chemical composition of apalutamide
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Arizona Cancer Center - Prevention Research Clinic | Tucson | Arizona | United States | 85719 |
| 2 | USC / Norris Comprehensive Cancer Center | Los Angeles | California | United States | 90033 |
| 3 | UC San Diego Medical Center - Hillcrest | San Diego | California | United States | 92103 |
| 4 | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland | United States | 21287 |
| 5 | NCI - Center for Cancer Research | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Juan Chipollini, University of Arizona Cancer Center - Prevention Research Clinic
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2020-06322
- NCI-2020-06322
- 2102475889
- UAZ20-01-01
- P30CA023074
- UG1CA242596