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.
Recruiting
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Apalutamide | ARN 509, ARN-509, ARN509, Erleada, JNJ 56021927, JNJ-56021927 | Treatment (apalutamide) |
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. Intra-prostatic immune cell infiltration. Id. Health-related quality of
life. Ie. Gleason score of pre- and post-intervention tumor(s) with matched location.
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 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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Treatment (apalutamide) | Experimental | The first 40 patients taking part in this trial receive apalutamide PO 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 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 12 weeks before prostate surgery (in the event surgery is delayed). |
|
Inclusion Criteria:
- Histologically confirmed organ-confined adenocarcinoma of the prostate (PCa) suitable
for prostatectomy
- Gleason score =< (4+4)
- Current serum PSA < 10 ng/ml OR PSA >= 10 ng/ml with PSA density < 0.3 ng/ml^2.
- 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 and for 3 months following the last dose of study
drug; must also agree not to donate sperm during the study and for 3 months after
receiving the last dose of study drug
- 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) < 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Male |
| Healthy Volunteers: | No |
| Measure: | Change in prostate specific antigen (PSA) levels |
| Time Frame: | Baseline up to end of treatment |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Reversibility of testosterone levels |
| Time Frame: | Baseline, and at 7-14 days post-intervention (post-operative) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-intervention plasma trough apalutamide concentrations |
| Time Frame: | Up to 7-14 days after prostate surgery |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Intra-prostatic immune cell infiltration |
| Time Frame: | Up to 7-14 days after prostate surgery |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Health-related quality of life (HRQOL) |
| Time Frame: | Baseline, until end of intervention |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Gleason score of pre- and post-intervention tumor(s) with matched location |
| Time Frame: | Up to 7-14 days after prostate surgery |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Incidence of adverse events |
| Time Frame: | From the time of first dose of apalutamide, up to 7-14 days after prostate surgery |
| Safety Issue: | |
| Description: | Descriptive statistics of the type and frequency of all adverse events will be generated, including 95% confidence intervals. |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | National Cancer Institute (NCI) |
August 3, 2021
