Prostate Cancer
Conditions
Keywords
metastatic, castrate resistant
Brief summary
The primary goal is to prospectively estimate the median PFS of African American and Caucasian men with mCRPC taking apalutamide, abiraterone acetate, and prednisone. Secondary objectives include: PSA kinetics: to determine the duration of PSA response, time to nadir, and percent of men who achieve a PSA \< 0.1; Radiographic assessments: to estimate the rate of objective response and incidence of bone flares; Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations. This is a non-comparative pilot open-label, parallel arm, multicenter study of apalutamide and abiraterone acetate in African American and Caucasian men with mCRPC. It is anticipated that 3 additional sites will be needed to accrue 100 subjects (50 African American and 50 Caucasian) over a 24 month accrual period. The study agents will be administerd at the following doses: apalutamide 240mg orally once daily, abiraterone acetate 1000mg orally once daily, and prednisone 5 mg BID in 4-week cycles throughout the treatment period. Fifty (50) patients will be enrolled in each group (AA and Caucasians). The proportion of patients who experience PSA decline of 30%, 50% and 90% will be estimated with exact 95% confidence intervals based on the binomial distribution will be computed. In addition, post therapy changes in PSA will be explored as a continuous outcome. The Kaplan-Meier product limit method will be used to estimate the rPFS, biochemical PFS and overall survival distributions.
Interventions
DRUGARN-509
240 mg orally daily
DRUGAbiraterone Acetate
1000 mg orally daily
DRUGPrednisone
5 mg orally twice daily (for total daily dose 10 mg)
Sponsors
Janssen Scientific Affairs, LLC
Daniel George, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male, age ≥ 18 years 2. Karnofsky performance status ≥ 70 (Appendix 1) 3. Life expectancy of ≥ 12 months as determined by treating investigator 4. Written Authorization for Use and Release of Health and Research Study Information (HIPAA authorization per institutional requirements) 5. Willing/able to adhere to the prohibitions and restrictions specified in this protocol 6. Willing to take abiraterone acetate on an empty stomach, and should be able to swallow tablets whole, without crushing/chewing tablets. Must have the ability to swallow, retain, and absorb oral medication. 7. Medications known to lower the seizure threshold (see list under prohibited meds, appendix 2) must be discontinued or substituted at least 4 weeks prior to study entry 8. Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug 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. Abstinence is an acceptable method of birth control. 9. Adequate bone marrow function as shown by: ANC ≥ 1.0 x 109/L, Platelets ≥ 100 x 109/L, Hb≥9 g/dL, (independent of transfusion and/or growth factors within 3 months prior to Cycle 1 Day 1) 10. Serum potassium ≥ 3.5 mEq/L 11. Serum albumin of ≥ 3.0 g/dl 12. AST/SGOT and ALT/SGPT \<2.5 x Institutional Upper Limit of Normal (ULN) 13. Serum total bilirubin ≤ 1.5 x Institutional ULN (Note: In subjects with Gilbert's syndrome, if total bilirubin is \>1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject may be eligible) 14. GFR ≥45 mL/min 15. Histologically confirmed diagnosis of adenocarcinoma of the prostate. Histologic variants of prostate cancer comprising of \>50% of the tumor including neuroendocrine features and small cell carcinoma of the prostate are excluded. 16. Radiographic evidence of metastatic disease based on RECIST 1.1 Criteria OR by prostate cancer-specific PET imaging. Evaluable non-target lesions and/or bone only metastasis are permitted per RECIST 1.1 and PCWG3 guidelines. Non-target, pathological lymph nodes ≥ 10 mm and less than 15 mm in the short axis are permitted. 17. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed. 18. PSA ≥ 2.0 ng/mL 19. Evidence of castration resistant disease in the setting of ongoing ADT (medical or surgical) as evidenced by one of the following: * Absolute rise in PSA of 2.0 ng/mL or an increase \>25% from the nadir, minimum 2 consecutive rising PSA levels with an interval of ≥ 1 week between each PSA level, OR * CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to PCWG3 criteria or RECIST 1.1 criteria, OR * At least 1 new bone scan lesion as compared to the most immediate prior radiologic studies. 20. A minimum of 2 weeks elapsed off of antiandrogen therapy prior to start of study drug (i.e. flutamide, nilutamide, bicalutamide.) 21. A minimum of 2 weeks elapsed off of sipuleucel-T and radiation therapy prior to start of study drug 22. A minimum of 4 weeks from any major surgery prior to start of study drug. 23. Self-reported race of either African American or Caucasian. 24. Ability to understand and the willingness to sign a written informed consent document. If the subject is unable to understand the consent due to comorbidity, such as Alzheimer's disease, consent by a legally authorized representative and assent by the subject will be obtained.
Exclusion criteria
1. Prior treatment with abiraterone acetate, enzalutamide, apalutamide (ARN-509), galaterone (TOK-001), orteronel (TAK-700), or similar agent 2. Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated 3. Active or symptomatic infection including HIV, viral hepatitis or chronic liver disease 4. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid 5. Have known allergies, hypersensitivity, or intolerance to abiraterone acetate, apalutamide or prednisone or their excipients. 6. Pathological finding consistent with small cell carcinoma of the prostate 7. Symptomatic liver or visceral organ metastasis 8. Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents 9. Known brain metastasis 10. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC. Note: sipulecel-T is permitted with a 2-week washout. 11. Previously treated with ketoconazole for prostate cancer for greater than 7 days 12. Prior systemic treatment with an azole anti-fungal drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1. 13. Uncontrolled hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment 14. Poorly controlled diabetes, FBS ≥200 mg/dL 15. History of pituitary or adrenal dysfunction 16. Symptomatic Atrial Fibrillation, or other symptomatic cardiac arrhythmia 17. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of recurrence within 24 months 18. History of any of the following: * Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 6 months of Cycle 1 Day 1, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy) * 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 first dose of study drug. Venous thrombolic events within 6 months are permitted IF they are not attributed to prostate cancer (in the opinion of the treating physician). 19. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. 20. Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate 21. Baseline moderate or severe hepatic impairment (Child Pugh Class B & C) 22. Use of herbal products that may decrease PSA levels (i.e., saw palmetto) refer to section 8.3.2 (no washout period required) 23. Administration of an investigational therapeutic within 30 days prior to Cycle 1, Day 1 24. Any condition which, in the opinion of the investigator, would preclude participation in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 2-Year Progression-Free Survival (PFS) | every 12 weeks, up to 2 years | Radiographic PFS based on PCWG2 criteria or based on the onset of a skeletal related event. Imaging obtained every 12 weeks. Kaplan-Meier estimate of percentage of participants is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to PSA Nadir | every 4 weeks, up to 2 years | Time to PSA nadir |
| Percent of Men Who Achieve a PSA < 0.1 | every 4 weeks, up to 2 years | Percent of men who achieve a PSA \< 0.1 |
| Radiologic Response Rates | every 12 weeks, up to 2 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions assessed by CT: Complete Response (CR), disappearance of all lesions and any pathologic lymph nodes (target or non-target) must have reduction in short axis to \<10 mm; Partial Response (PR), ≥30% decrease in the sum diameter of target lesions as compared to the baseline sum diameter; Overall Response (OR) = CR + PR |
| 2-year PSA Progression Free Survival | every 4 weeks, up to 2 years | PSA progression-free survival |
| Percentage of Participants With Hypertension | up to 2 years | Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations. Grade assessed according to NCI CTC v4.0 with higher grade being worse is reported. |
| Median Overall Survival | every 6 months, up to 82 months | Survival of subjects over the time the study is ongoing |
| Percentage of Participants With Bone Flares | 12 weeks | Percentage of participants who experienced bone flares per radiographic assessments |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Caucasian Self-identified Caucasian patients with mCRPC | 50 |
| African American Self-identified African American patients with mCRPC | 43 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Lack of Efficacy | 30 | 15 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Caucasian | Total | African American |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 7 | 70 years STANDARD_DEVIATION 9 | 70 years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 93 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 43 Participants | 43 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 50 Participants | 50 Participants | 0 Participants |
| Region of Enrollment United States | 50 participants | 93 participants | 43 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 50 Participants | 93 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 34 / 50 | 20 / 43 |
| other Total, other adverse events | 50 / 50 | 43 / 43 |
| serious Total, serious adverse events | 12 / 50 | 10 / 43 |
Outcome results
Primary
Percentage of Participants With 2-Year Progression-Free Survival (PFS)
Radiographic PFS based on PCWG2 criteria or based on the onset of a skeletal related event. Imaging obtained every 12 weeks. Kaplan-Meier estimate of percentage of participants is reported.
Time frame: every 12 weeks, up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caucasian | Percentage of Participants With 2-Year Progression-Free Survival (PFS) | 38 Percentage of participants |
| African American | Percentage of Participants With 2-Year Progression-Free Survival (PFS) | 61 Percentage of participants |
Secondary
2-year PSA Progression Free Survival
PSA progression-free survival
Time frame: every 4 weeks, up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caucasian | 2-year PSA Progression Free Survival | 38 percent |
| African American | 2-year PSA Progression Free Survival | 60 percent |
Secondary
Median Overall Survival
Survival of subjects over the time the study is ongoing
Time frame: every 6 months, up to 82 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Caucasian | Median Overall Survival | 36 months |
| African American | Median Overall Survival | 72 months |
Secondary
Percentage of Participants With Bone Flares
Percentage of participants who experienced bone flares per radiographic assessments
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caucasian | Percentage of Participants With Bone Flares | 16 percent |
| African American | Percentage of Participants With Bone Flares | 9 percent |
Secondary
Percentage of Participants With Hypertension
Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations. Grade assessed according to NCI CTC v4.0 with higher grade being worse is reported.
Time frame: up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Caucasian | Percentage of Participants With Hypertension | Grade 2 hypertension | 40 percent of participants |
| Caucasian | Percentage of Participants With Hypertension | Grade 3 hypertension | 16 percent of participants |
| Caucasian | Percentage of Participants With Hypertension | Grade 4 hypertension | 0 percent of participants |
| African American | Percentage of Participants With Hypertension | Grade 2 hypertension | 40 percent of participants |
| African American | Percentage of Participants With Hypertension | Grade 3 hypertension | 14 percent of participants |
| African American | Percentage of Participants With Hypertension | Grade 4 hypertension | 2 percent of participants |
Secondary
Percent of Men Who Achieve a PSA < 0.1
Percent of men who achieve a PSA \< 0.1
Time frame: every 4 weeks, up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caucasian | Percent of Men Who Achieve a PSA < 0.1 | 26 percent of participant |
| African American | Percent of Men Who Achieve a PSA < 0.1 | 40 percent of participant |
Secondary
Radiologic Response Rates
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions assessed by CT: Complete Response (CR), disappearance of all lesions and any pathologic lymph nodes (target or non-target) must have reduction in short axis to \<10 mm; Partial Response (PR), ≥30% decrease in the sum diameter of target lesions as compared to the baseline sum diameter; Overall Response (OR) = CR + PR
Time frame: every 12 weeks, up to 2 years
Population: Four patients were unevaluable. Two patients did not have response recorded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caucasian | Radiologic Response Rates | 10 percent |
| African American | Radiologic Response Rates | 14 percent |
Secondary
Time to PSA Nadir
Time to PSA nadir
Time frame: every 4 weeks, up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Caucasian | Time to PSA Nadir | 1.9 months |
| African American | Time to PSA Nadir | 5.3 months |