ASCLEPIuS: A Multi-Center Trial of Androgen Suppression With Abiraterone Acetate, Leuprolide, PARP Inhibition and Stereotactic Body Radiotherapy in Prostate Cancer
Study Details
Study Description
Brief Summary
The purpose of this study is to establish the maximum tolerable dose of niraparib when combined with prostate stereotactic body radiotherapy (SBRT), abiraterone, leuprolide, and prednisone (the phase 1 portion of the study) and determine 3-year biochemical PSA recurrence free-survival with this treatment approach (the phase 2 portion of the study).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Niraparid Dose Escalation Dose Level 1: 100 mg PO daily of Niraparib but held for 5 days (+/- 2 days) prior to RT, during SBRT, and 5 days (+/- 2 days) after last fraction of SBRT Dose Level 2: 200 mg PO daily of Niraparib but held for 5 days (+/- 2 days) prior to RT, during SBRT, and 5 days (+/- 2 days) after last fraction of SBRT Dose Level 3: 200 mg PO daily of Niraparib without breaks during SBRT until completion of 6 cycles. |
Drug: Niraparib
given PO per dose escalation schedule
Drug: Leuprolide
22.5 mg q3 month
Drug: Abiraterone Acetate
1000 mg daily
Radiation: Stereotactic body radiotherapy (SBRT)
5-6 fraction SBRT (total dose: 37.5-40 Gy)
Other Names:
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Outcome Measures
Primary Outcome Measures
- Dose-limiting toxicities (Phase 1) [Up to 112 days after initial dose of niraparib]
The proportion of patients at each dose level with dose-limiting toxicity (DLT), defined as any treatment related grade 3-5 adverse event experienced within the first 4 treatment cycles (112 days), assessed per NCI's CTCAE version 5.0.
- Proportion of patients experiencing biochemical failure [Up to 3 years after first dose of niraparib]
Change in PSA level from the beginning of study treatment for up to 3 years later will determine the biochemical failure rate. Biochemical failure will be defined using the Phoenix definition of the PSA nadir + 2 ng/mL.
Secondary Outcome Measures
- Change in health related quality of life [From baseline up to 3 years after last dose of niraparib]
Assessed via EPIC-26 questionnaire
- Proportion of patients with undetectable post-treatment PSA [Measured during the end of the 6th cycle of therapy (during week 24 +/- 7 days)]
Undetectable PSA will be defined as a PSA ≤0.1 ng/mL.
- Proportion of patients with distant metastases [Up to 5 years after first dose of niraparib]
Distant metastases will be defined as any clinical or radiographic evidence of lymph node, bone, or visceral involvement of prostate cancer.
- Prostate cancer specific survival [Up to 5 years after first dose of niraparib]
Prostate cancer specific survival will be defined as the duration of time from the start of treatment to death attributable to prostate cancer. Patients who have not died or die of non-prostate cancer related causes will be censored at the last known follow-up or date of death, respectively. Summarized using cumulative incidence or Kaplan-Meier curves as appropriate.
- Overall survival [Up to 5 years after first dose of niraparib]
Overall survival (OS) will be defined as the duration of time from the start of treatment to death from any cause. Patients who have not died will be censored at the last known follow-up.Summarized using cumulative incidence or Kaplan-Meier curves as appropriate.
Eligibility Criteria
Criteria
Inclusion Criteria
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Pathologic biopsy proven adenocarcinoma of the prostate
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At least one of the following criteria:
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cN1 on conventional or PET imaging
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Grade group 5
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Grade group 4 and PSA ≥10 ng/mL
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Grade group 3 and PSA ≥20 ng/mL
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High probability of Radiographic T3 on MRI AND Grade group ≥2
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Grade Group 3 AND PSA ≥10 ng/mL AND ≥50% positive biopsy cores
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Age ≥ 18
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ECOG < 1
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Adequate organ and marrow function as defined per protocol.
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Use of highly effective contraception (e.g. condoms) for the duration of treatment and a minimum of 90 days thereafter. Men must also agree not to donate sperm for the duration of the study participation, and for at least 90 days thereafter.
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International Prostate Symptoms Score (IPSS) ≤ 20
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Medically fit for treatment and agreeable to follow-up
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Ability to understand and the willingness to sign a written informed consent
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Tissue available for MiOncoSeq testing to assign DNA repair deficiency status
Exclusion Criteria
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Clinical or radiographic evidence of distant metastatic disease by CT/bone scan
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Clinical or radiographic evidence of high probability of clinical T4 disease
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Prostate gland size >80 cc measured by ultrasound or MRI
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Prominent median lobe assessed by treating physician
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Lack of tissue from biopsy to be sent for correlative studies
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Any prior treatment for prostate cancer (incudes TURP, chemotherapy, radiation therapy, or anti-androgen therapy)
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Prohibited within 30 days prior to administration to study treatment: spironolactone and other investigational drug therapies.
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Prohibited 3 months before participant registration and during administration of study treatment: non-steroidal anti-androgens (e.g., bicalutamide, flutamide, nilutamide), steroidal antiandrogens (megestrol acetate, cyproterone acetate), oral ketoconazole, chemotherapy, immunotherapy, estrogens, radiopharmaceuticals.
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History of prior pelvic radiation therapy
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Concurrent treatment with strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
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Enrollment concurrently in another investigational drug study within 1 month of registration
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History of another active malignancy within the previous 3 years except for adequately treated skin cancer or superficial bladder cancer
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History of or active Crohn's disease or ulcerative colitis
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Contraindication to or inability to tolerate MRIs
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Patients with severe depression
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Uncontrolled diabetes or known HbA1c>10
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Any gastrointestinal disorder affecting absorption
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Active pituitary or adrenal dysfunction
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Patients with significant cardiovascular disease potentially including severe / unstable angina, recent history of myocardial infarction, clinically significant heart failure, cerebrovascular disease, venous thromboembolic events, clinically significant arrhythmias)
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Uncontrolled hypertension with persistently elevated systolic blood pressure >160 mmgHg or diastolic blood pressure >100 mmHg despite anti-hypertensive agents.
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Prolonged QTc >450 ms or any ECG changes that interfere with QT interval interpretation
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Major surgery within 1 month of registration
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History of myelodysplastic syndrome or leukemia
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A known hypersensitivity to niraparib, abiraterone acetate, leuprolide, and/or prednisone
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Active infection or other medical condition that would be a contraindication to prednisone use
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Patients with known active hepatitis or chronic liver disease including cirrhosis
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Any condition that in the opinion of the investigator would preclude participation in this study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Michigan Rogel Cancer Center | Ann Arbor | Michigan | United States | 48109 |
| 2 | Weill Cornell Medicine | New York | New York | United States | 10065 |
| 3 | University Hospitals Seidman Cancer Center | Cleveland | Ohio | United States | 44106 |
| 4 | University of Texas Southwestern | Dallas | Texas | United States | 75390 |
Sponsors and Collaborators
- University of Michigan Rogel Cancer Center
- Janssen Scientific Affairs, LLC
Investigators
- Study Chair: Daniel Spratt, M.D., Case Western Reserve University - Seidman Comprehensive Cancer Center
- Principal Investigator: William Jackson, M.D., University of Michigan Rogel Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UMCC 2019.117
- HUM00167325