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Abiraterone Acetate, Prednisone, Leuprolide, Niraparib, and Stereotactic Body Radiotherapy for the Treatment of High Risk or Node Positive Prostate Cancer, The ASCLEPIuS Trial

Trial Status: Approved

This phase I / II trial investigates the best dose of niraparib and how well it works when given together with abiraterone acetate, prednisone, leuprolide, and stereotactic body radiotherapy in treating patients with high risk or node positive prostate cancer. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as niraparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Abiraterone acetate and leuprolide may fight prostate cancer by lowering the amount of testosterone made by the body. Anti-inflammatory drugs, such as prednisone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Stereotactic body radiotherapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving niraparib together with abiraterone acetate, prednisone, leuprolide and stereotactic body radiotherapy may kill more tumor cells.

Inclusion Criteria

  • Pathologic biopsy proven adenocarcinoma of the prostate
  • Need >= 1 criteria: • cN1 on conventional or positron emission tomography (PET) imaging • Grade group 5 • Grade group 4 and PSA >= 10 ng/mL • Grade group 3 and PSA >= 20 ng/mL • High probability of radiographic T3 on magnetic resonance imaging (MRI) AND grade group >= 2 • Grade group 3 AND PSA >= 10 ng/mL AND >= 50% positive biopsy cores
  • Eastern Cooperative Oncology Group (ECOG) =< 1
  • Total bilirubin =< 1.5 times the upper institutional limit of normal [ULN] OR direct bilirubin =< 1 x 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
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN
  • Creatinine =< 1.5 x ULN
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000 / mcL
  • Albumin >= 3.0 g/dL
  • Potassium >= 3.5 mmol/L
  • 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
  • International Prostate Symptoms Score (IPSS) =< 20
  • Medically fit for treatment and agreeable to follow-up
  • Ability to understand and the willingness to sign a written informed consent
  • Tissue available for MiOncoSeq testing to assign DNA repair deficiency status

Exclusion Criteria

  • Clinical or radiographic evidence of distant metastatic disease by computed tomography (CT)/bone scan
  • Clinical or radiographic evidence of high probability of clinical T4 disease
  • Prostate gland size > 80 cc measured by ultrasound or MRI
  • Prominent median lobe assessed by treating physician
  • Lack of tissue from biopsy to be sent for correlative studies
  • Any prior treatment for prostate cancer (includes transurethral resection of prostate [TURP], chemotherapy, radiation therapy, or anti-androgen therapy)
  • Prohibited within 30 days prior to administration to study treatment: spironolactone and other investigational drug therapies.
  • 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
  • History of prior pelvic radiation therapy
  • Concurrent treatment with strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
  • Enrollment concurrently in another investigational drug study within 1 month of registration
  • History of another active malignancy within the previous 3 years except for adequately treated skin cancer or superficial bladder cancer
  • History of or active Crohn’s disease or ulcerative colitis
  • Contraindication to or inability to tolerate MRIs
  • Patients with severe depression
  • Uncontrolled diabetes or known glycosylated hemoglobin A1C (HbA1c) >= 10
  • Any gastrointestinal disorder affecting absorption
  • Active pituitary or adrenal dysfunction
  • 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)
  • Uncontrolled hypertension with persistently elevated systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite anti-hypertensive agents
  • Prolonged corrected QT (QTc) > 450 ms or any electrocardiogram (ECG) changes that interfere with QT interval interpretation
  • Major surgery within 1 month of registration
  • History of myelodysplastic syndrome or leukemia
  • A known hypersensitivity to niraparib, abiraterone acetate, leuprolide, and/or prednisone
  • Active infection or other medical condition that would be a contraindication to prednisone use
  • Patients with known active hepatitis or chronic liver disease including cirrhosis
  • Any condition that in the opinion of the investigator would preclude participation in this study

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: APPROVED
Contact: Daniel Eidelberg Spratt
Phone: 734-936-9630

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose for niraparib tosylate monohydrate (niraparib) when administered with abiraterone acetate (abiraterone), prednisone, leuprolide, and prostate stereotactic body radiotherapy (SBRT).

II. To determine the 3-year rate of biochemical failure following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

SECONDARY OBJECTIVES:

I. To determine the rate of obtaining an undetectable post-treatment prostate specific antigen (PSA) following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

II. To determine the rate of persistently positive 2-year post treatment prostate biopsies following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

III. To describe acute and late treatment toxicity following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

IV. To describe post treatment patient reported quality of life following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

V. To determine the cumulative incidence of distant metastases and prostate cancer-specific survival following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

VI. To determine overall survival following treatment with prostate SBRT, niraparib, abiraterone, prednisone, and leuprolide.

VII. To determine PSA nadir, undetectable PSA post-treatment, 2-year post-treatment biopsy rate, and 3-year biochemical relapse-free survival (bRFS) by deoxyribonucleic acid (DNA) repair alteration status.

VIII. To determine PSA nadir, undetectable PSA post-treatment, 2-year post-treatment biopsy rate, and 3-year bRFS by androgen receptor (AR)-activity status.

EXPLORATORY OBJECTIVE:

I. To correlate DNA, ribonucleic acid (RNA), and circulating biomarkers with oncologic endpoints of response to treatment.

OUTLINE: This is a phase I, dose-escalation study of niraparib, followed by a phase II study.

Patients receive niraparib orally (PO) once daily (QD) on days 1-28 but held 5 days prior to SBRT, during SBRT, and 5 days after the last fraction of SBRT for lower doses. Patients also receive abiraterone acetate PO QD and prednisone PO twice daily (BID) on days 1-28, and leuprolide intramuscularly (IM) on day 1 of cycles 1 and 4. Beginning day 5 of cycle 4, patients undergo SBRT in 5 or 6 fractions on alternating days over 3 weeks. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After initiation of study treatment, patients are followed up every 3 months for 1 year, then every 4-6 months for 1 year, and then every 6 months for 3 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Daniel Eidelberg Spratt

  • Primary ID UMCC 2019.117
  • Secondary IDs NCI-2020-04465
  • Clinicaltrials.gov ID NCT04194554