A Multi-Center Trial of Androgen Suppression With Abiraterone Acetate, Leuprolide, PARP Inhibition and Stereotactic Body Radiotherapy in Prostate Cancer (ASCLEPIuS)

• ClinicalTrials.gov Identifier: NCT04194554
• Recruitment Status: Recruiting
• First Posted: December 11, 2019
• Last Update Posted: October 19, 2022
• Sponsor: University of Michigan Rogel Cancer Center
• Collaborator: Janssen Scientific Affairs, LLC
• Information provided by (Responsible Party): University of Michigan Rogel Cancer Center

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
Prostate Cancer	Drug: Niraparib; Drug: Leuprolide; Drug: Abiraterone Acetate; Radiation: Stereotactic body radiotherapy (SBRT)	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Time to Event Continual Reassessment Method (TITE-CRM) dose-finding clinical trial design.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center Trial of Androgen Suppression With Abiraterone aCetate, LEuprolide, PARP Inhibition and Stereotactic Body Radiotherapy (ASCLEPIuS): A Phase I/2 Trial in High Risk and Node Positive Prostate Cancer
• Actual Study Start Date: November 6, 2020
• Estimated Primary Completion Date: November 2026
• Estimated Study Completion Date: May 2027

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 Name: Ultra-hypofractionated radiotherapy

Outcome Measures

Primary Outcome Measures :

1. Dose-limiting toxicities (Phase 1) [ Time Frame: 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.
2. Proportion of patients experiencing biochemical failure [ Time Frame: 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 :

1. Change in health related quality of life [ Time Frame: From baseline up to 3 years after last dose of niraparib ]
   Assessed via EPIC-26 questionnaire
2. Proportion of patients with undetectable post-treatment PSA [ Time Frame: 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.
3. Proportion of patients with distant metastases [ Time Frame: 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.
4. Prostate cancer specific survival [ Time Frame: 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.
5. Overall survival [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

1. Pathologic biopsy proven adenocarcinoma of the prostate

2. At least one of the following criteria:

   • cN1 on conventional or PET imaging
   • Grade group 5
   • Grade group 4
   • Grade group 3 and PSA ≥20 ng/mL
   • High probability of Radiographic T3 on MRI AND Grade group ≥2
   • Grade Group 3 AND PSA ≥10 ng/mL AND ≥50% positive biopsy cores
3. Age ≥ 18
4. ECOG < 1
5. Adequate organ and marrow function as defined per protocol.
6. 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.
7. International Prostate Symptoms Score (IPSS) ≤ 20
8. Medically fit for treatment and agreeable to follow-up
9. Ability to understand and the willingness to sign a written informed consent
10. Tissue available for MiOncoSeq testing to assign DNA repair deficiency status

Exclusion Criteria

1. Clinical or radiographic evidence of distant metastatic disease by CT/bone scan
2. Clinical or radiographic evidence of high probability of clinical T4 disease
3. Prostate gland size >80 cc measured by ultrasound or MRI
4. Prominent median lobe assessed by treating physician
5. Lack of tissue from biopsy to be sent for correlative studies
6. Any prior treatment for prostate cancer (incudes history of TURP within 5 years of enrollment, chemotherapy, radiation therapy, or anti-androgen therapy)
7. Prohibited within 30 days prior to administration to study treatment: spironolactone and other investigational drug therapies.
8. 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.
9. History of prior pelvic radiation therapy
10. Concurrent treatment with strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
11. Enrollment concurrently in another investigational drug study within 1 month of registration
12. History of another active malignancy within the previous 3 years except for adequately treated skin cancer or superficial bladder cancer
13. History of or active Crohn's disease or ulcerative colitis
14. Contraindication to or inability to tolerate MRIs
15. Patients with severe depression
16. Uncontrolled diabetes or known HbA1c>10
17. Any gastrointestinal disorder affecting absorption
18. Active pituitary or adrenal dysfunction
19. 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)
20. Uncontrolled hypertension with persistently elevated systolic blood pressure >160 mmgHg or diastolic blood pressure >100 mmHg despite anti-hypertensive agents.
21. Prolonged QTc >450 ms or any ECG changes that interfere with QT interval interpretation
22. Major surgery within 1 month of registration
23. History of myelodysplastic syndrome or leukemia
24. A known hypersensitivity to niraparib, abiraterone acetate, leuprolide, and/or prednisone
25. Active infection or other medical condition that would be a contraindication to prednisone use
26. Patients with known active hepatitis or chronic liver disease including cirrhosis
27. Any condition that in the opinion of the investigator would preclude participation in this study

Contacts and Locations

Contacts

Contact: UM Cancer AnswerLine; 800-865-1125; CancerAnswerLine@med.umich.edu

Locations

United States, Michigan

University of Michigan Rogel Cancer Center; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Cancer AnswerLine 800-865-1125 CancerAnswerLine@med.umich.edu

Principal Investigator: William Jackson, M.D.

United States, New York

Weill Cornell Medicine; Recruiting

New York, New York, United States, 10065

Contact: Sharanya Chandrasekhar, M.S. 646-962-2196 shc2043@med.cornell.edu

Contact: Pragya Yadav, Ph.D. 646-962-2199 pry2003@med.cornell.edu

Principal Investigator: Himanshu Nagar, M.D.

United States, Ohio

University Hospitals Seidman Cancer Center; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Daniel Spratt, MD 216-293-6191 Daniel.Spratt@UHHospitals.org

Principal Investigator: Daniel Spratt, MD

United States, Texas

University of Texas Southwestern; Recruiting

Dallas, Texas, United States, 75390

Contact: Cancer AnswerLine at UTSW 833-722-6237 canceranswerline@utsouthwestern.edu

Principal Investigator: Neil Desai, MD, MHS

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

More Information

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT04194554
• Other Study ID Numbers: UMCC 2019.117; HUM00167325 ( Other Identifier: University of Michigan )
• First Posted: December 11, 2019
• Last Update Posted: October 19, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data that may be shared will only include individual participant data that underlie the results reported publicly in ClinicalTrials.gov or published articles, after deidentification (text, tables, figures, appendices).
• Supporting Materials: Study Protocol
• Time Frame: The time frame for data sharing will begin 12 months after the initial publication and continue until 36 months after publication in ClinicalTrials.gov.
• Access Criteria: Once the final results of the trial have been reported parties interested in accessing the data should contact the trial PI (Dr. Daniel Spratt) to discuss any potential data sharing requests. An analysis plan is required and intended use of the data must be disclosed. Only de-identified data may be shared and all agreements must comply with current policies of both parties to share data.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Leuprolide; Abiraterone Acetate; Niraparib; Fertility Agents, Female; Fertility Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors