Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects
Primary Purpose
ATM Gene Mutation, BRCA1 Gene Mutation, BRCA2 Gene Mutation
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Niraparib
Niraparib Tosylate Monohydrate
Radical Prostatectomy
Sponsored by
About this trial
This is an interventional treatment trial for ATM Gene Mutation
Eligibility Criteria
Inclusion Criteria:
- Ability to understand and willingness to sign an informed consent form
- Ability to adhere to the study visit schedule and other protocol requirements
- Patients must have histologically or cytologically confirmed prostate cancer that is clinically localized as defined by negative cross-section imaging and/or bone scan, and classified as high or very high risk per National Comprehensive Cancer Network (NCCN) guideline
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1
- Life expectancy >= 10 years
- Men who have selected radical prostatectomy as the primary treatment for their prostate cancer
- Prostate cancer tumors with alterations in key DNA repair genes. This will include at least one alteration in a gene involved in DNA repair primarily through the homologous recombination pathway including BRCA1/2, ATM, CHEK1/2 FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, RAD51c, and BRIP1. Mutations will be selected that are known or likely pathogenic. Mean allele frequencies will be assessed to estimate mono versus biallelic loss of function. Patients with biallelic deletions or mutations will be prioritized for inclusion to make up at least 30% of the enrollment (i.e., 10 patients) to gauge response in this group over monoallelic loss. Final inclusion will be determined by the principal investigator
- Must be able to swallow whole capsules
To avoid risk of drug exposure through the ejaculate, male subjects (even if they have undergone a successful vasectomy) must agree while on study therapy (including during dose interruptions) and for 3 months following the last dose of study drug to:
- Use a condom during sexual activity or practice complete sexual abstinence
- Not donate sperm
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days of the first study treatment)
- Platelet count >= 100 x 10^9/L (obtained =< 14 days of the first study treatment)
- Hemoglobin >= 9 g/dL (may have been transfused) (obtained =< 14 days of the first study treatment)
- Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range (obtained =< 14 days of the first study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x ULN or AST and ALT levels =< 5 x ULN (for subjects with documented metastatic disease to the liver) (obtained =< 14 days of the first study treatment)
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (for patients on anticoagulation they must be receiving a stable dose for at least 1 week prior to randomization) (obtained =< 14 days of the first study treatment)
- Creatinine clearance > 30 mL/min by Cockcroft-Gault formula (or local institutional standard method) (obtained =< 14 days of the first study treatment)
Exclusion Criteria:
- Any condition that would prohibit the understanding or rendering of informed consent
- Prior treatment for prostate cancer
- Prior treatment with a PARP inhibitor
- Prior treatment with androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH] agonist/antagonist), antiandrogen (e.g., bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g., abiraterone, orteronel)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Uncontrolled concomitant disease that in the opinion of the investigator would interfere with the patient's safety or compliance on trial
- Severe infection that in the opinion of the investigator would interfere with the patient's safety or compliance on trial within 4 weeks prior to enrollment
- Known allergies, hypersensitivity, or intolerance to niraparib or its excipients (refer to investigator's brochure)
- Known disorder affecting gastrointestinal absorption
- Corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiography (ECG) > 450 msec
- Receiving concomitant medications that prolong QTc and are unable to discontinue use while receiving study drug
- History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
Known human immunodeficiency virus (HIV) positive subjects with 1 or more of the following:
- Not receiving antiretroviral therapy
- A change in antiretroviral therapy within 6 months of the start of screening (except if, after consultation with the sponsor, a change is made to avoid a potential drug-drug interaction with the study drug)
- Receiving antiretroviral therapy that may interfere with the study drug (consult the principal investigator [PI] for review of medication prior to enrollment)
- CD4 count < 350 at screening
- An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening
Sites / Locations
- University of California Davis Comprehensive Cancer CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (niraparib)
Arm Description
Patients receive niraparib PO QD on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Following completion of treatment, patients then undergo standard of care surgery.
Outcomes
Primary Outcome Measures
Pathologic response rate (pRR)
The study will assess the impact of neoadjuvant niraparib therapy prior to radical prostatectomy (RP) on pathologic tumor stage, frequency of lymph node metastases and positive margin rates for patients undergoing radical prostatectomy for high-risk, clinically localized prostate cancer with alterations in deoxyribonucleic acid (DNA) repair pathways. Pathologic complete response (PCR) defined as no tumor identified on hematoxylin and eosin (H&E) stained sections will be assessed; minimal residual disease (MRD) will be defined as tumor clusters limited to < 5 mm and confined to prostate gland.
Exact 95% confidence intervals for pRR and other binary outcomes, adjusted for the two-stage design, will be calculated as described by Koyama and Chen. Response rates will be compared between patients with biallelic and monoallelic loss using Fisher's Exact Test.
Secondary Outcome Measures
Biochemical prostate specific antigen (PSA) progression free survival
Median biochemical progression free survival (bPFS) and quartiles (when reached) will be calculated from Kaplan-Meier estimates, and 95% confidence intervals will be calculated using Greenwood's formula.
Full Information
NCT ID
NCT04030559
First Posted
July 22, 2019
Last Updated
October 27, 2022
Sponsor
University of California, Davis
Collaborators
National Cancer Institute (NCI), Janssen, LP
1. Study Identification
Unique Protocol Identification Number
NCT04030559
Brief Title
Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects
Official Title
Phase II Trial of PARP Inhibitor Niraparib for Men With High Risk Prostate Cancer and DNA Damage Response Defects
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 25, 2020 (Actual)
Primary Completion Date
August 1, 2024 (Anticipated)
Study Completion Date
February 1, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, Davis
Collaborators
National Cancer Institute (NCI), Janssen, LP
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase II trial studies how well niraparib, when given before surgery, works in treating patients with high risk prostate cancer that has not spread to other parts of the body (localized) and alterations in deoxyribonucleic acid (DNA) repair pathways. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. To assess the impact of neoadjuvant niraparib tosylate monohydrate (niraparib) therapy prior to radical prostatectomy (RP) on pathologic tumor stage, frequency of lymph node metastases and positive margin rates for patients undergoing radical prostatectomy for high-risk, clinically localized prostate cancer with alterations in DNA repair pathways.
SECONDARY OBJECTIVE:
I. To assess 5-year biochemical recurrence in subjects with high-risk prostate cancer and DNA-damage response defects after prostatectomy.
OUTLINE:
Patients receive niraparib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Following completion of treatment, patients then undergo standard of care surgery.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, and then every 6 months for up to 3 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ATM Gene Mutation, BRCA1 Gene Mutation, BRCA2 Gene Mutation, BRIP1 Gene Mutation, CDK12 Gene Mutation, CHEK1 Gene Mutation, CHEK2 Gene Mutation, DNA Damage Response Gene Mutation, DNA Repair Gene Mutation, FANCA Gene Mutation, FANCD2 Gene Mutation, FANCL Gene Mutation, GEN1 Gene Mutation, NBN Gene Mutation, Prostate Carcinoma, RAD51 Gene Mutation, RAD51C Gene Mutation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (niraparib)
Arm Type
Experimental
Arm Description
Patients receive niraparib PO QD on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Following completion of treatment, patients then undergo standard of care surgery.
Intervention Type
Drug
Intervention Name(s)
Niraparib
Other Intervention Name(s)
MK-4827, MK4827
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Niraparib Tosylate Monohydrate
Other Intervention Name(s)
Zejula
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Radical Prostatectomy
Other Intervention Name(s)
Prostatovesiculectomy
Intervention Description
Undergo standard of care surgery
Primary Outcome Measure Information:
Title
Pathologic response rate (pRR)
Description
The study will assess the impact of neoadjuvant niraparib therapy prior to radical prostatectomy (RP) on pathologic tumor stage, frequency of lymph node metastases and positive margin rates for patients undergoing radical prostatectomy for high-risk, clinically localized prostate cancer with alterations in deoxyribonucleic acid (DNA) repair pathways. Pathologic complete response (PCR) defined as no tumor identified on hematoxylin and eosin (H&E) stained sections will be assessed; minimal residual disease (MRD) will be defined as tumor clusters limited to < 5 mm and confined to prostate gland.
Exact 95% confidence intervals for pRR and other binary outcomes, adjusted for the two-stage design, will be calculated as described by Koyama and Chen. Response rates will be compared between patients with biallelic and monoallelic loss using Fisher's Exact Test.
Time Frame
At the time of radical prostatectomy procedure
Secondary Outcome Measure Information:
Title
Biochemical prostate specific antigen (PSA) progression free survival
Description
Median biochemical progression free survival (bPFS) and quartiles (when reached) will be calculated from Kaplan-Meier estimates, and 95% confidence intervals will be calculated using Greenwood's formula.
Time Frame
Up to 5 years
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Ability to understand and willingness to sign an informed consent form
Ability to adhere to the study visit schedule and other protocol requirements
Patients must have histologically or cytologically confirmed prostate cancer that is clinically localized as defined by negative cross-section imaging and/or bone scan, and classified as high or very high risk per National Comprehensive Cancer Network (NCCN) guideline
Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1
Life expectancy >= 10 years
Men who have selected radical prostatectomy as the primary treatment for their prostate cancer
Prostate cancer tumors with alterations in key DNA repair genes. This will include at least one alteration in a gene involved in DNA repair primarily through the homologous recombination pathway including BRCA1/2, ATM, CHEK1/2 FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, RAD51c, and BRIP1. Mutations will be selected that are known or likely pathogenic. Mean allele frequencies will be assessed to estimate mono versus biallelic loss of function. Patients with biallelic deletions or mutations will be prioritized for inclusion to make up at least 30% of the enrollment (i.e., 10 patients) to gauge response in this group over monoallelic loss. Final inclusion will be determined by the principal investigator
Must be able to swallow whole capsules
To avoid risk of drug exposure through the ejaculate, male subjects (even if they have undergone a successful vasectomy) must agree while on study therapy (including during dose interruptions) and for 3 months following the last dose of study drug to:
Use a condom during sexual activity or practice complete sexual abstinence
Not donate sperm
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days of the first study treatment)
Platelet count >= 100 x 10^9/L (obtained =< 14 days of the first study treatment)
Hemoglobin >= 9 g/dL (may have been transfused) (obtained =< 14 days of the first study treatment)
Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range (obtained =< 14 days of the first study treatment)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x ULN or AST and ALT levels =< 5 x ULN (for subjects with documented metastatic disease to the liver) (obtained =< 14 days of the first study treatment)
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (for patients on anticoagulation they must be receiving a stable dose for at least 1 week prior to randomization) (obtained =< 14 days of the first study treatment)
Creatinine clearance > 30 mL/min by Cockcroft-Gault formula (or local institutional standard method) (obtained =< 14 days of the first study treatment)
Exclusion Criteria:
Any condition that would prohibit the understanding or rendering of informed consent
Prior treatment for prostate cancer
Prior treatment with a PARP inhibitor
Prior treatment with androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH] agonist/antagonist), antiandrogen (e.g., bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g., abiraterone, orteronel)
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Uncontrolled concomitant disease that in the opinion of the investigator would interfere with the patient's safety or compliance on trial
Severe infection that in the opinion of the investigator would interfere with the patient's safety or compliance on trial within 4 weeks prior to enrollment
Known allergies, hypersensitivity, or intolerance to niraparib or its excipients (refer to investigator's brochure)
Known disorder affecting gastrointestinal absorption
Corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiography (ECG) > 450 msec
Receiving concomitant medications that prolong QTc and are unable to discontinue use while receiving study drug
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
Known human immunodeficiency virus (HIV) positive subjects with 1 or more of the following:
Not receiving antiretroviral therapy
A change in antiretroviral therapy within 6 months of the start of screening (except if, after consultation with the sponsor, a change is made to avoid a potential drug-drug interaction with the study drug)
Receiving antiretroviral therapy that may interfere with the study drug (consult the principal investigator [PI] for review of medication prior to enrollment)
CD4 count < 350 at screening
An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Dall'Era
Organizational Affiliation
University of California, Davis
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Davis Comprehensive Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marc Dall'Era
Phone
916-734-3771
Email
mdallera@ucdavis.edu
First Name & Middle Initial & Last Name & Degree
Marc Dall'Era
12. IPD Sharing Statement
Links:
URL
https://studypages.com/s/a-study-of-the-experimental-medicine-niraparib-for-men-with-high-risk-prostate-cancer-713066/
Description
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Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects
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