Niraparib With Standard Combination Radiation Therapy and Androgen Deprivation Therapy in Treating Patients With High Risk Prostate Cancer

Prostate Adenocarcinoma Clinical Trial

— NADIR  

Official title:

Randomized Phase II Trial of Niraparib With Standard Combination Radiotherapy and Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer (With Initial Phase I)

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04037254
• Other study ID #: NRG-GU007
• Secondary ID: NCI-2019-02260NR
• Status: Suspended
• Phase: Phase 2
• Start date: June 3, 2019
• Est. completion date: December 31, 2028

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the side effects and best dose of niraparib, and to see how well it works in combination with standard of care radiation therapy and hormonal therapy (androgen deprivation therapy) in treating patients with prostate cancer that has a high chance of coming back (high risk). Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding niraparib to the usual treatments of radiation therapy and hormonal therapy may lower the chance of prostate cancer growing or returning.

Description:

PRIMARY OBJECTIVES:

I. To establish the preferred dose of niraparib in combination with radiation and antiandrogen therapy (ADT). (Phase I) II. To compare the disease-free state, defined as PSA remaining < 0.1 ng/ml at the end of ADT therapy in men with high risk prostate cancer treated with standard therapy with or without the addition of niraparib. (Phase IIR)

SECONDARY OBJECTIVES:

I. To further establish the safety and toxicity profile of standard treatment with radiation and androgen deprivation therapy specifically, two years from initiation of ADT, plus niraparib at the phase II dose.

II. To compare the overall survival, prostate cancer-specific survival, local/regional or distant progression, and distant metastatic disease rates of standard therapy with or without the addition of niraparib.

EXPLORATORY OBJECTIVES:

I. To identify genomic biomarkers of response to combination therapy with radiation, ADT and PARP inhibition.

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

PHASE I: Patients receive niraparib orally (PO) once daily (QD) and receive standard of care gonadotrophin releasing hormone (GnRH) agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 arms:

ARM I: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years, then annually for 3 years.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 180
• Est. completion date: December 31, 2028
• Est. primary completion date: January 30, 2028
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed (within 180 days prior to registration) adenocarcinoma of the prostate at high risk for recurrence as determined by the following criteria, according to American Joint Committee on Cancer (AJCC) 8th edition:

• Phase I enrollment

• Gleason = 9, PSA = 150 ng/mL, any T-stage

• Phase II enrollment

• Gleason = 9, PSA = 150 ng/mL, any T-stage

• Gleason 8, PSA < 20 ng/mL, and = T2

• Gleason 8, PSA = 20-150 ng/mL, any T-stage

• Gleason 7, PSA = 20-150 ng/mL, any T-stage

• No distant metastases as evaluated by:

• Bone scan 90 days prior to registration

• Lymph node assessment by computed tomography (CT) or magnetic resonance (MR) of pelvis or nodal sampling within 90 days prior to registration (Please note: Lymph nodes will be considered negative (N0) if they are < 1.5 cm short axis)

• History/physical examination within 90 days prior to registration

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 180 days prior to registration

• Pretreatment serum PSA, obtained prior to any androgen suppression therapy and within 180 days of registration

• Phase I patients: Prior androgen suppression for prostate cancer is not allowed prior to registration

• Phase II patients: Prior androgen suppression for prostate cancer is allowed = 45 days prior to registration

• Hemoglobin = 9.0 g/dL (within 90 days prior to registration)

• Platelets = 100,000 cells/mm^3 (within 90 days prior to registration)

• Absolute neutrophil count (ANC) = 1.5 x 10^9/L (within 90 days prior to registration)

• Serum creatinine =1.5 x upper limit of normal (ULN) OR a calculated creatinine clearance >= 30 mL/min estimated using Cockcroft-Gault equation (within 90 days prior to registration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0 x ULN (within 90 days prior to registration)

• Serum albumin = 3 g/dL (within 90 days prior to registration)

• Serum potassium = 3.5 mmol/L (within 90 days prior to registration)

• Serum total bilirubin = 1.5 x ULN or direct bilirubin = 1 x ULN (Note: in subjects with Gilberts 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) (within 90 days prior to registration)

• Men of child-producing potential must be willing to consent to use effective contraception while on treatment and for at least 3 months afterwards

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• PSA > 150 ng/mL

• Definitive clinical or radiologic evidence of metastatic disease

• Pathologically positive lymph nodes or nodes > 1.5 cm short axis on CT or MR imaging

• Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason

• Any active malignancy within 2 years of study registration that may alter the course of prostate cancer treatment.

• Prior systemic therapy for prostate cancer; note that prior therapy for a different cancer is allowable

• Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields

• Current treatment with first generation anti-androgens (bicalutamide, nilutamide, flutamide). For patients enrolled to phase II, if prior anti-androgens were administered, a washout period of >= 30 days is required prior to enrollment

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

• Uncontrolled acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >=160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment

• Prior allergic reaction to the drugs involved in this protocol (including known allergies, hypersensitivity or intolerance to the excipients of niraparib. Please see Niraparib IB for details.)

• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter

• Note that patients who are HIV positive are eligible, provided they have a CD4 count >= 200 cells/microliter within 90 days prior to registration. Patients receiving treatment with highly active antiretroviral therapy (HAART) will not be eligible due to concern for radiosensitization

• Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be affected by these drugs.

• Any history or current diagnosis of Myelodysplasitc Syndromes (MDS)/ Acute Myeloid Leukemia (AML).

• Prior or current treatment with PARP inhibitor

Related Conditions & MeSH terms

• Prostate Adenocarcinoma
• Prostatic Neoplasms
• Stage IIC Prostate Cancer AJCC v8
• Stage III Prostate Cancer AJCC v8
• Stage IIIA Prostate Cancer AJCC v8
• Stage IIIB Prostate Cancer AJCC v8
• Stage IIIC Prostate Cancer AJCC v8
• Stage IVA Prostate Cancer AJCC v8

Intervention

Biological:
• Gonadotrophin Releasing Hormone
Receive standard of care GnRH agonist androgen suppression therapy

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo standard of care IMRT

Drug:
• Niraparib
Given PO

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
United States	Summa Health System - Akron Campus	Akron	Ohio
United States	Alton Memorial Hospital	Alton	Illinois
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Summa Health System - Barberton Campus	Barberton	Ohio
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	AtlantiCare Health Park-Cape May Court House	Cape May Court House	New Jersey
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	McLaren Cancer Institute-Clarkston	Clarkston	Michigan
United States	Case Western Reserve University	Cleveland	Ohio
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	AtlantiCare Surgery Center	Egg Harbor Township	New Jersey
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Singh and Arora Hematology Oncology PC	Flint	Michigan
United States	The New York Hospital Medical Center of Queens	Flushing	New York
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan
United States	Mid-Michigan Physicians-Lansing	Lansing	Michigan
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Fremont - Rideout Cancer Center	Marysville	California
United States	Summa Health Medina Medical Center	Medina	Ohio
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Zablocki Veterans Administration Medical Center	Milwaukee	Wisconsin
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	CTCA at Southeastern Regional Medical Center	Newnan	Georgia
United States	Henry Ford Medical Center-Columbus	Novi	Michigan
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	Eastern Regional Medical Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	McLaren-Port Huron	Port Huron	Michigan
United States	Highland Hospital	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Henry Ford Macomb Health Center - Shelby Township	Shelby	Michigan
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Holy Name Hospital	Teaneck	New Jersey
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	University of Arizona Cancer Center-Orange Grove Campus	Tucson	Arizona
United States	City of Hope Upland	Upland	California
United States	Carle Cancer Center	Urbana	Illinois
United States	George Washington University Medical Center	Washington	District of Columbia
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exome sequencing of deoxyribonucleic acid (DNA) repair genes and detected alterations	Descriptive statistics will be generated summarizing the frequency of gene alterations, mutations, and gene expression levels. The percentage of patients with baseline or post-therapy alterations in targeted genes will be reported and the association between the occurrence of reversion mutations in DNA repair genes and clinical outcomes will be assessed using logistic regression models for dichotomous endpoints (disease-free state, pCR), and Cox regression or competing risk regression modeling for time-to-event data.	Up to 3 years
Other	Transcription-wide analysis of gene expression	Will be assessed using a high-density Affymetrix oligonucleotide array to profile the transcriptome of tumor samples. Descriptive statistics will be generated summarizing the frequency of gene alterations, mutations, and gene expression levels. The percentage of patients with baseline or post-therapy alterations in targeted genes will be reported and the association between the occurrence of reversion mutations in DNA repair genes and clinical outcomes will be assessed using logistic regression models for dichotomous endpoints (disease-free state, pCR), and Cox regression or competing risk regression modeling for time-to-event data.	Up to 3 years
Other	Single nucleotide polymorphisms	Will be analyzed in whole blood samples previously associated with prostate risk. Plasma samples will be assessed for baseline and post-therapy alterations in a targeted gene panel and for reversion mutations in DNA repair genes as early biomarkers of treatment resistance. Descriptive statistics will be generated summarizing the frequency of gene alterations, mutations, and gene expression levels. The percentage of patients with baseline or post-therapy alterations in targeted genes will be reported and the association between the occurrence of reversion mutations in DNA repair genes and clinical outcomes will be assessed using logistic regression models for dichotomous endpoints (disease-free state, pCR), and Cox regression or competing risk regression modeling for time-to-event data.	Up to 3 years
Primary	Maintenance of disease-free state	Will be characterized by PSA values sustained below 0.1 ng/ml. A modified intent-to-treat analysis will be conducted. The proportion of patients disease-free at 24 months will be compared in the two treatment arms using a non continuity-corrected chi-square test. As a secondary analysis, a logistic regression model will be fit to adjust for the stratification factors (risk group and type of radiation therapy).	Up to 2 years following the start of antiandrogen therapy
Secondary	Overall Survival	Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.	From randomization until death from any cause, assessed up to 3 years
Secondary	Prostate cancer-specific survival	Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.	From randomization until death from prostate cancer, assessed up to 3 years
Secondary	Pathologic Complete Response (pCR)	Will be assessed among patients undergoing 12-core biopsy. Will be compared using a chi-square test.	At 24 months
Secondary	Time to local/regional or distant progression	Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).	Up to 3 years
Secondary	Time to distant metastases	Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).	From randomization until detection of distant metastatic disease, assessed up to 3 years
Secondary	Biochemical Progression-Free Survival	Will be defined as PSA >= 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or death from prostate cancer. Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.	Up to 3 years
Secondary	Incidence of Adverse Events (Phase II)	Adverse event (AE) rates in the two treatment arms will be summarized by time of occurrence (early versus late), type, grade, and attribution to treatment. For each type of AE, the worst grade occurring during the early treatment period, late treatment period, or entire treatment period will be determined. For each time period, treatment group comparisons will be conducted using chi-square or Fisher exact tests.	Up to 3 years