Clinical trial NCT04037254: Testing the Addition of a New Anti-Cancer Drug, Niraparib, to the Usual Treatment (Hormone and Radiation Therapy) for Prostate Cancer With a High Chance of Recurring
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) (NADIR*) *Randomized Phase II Trial of Niraparib With Standard Combination Androgen DeprIvation Therapy (ADT) and Radiotherapy in High Risk Prostate Cancer (With Initial Phase I)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Prostate Adenocarcinoma
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
Lead sponsor: NRG Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2019-07-30
Enrollment: 18
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase I-II trial to find the safety and activity of adding a new drug (neratinib) to the usual treatment (radiation combined with male hormone deprivation therapy) in lowering the chance of prostate cancer growing or returning. Niraparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Adding niraparib to the usual care may lower the chance of prostate cancer growing or returning.

Detailed 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 prostate specific antigen (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 OBJECTIVE:

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 randomized 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. Patients also undergo magnetic resonance imaging (MRI) on study.

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. Patients also undergo MRI on study.

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. Patients also undergo MRI on study.

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

Eligibility criteria: 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
* Age \>= 18
* 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)
* 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 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
* Prior or current treatment with PARP inhibitor

Primary outcomes:
measure: Maintenance of disease-free state
timeFrame: Up to 2 years following the start of antiandrogen therapy
Secondary outcomes:
measure: Overall survival
timeFrame: From randomization until death from any cause, assessed up to 3 years
measure: Prostate cancer-specific survival
timeFrame: From randomization until death from prostate cancer, assessed up to 3 years
measure: Pathologic complete response (pCR)
timeFrame: At 24 months
measure: Time to local/regional or distant progression
timeFrame: Up to 3 years
measure: Time to distant metastases
timeFrame: From randomization until detection of distant metastatic disease, assessed up to 3 years
measure: Biochemical progression-free survival
timeFrame: Up to 3 years
measure: Incidence of adverse events (Phase II)
timeFrame: Up to 3 years
Other outcomes:
measure: Exome sequencing of deoxyribonucleic acid (DNA) repair genes and detected alterations
timeFrame: Up to 3 years
measure: Transcription-wide analysis of gene expression
timeFrame: Up to 3 years
measure: Single nucleotide polymorphisms
timeFrame: Up to 3 years
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center-Orange Grove Campus
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center-North Campus
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Marysville
country: United States
facility: Fremont - Rideout Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Upland
country: United States
facility: City of Hope Upland
state: California
city: Newark
country: United States
facility: Helen F Graham Cancer Center
state: Delaware
city: Newark
country: United States
facility: Medical Oncology Hematology Consultants PA
state: Delaware
city: Washington
country: United States
facility: George Washington University Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Grady Health System
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Newnan
country: United States
facility: CTCA at Southeastern Regional Medical Center
state: Georgia
city: Alton
country: United States
facility: Alton Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Columbia
country: United States
facility: Central Maryland Radiation Oncology in Howard County
state: Maryland
city: Glen Burnie
country: United States
facility: UM Baltimore Washington Medical Center/Tate Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Bay City
country: United States
facility: McLaren Cancer Institute-Bay City
state: Michigan
city: Brownstown
country: United States
facility: Henry Ford Cancer Institute-Downriver
state: Michigan
city: Clarkston
country: United States
facility: McLaren Cancer Institute-Clarkston
state: Michigan
city: Clinton Township
country: United States
facility: Henry Ford Macomb Hospital-Clinton Township
state: Michigan
city: Dearborn
country: United States
facility: Henry Ford Medical Center-Fairlane
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Farmington Hills
country: United States
facility: Weisberg Cancer Treatment Center
state: Michigan
city: Flint
country: United States
facility: McLaren Cancer Institute-Flint
state: Michigan
city: Flint
country: United States
facility: Singh and Arora Hematology Oncology PC
state: Michigan
city: Lansing
country: United States
facility: Karmanos Cancer Institute at McLaren Greater Lansing
state: Michigan
city: Lansing
country: United States
facility: Mid-Michigan Physicians-Lansing
state: Michigan
city: Lapeer
country: United States
facility: McLaren Cancer Institute-Lapeer Region
state: Michigan
city: Mount Clemens
country: United States
facility: McLaren Cancer Institute-Macomb
state: Michigan
city: Novi
country: United States
facility: Henry Ford Medical Center-Columbus
state: Michigan
city: Petoskey
country: United States
facility: McLaren Cancer Institute-Northern Michigan
state: Michigan
city: Port Huron
country: United States
facility: McLaren-Port Huron
state: Michigan
city: Shelby
country: United States
facility: Henry Ford Macomb Health Center - Shelby Township
state: Michigan
city: West Bloomfield
country: United States
facility: Henry Ford West Bloomfield Hospital
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Kansas City
country: United States
facility: University of Kansas Cancer Center - North
state: Missouri
city: Lee's Summit
country: United States
facility: University of Kansas Cancer Center - Lee's Summit
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Cape May Court House
country: United States
facility: AtlantiCare Health Park-Cape May Court House
state: New Jersey
city: Egg Harbor Township
country: United States
facility: AtlantiCare Surgery Center
state: New Jersey
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Teaneck
country: United States
facility: Holy Name Hospital
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Flushing
country: United States
facility: The New York Hospital Medical Center of Queens
state: New York
city: Rochester
country: United States
facility: Highland Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Akron
country: United States
facility: Summa Health System - Akron Campus
state: Ohio
city: Barberton
country: United States
facility: Summa Health System - Barberton Campus
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center-UC Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Medina
country: United States
facility: Summa Health Medina Medical Center
state: Ohio
city: West Chester
country: United States
facility: University of Cincinnati Cancer Center-West Chester
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Chadds Ford
country: United States
facility: Christiana Care Health System-Concord Health Center
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Lewisburg
country: United States
facility: Geisinger Medical Oncology-Lewisburg
state: Pennsylvania
city: Lewistown
country: United States
facility: Lewistown Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Eastern Regional Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC-Shadyside Hospital
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley/Henry Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Faris
state: South Carolina
city: Greenville
country: United States
facility: Saint Francis Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Eastside
state: South Carolina
city: Greenwood
country: United States
facility: Self Regional Healthcare
state: South Carolina
city: Greer
country: United States
facility: Prisma Health Cancer Institute - Greer
state: South Carolina
city: Seneca
country: United States
facility: Prisma Health Cancer Institute - Seneca
state: South Carolina
city: Morgantown
country: United States
facility: West Virginia University Healthcare
state: West Virginia
city: Menomonee Falls
country: United States
facility: Froedtert Menomonee Falls Hospital
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Zablocki Veterans Administration Medical Center
state: Wisconsin
city: Oak Creek
country: United States
facility: Drexel Town Square Health Center
state: Wisconsin
city: Oconomowoc
country: United States
facility: ProHealth Oconomowoc Memorial Hospital
state: Wisconsin
city: Waukesha
country: United States
facility: UW Cancer Center at ProHealth Care
state: Wisconsin
city: West Bend
country: United States
facility: Froedtert West Bend Hospital/Kraemer Cancer Center
state: Wisconsin
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
Study officials:
affiliation: NRG Oncology
name: M. D Michaelson
role: PRINCIPAL_INVESTIGATOR
References: