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

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ClinicalTrials.gov Identifier: NCT04037254
Recruitment Status : Recruiting
First Posted : July 30, 2019
Last Update Posted : September 5, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Tracking Information
First Submitted Date  ICMJE July 26, 2019
First Posted Date  ICMJE July 30, 2019
Last Update Posted Date September 5, 2019
Actual Study Start Date  ICMJE June 3, 2019
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 26, 2019)
Maintenance of disease-free state [ Time Frame: Up to 2 years following the start of antiandrogen therapy ]
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT04037254 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2019)
  • Overall survival [ Time Frame: From randomization until death from any cause, assessed up to 3 years ]
    Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
  • Prostate cancer-specific survival [ Time Frame: From randomization until death from prostate cancer, assessed up to 3 years ]
    Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
  • Pathologic complete response (pCR) [ Time Frame: At 24 months ]
    Will be assessed among patients undergoing 12-core biopsy. Will be compared using a chi-square test.
  • Time to local/regional or distant progression [ Time Frame: Up to 3 years ]
    Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).
  • Time to distant metastases [ Time Frame: From randomization until detection of distant metastatic disease, assessed up to 3 years ]
    Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).
  • Biochemical progression-free survival [ Time Frame: Up to 3 years ]
    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.
  • Incidence of adverse events (Phase II) [ Time Frame: Up to 3 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 26, 2019)
  • Exome sequencing of deoxyribonucleic acid (DNA) repair genes and detected alterations [ Time Frame: Up to 3 years ]
    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.
  • Transcription-wide analysis of gene expression [ Time Frame: Up to 3 years ]
    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.
  • Single nucleotide polymorphisms [ Time Frame: Up to 3 years ]
    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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Niraparib With Standard Combination Radiation Therapy and Androgen Deprivation Therapy in Treating Patients With High Risk Prostate Cancer
Official Title  ICMJE Randomized Phase II Trial of Niraparib With Standard Combination Radiotherapy and Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer (With Initial Phase I)
Brief 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.
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Biological: Gonadotrophin Releasing Hormone
    Receive standard of care GnRH agonist androgen suppression therapy
    Other Names:
    • AY-24031
    • D-His-6-Pro-8-NEt-LHRH
    • Follicle Stimulating Hormone-Releasing Factor
    • GN-RH
    • GnRH
    • Gonadoliberin
    • Gonadorelin
    • Gonadorelinum
    • gonadotropin-releasing hormone
    • Hoe- 471
    • LH-RF
    • LH-RH
    • LH/FSH-RF
    • LH/FSH-RH
    • LHRH
    • Luliberin
    • Luteinising Hormone-Releasing Factor
    • Luteinizing Hormone-Releasing Factor
    • luteinizing hormone-releasing hormone
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo standard of care IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Drug: Niraparib
    Given PO
    Other Names:
    • MK-4827
    • MK4827
Study Arms  ICMJE
  • Experimental: Phase I (niraparib, GnRH, IMRT)
    Patients receive niraparib PO QD and receive standard of care 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 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.
    Interventions:
    • Biological: Gonadotrophin Releasing Hormone
    • Radiation: Intensity-Modulated Radiation Therapy
    • Drug: Niraparib
  • Active Comparator: Phase II, Arm I (GnRH, IMRT)
    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.
    Interventions:
    • Biological: Gonadotrophin Releasing Hormone
    • Radiation: Intensity-Modulated Radiation Therapy
  • Experimental: Phase II, Arm II (niraparib, GnRH, IMRT)
    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.
    Interventions:
    • Biological: Gonadotrophin Releasing Hormone
    • Radiation: Intensity-Modulated Radiation Therapy
    • Drug: Niraparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 26, 2019)
180
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2028
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 >= 60 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 mg/dL (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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04037254
Other Study ID Numbers  ICMJE NRG-GU007
NCI-2019-02260 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GU007 ( Other Identifier: NRG Oncology )
NRG-GU007 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NRG Oncology
Study Sponsor  ICMJE NRG Oncology
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: M. D Michaelson NRG Oncology
PRS Account NRG Oncology
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP