Clinical Trials /

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

NCT04037254

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Niraparib With Standard Combination Radiation Therapy and Androgen Deprivation Therapy in Treating Patients With High Risk Prostate Cancer
  • 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 IDs

  • ORG STUDY ID: NRG-GU007
  • SECONDARY ID: NCI-2019-02260
  • SECONDARY ID: NRG-GU007
  • SECONDARY ID: NRG-GU007
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04037254

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

Interventions

DrugSynonymsArms
Gonadotrophin Releasing HormoneAY-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 hormonePhase I (niraparib, GnRH, IMRT)
NiraparibMK-4827, MK4827Phase I (niraparib, GnRH, IMRT)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I (niraparib, GnRH, IMRT)ExperimentalPatients 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.
  • Gonadotrophin Releasing Hormone
  • Niraparib
Phase II, Arm I (GnRH, IMRT)Active ComparatorPatients 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.
  • Gonadotrophin Releasing Hormone
Phase II, Arm II (niraparib, GnRH, IMRT)ExperimentalPatients 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.
  • Gonadotrophin Releasing Hormone
  • Niraparib

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maintenance of disease-free state
Time Frame:Up to 2 years following the start of antiandrogen therapy
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From randomization until death from any cause, assessed up to 3 years
Safety Issue:
Description:Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
Measure:Prostate cancer-specific survival
Time Frame:From randomization until death from prostate cancer, assessed up to 3 years
Safety Issue:
Description:Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
Measure:Pathologic complete response (pCR)
Time Frame:At 24 months
Safety Issue:
Description:Will be assessed among patients undergoing 12-core biopsy. Will be compared using a chi-square test.
Measure:Time to local/regional or distant progression
Time Frame:Up to 3 years
Safety Issue:
Description:Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).
Measure:Time to distant metastases
Time Frame:From randomization until detection of distant metastatic disease, assessed up to 3 years
Safety Issue:
Description:Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).
Measure:Biochemical progression-free survival
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Incidence of adverse events (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NRG Oncology

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