Clinical Trials /

Cognitive Effects of Androgen Receptor Directed Therapies for Advanced Prostate Cancer

NCT03016741

Description:

This clinical trial studies cognitive function in men with prostate cancer treated with androgen receptor directed therapies such as abiraterone acetate and enzalutamide. The investigators use MRI imaging (non-invasive, non-contrast) to see whether there are changes in brain structure or activity related to treatment that may be related to changes in cognitive function. The investigators are also looking for genetic variations that might make patients more or less sensitive to cognitive changes during treatment for prostate cancer.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 4

Trial Eligibility

Document

Title

  • Brief Title: Cognitive Effects of Androgen Receptor Directed Therapies for Advanced Prostate Cancer
  • Official Title: Cognitive Effects of Androgen Receptor (AR) Directed Therapies for Advanced Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: VICC URO 16133
  • SECONDARY ID: NCI-2016-01795
  • NCT ID: NCT03016741

Conditions

  • Castration-Resistant Prostatic Cancer
  • Metastatic Prostate Carcinoma
  • Recurrent Prostate Carcinoma
  • Stage IV Prostate Cancer
  • Hormone-Refractory Prostate Cancer

Interventions

DrugSynonymsArms
GnRH agonist/antagonistArm I (abiraterone acetate, prednisone)
PrednisoneArm I (abiraterone acetate, prednisone)
Abiraterone AcetateZytigaArm I (abiraterone acetate, prednisone)
EnzalutamideXtandiArm II (enzalutamide)

Purpose

This clinical trial studies cognitive function in men with prostate cancer treated with androgen receptor directed therapies such as abiraterone acetate and enzalutamide. The investigators use MRI imaging (non-invasive, non-contrast) to see whether there are changes in brain structure or activity related to treatment that may be related to changes in cognitive function. The investigators are also looking for genetic variations that might make patients more or less sensitive to cognitive changes during treatment for prostate cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare cognitive function and associated mediators of cognitive function (quality of
      life, depression, pain, and fatigue) of men with metastatic castration-resistant prostate
      cancer (mCRPC) during treatment with enzalutamide and abiraterone acetate.

      SECONDARY OBJECTIVES:

      I. To identify characteristics of men with mCRPC associated with change in cognitive function
      during treatment with androgen receptor (AR) directed therapy.

      II. To compare quality of life and associated factors, including fatigue, pain, and
      depression, of men with mCRPC during treatment with enzalutamide and abiraterone acetate.

      TERTIARY OBJECTIVES:

      I. To analyze whether single nucleotide polymorphisms (SNPs) may be associated with change in
      cognitive function during treatment with AR directed therapy.

      II. To compare the functional and structural components of the brain over time and between
      the brains of men with mCRPC treated with enzalutamide or abiraterone acetate using diffusion
      tensor imaging (DTI), functional MRI (fMRI), arterial spin labeling (ASL), and other advanced
      neuroimaging techniques.

      OUTLINE: Treatment patients with metastatic castration-resistant prostate cancer are
      randomized to 1 of 2 arms. Control patients receiving long term androgen deprivation therapy
      will be assessed with the same measures as a control arm.

      ARM I: Patients receive standard of care treatment with gonadotrophin releasing hormone
      (GnRH) agonist/antagonist therapy. Patients also receive abiraterone acetate orally (PO) and
      prednisone PO twice daily (BID) in the absence of disease progression or unacceptable
      toxicity. Patients then undergo cognitive assessment comprising of neuro-cognitive tests and
      assessments of overall quality of life, fatigue, pain, and symptoms at baseline, 3, 6, and 12
      months. Patients also undergo MRI program for 40 minutes comprising of DTI, fMRI, ASL MRI,
      Magnetization Prepared Rapid Gradient Echo (MPRAGE) MRI, Fluid attenuated Inversion Recovery
      (FLAIR) MRI, and blood oxygenation level-dependent (BOLD) MRI at baseline and 3 months.

      ARM II: Patients receive standard of care treatment with GnRH agonist/antagonist therapy.
      Patients also receive enzalutamide PO QD in the absence of disease progression or
      unacceptable toxicity. Patients undergo cognitive assessment and MRI program as in Arm I.

      ARM III: Patients receive standard of care treatment with GnRH agonist/antagonist therapy and
      undergo cognitive assessment and MRI program as in Arm I.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (abiraterone acetate, prednisone)OtherPatients receive standard of care treatment with GnRH agonist/antagonist therapy. Patients also receive abiraterone acetate PO and prednisone PO BID in the absence of disease progression or unacceptable toxicity. Patients then undergo cognitive assessment comprising of neuro-cognitive tests and assessments of overall quality of life, fatigue, pain, and symptoms at baseline, 3, 6, and 12 months. Patients also undergo MRI program for 40 minutes comprising of DTI, fMRI, ASL MRI, MPRAGE MRI, FLAIR MRI, and BOLD MRI at baseline and 3 months.
  • Prednisone
  • Abiraterone Acetate
Arm II (enzalutamide)OtherPatients receive standard of care treatment with GnRH agonist/antagonist therapy. Patients also receive enzalutamide PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo cognitive assessment and MRI program as in Arm I.
  • Enzalutamide

Eligibility Criteria

        Inclusion Criteria:

          -  Have pathologic diagnosis of prostate cancer and have received treatment with GnRH
             agonist or antagonist therapy for at least 3 months prior to enrollment

          -  Willing and able to complete survey questionnaires in English with or without
             assistance through the duration of the study

          -  Life expectancy >= 6 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Ability to understand and the willingness to sign a written informed consent document
             written in English that is approved by an institutional review board

          -  TREATMENT ARM PATIENTS

          -  Have castration-resistant metastatic disease (mCRPC) defined by the following:

               -  Castrate serum testosterone level =< 50 ng/dL (1.7 nmol/L)

               -  Bilateral orchiectomy or maintenance on androgen ablation therapy with GnRH
                  agonist or antagonist throughout the study (including the follow-up period)

               -  Serum prostate specific antigen (PSA) progression, defined as two consecutive
                  increases in PSA over a previous reference value within 6 months prior to
                  enrollment, with each progression measurement at least 1 week apart

          -  Willing and medically able to receive treatment with first-line AR directed therapy
             with abiraterone acetate or enzalutamide as determined and prescribed by the primary
             physician

          -  Patients may have received the following prior AR directed therapy >= 24 months prior
             to enrollment: bicalutamide, ketoconazole; prior to enrollment, patients may have
             received treatment with abiraterone acetate or enzalutamide for no more than 7 days
             before completing baseline studies

          -  Patients may have received chemotherapy for hormone-sensitive metastatic prostate
             cancer only, but it must not have lasted for more than 6 months; at least 12 months
             must have elapsed since completion of chemotherapy

          -  Patients may have received prior radiation therapy or surgery; however, at least 60
             days must have elapsed since completion of radiation therapy or surgery and patient
             must have only grade 2 or less adverse effects at the time of registration

          -  Patients must be able to take oral medication

          -  CONTROL PATIENTS

          -  Control patients must be expected to stay on GnRH agonist or antagonist therapy for
             high-risk localized, biochemical recurrent or hormone-sensitive metastatic prostate
             cancer for the entire 12 months of the study; examples of eligible patients include
             long-term androgen deprivation therapy (ADT) use after definitive external beam
             radiation for high-risk localized prostate cancer, long-term ADT use after
             prostatectomy for lymph node positive disease, long-term ADT use for biochemical
             recurrence or elevated PSA post-prostatectomy, or long-term ADT use for hormone
             sensitive metastatic prostate cancer; control patients should not expect to receive
             additional treatments for their prostate cancer during the 12 months of the study,
             including but not limited to additional salvage or adjuvant radiation, surgery,
             chemotherapy, or other intervention; if these interventions are expected, enrollment
             should be delayed until after the intervention; unexpected changes in treatment,
             including the use of medications for mCRPC, are completely acceptable and at the
             discretion of the treating physician; questions regarding the eligibility of control
             patients should be directed to the principal investigator (PI)

        Exclusion Criteria:

          -  Prior treatment with enzalutamide or abiraterone acetate for > 7 days prior to
             enrollment and completion of baseline tests

          -  Receipt of chemotherapy for prostate or other cancer within the past 12 months with
             residual cognitive deficits, or receipt of chemotherapy for mCRPC; patients/physicians
             planning treatment with chemotherapy during the 12 month period of the investigation
             are also ineligible

          -  History of cognitive impairment or dysfunction, including a history of dementia,
             Alzheimer's disease, stroke with residual cognitive deficits, cognitive dysfunction
             related to alcohol or substance abuse, or cognitive dysfunction related to prior
             treatment for any cancer

          -  Patients with a seizure history, history of recurrent falls, or known brain metastases
             are excluded from this clinical trial because of their poor prognosis and because of
             their heightened risk of seizure or progressive cognitive and/or neurologic
             dysfunction that would confound the evaluation

          -  Uncontrolled intercurrent illness including, but not limited to, uncontrolled
             diabetes, ongoing or active infection, symptomatic congestive heart failure (New York
             Heart Association class III and IV heart failure), unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations/substance abuse that would limit
             compliance with study requirements

          -  Patients with a "currently active" second malignancy other than non-melanoma skin
             cancers are not eligible; patients are not considered to have a "currently active"
             malignancy if they have completed all therapy and are now considered without evidence
             of disease for 1 year; patients with cognitive dysfunction related to treatment of
             another malignancy, including a history of "chemo-brain", are ineligible

          -  Patients taking psychotropic medications or illicit drugs that may alter cognition,
             concentration, or behavior; appropriate treatment by a licensed provider with
             medications for depression or anxiety, including but not limited to selective
             serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
             (SNRIs), and standard dose benzodiazepines at a stable dose, is permitted

          -  Control patients cannot have a diagnosis of mCRPC
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cognitive function defined by overall Cogstate score and Cogstate module scores for each domain
Time Frame:Measured at baseline, 3 months, 6 months, and 12 months
Safety Issue:
Description:Raw scores on each module of the Cogstate test will be converted to standardized scores (z-scores and T-scores) according to age and/or education-adjusted published normative data per the Cogstate protocol. Linear regressions will be utilized to assess the mean differences between groups at each time point after the baseline while adjusting for baseline scores.

Secondary Outcome Measures

Measure:Quality of life assessed using European Organization for Research and Treatment of Cancer quality of life questionnaire-C30 (EORTC QLQ C-30)
Time Frame:Measured at baseline, 3 months, 6 months, and 12 months
Safety Issue:
Description:The outcome measure for this questionnaire is the score as determined per standard scoring practices in the EORTC QLQ-C30 scoring manual. Mean scores from the EORTC QLQ-C30 survey instrument will be compared between groups at each time point, and changes in score will be assessed over time for each individual. Generalized linear regressions will be performed to estimate the differences between groups at each time point with adjustment for baseline and other covariates. GEE analysis will be used for the longitudinal data. Spearman p correlation coefficients between the standardized cognitive test scores and the mediators will be evaluated. Multivariable linear regressions for each time point will be performed to test the interactions between the group identity and each of the interested sociodemographic and clinical factors while adjusting for baseline and other covariates.
Measure:Fatigue assessed using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT- Fatigue)
Time Frame:Measured at baseline, 3 months, 6 months, and 12 months
Safety Issue:
Description:The outcome measure for this questionnaire is the score as determined per standard scoring practices with the FACIT-Fatigue scoring manual. Mean scores from the FACIT-Fatigue survey instrument will be compared between groups at each time point, and changes in score will be assessed over time for each individual. Generalized linear regressions will be performed to estimate the differences between groups at each time point with adjustment for baseline and other covariates. GEE analysis will be used for the longitudinal data. Spearman p correlation coefficients between the standardized cognitive test scores and the mediators will be evaluated. Multivariable linear regressions for each time point will be performed to test the interactions between the group identity and each of the interested sociodemographic and clinical factors while adjusting for baseline and other covariates
Measure:Subjective measure of cognitive function by FACT-Cog
Time Frame:Measured at baseline, 3 months, 6 months, and 12 months
Safety Issue:
Description:The outcome measure for this questionnaire is the score as determined per standard scoring practices with the FACT-Cog scoring manual. Mean scores from the FACT-Cog survey instrument will be compared between groups at each time point, and changes in score will be assessed over time for each individual. Generalized linear regressions will be performed to estimate the differences between groups at each time point with adjustment for baseline and other covariates. GEE analysis will be used for the longitudinal data. Spearman p correlation coefficients between the standardized cognitive test scores and the mediators will be evaluated. Multivariable linear regressions for each time point will be performed to test the interactions between the group identity and each of the interested sociodemographic and clinical factors while adjusting for baseline and other covariates.
Measure:Depression by Patient Health Questionnaire (PHQ-9)
Time Frame:Measured at baseline, 3 months, 6 months, and 12 months
Safety Issue:
Description:The outcome measure for this questionnaire is the score as determined per standard scoring practices with the PH-Q 9 scoring manual. Mean scores from the PHQ-9 survey instrument will be compared between groups at each time point, and changes in score will be assessed over time for each individual. Generalized linear regressions will be performed to estimate the differences between groups at each time point with adjustment for baseline and other covariates. GEE analysis will be used for the longitudinal data. Spearman p correlation coefficients between the standardized cognitive test scores and the mediators will be evaluated. Multivariable linear regressions for each time point will be performed to test the interactions between the group identity and each of the interested sociodemographic and clinical factors while adjusting for baseline and other covariates.
Measure:Instrumental activities of daily living by Texas Functional Living Scale
Time Frame:Measured at baseline, 3 months, 6 months, and 12 months
Safety Issue:
Description:This measure will provide a score to represent patient's ability to complete daily tasks, and is a "direct assessment" based approach to measure instrumental activities of daily living.

Details

Phase:Phase 4
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Trial Keywords

  • cognitive function
  • hormonal therapy
  • cancer survivorship
  • dementia
  • cognitive dysfunction
  • mild cognitive impairment

Last Updated

May 22, 2017