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Cognitive Effects of Androgen Receptor Directed Therapies for Advanced Prostate Cancer

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ClinicalTrials.gov Identifier: NCT03016741
Recruitment Status : Recruiting
First Posted : January 11, 2017
Last Update Posted : August 16, 2018
Sponsor:
Information provided by (Responsible Party):
Northwestern University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Castration-Resistant Prostatic Cancer Metastatic Prostate Carcinoma Recurrent Prostate Carcinoma Stage IV Prostate Cancer Hormone-Refractory Prostate Cancer Biological: GnRH agonist/antagonist Drug: Prednisone Drug: Abiraterone Acetate Drug: Enzalutamide Phase 4

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) or metastatic hormone sensitive prostate cancer during treatment with enzalutamide (mCRPC only) and abiraterone acetate (mHSPC or mCRPC).

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Cognitive Effects of Androgen Receptor (AR) Directed Therapies for Advanced Prostate Cancer
Actual Study Start Date : March 31, 2017
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Arm I (abiraterone acetate, prednisone)
Patients 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.
Biological: GnRH agonist/antagonist
Given GnRH agonist/antagonist therapy

Drug: Prednisone
Given by mouth

Drug: Abiraterone Acetate
Given by mouth
Other Name: Zytiga

Arm II (enzalutamide)
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.
Biological: GnRH agonist/antagonist
Given GnRH agonist/antagonist therapy

Drug: Enzalutamide
Given by mouth
Other Name: Xtandi




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. 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 ]
    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.

  2. Fatigue assessed using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT- Fatigue) [ Time Frame: Measured at baseline, 3 months, 6 months, and 12 months ]
    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

  3. Subjective measure of cognitive function by FACT-Cog [ Time Frame: Measured at baseline, 3 months, 6 months, and 12 months ]
    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.

  4. Depression by Patient Health Questionnaire (PHQ-9) [ Time Frame: Measured at baseline, 3 months, 6 months, and 12 months ]
    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.

  5. Instrumental activities of daily living by Texas Functional Living Scale [ Time Frame: Measured at baseline, 3 months, 6 months, and 12 months ]
    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.


Other Outcome Measures:
  1. SNPs associated with cognitive function [ Time Frame: SNP chip assessment using blood drawn at baseline or 3 month visit ]
    Multivariable linear regression will be utilized to compare the difference in primary outcomes between two allele groups at each time point for each SNP among patients in each treatment group. Baseline scores and other covariates will also be included in the model. Multivariable analyses using data from both treatment groups and control patients at each time point will be performed to identify SNPs whose associations with cognitive function are different between each treatment group and the control patients. The coefficient for the interaction between treatment group and allele group identity will be estimated and Wald-test p value will be provided. The p values will be ranked for the difference obtained from separate analysis for each SNP. A positive false discovery rate adjusted p values (q) will be calculated.

  2. Imaging assessed by MRI [ Time Frame: Baseline and 3 months ]
    MRI sequences will be compared by qualitative and quantitative analyses comparing MRI at baseline to MRI at 3 months for each patient. Changes will be compared qualitatively and quantitaively between treatment groups at baseline and 3 months also.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have diagnosis of prostate cancer and have received treatment with GnRH agonist or antagonist therapy for at least 1 month prior to enrollment.
  • Willing and able to complete survey questionnaires in English without assistance through the duration of the study. This stipulation is in place because not all of the proposed quality of life or cognitive tests are available or validated in other languages.
  • Age ≥ 18 years.
  • Ability to understand and the willingness to sign a written informed consent document written in English that is approved by an institutional review board.
  • Have either newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) or castration-resistant metastatic prostate cancer (mCRPC) and eligible to undergo treatment with abiraterone acetate (mHSPC or mCRPC) or enzalutamide (mCRPC)
  • Patients may have received the following prior AR directed therapy prior to enrollment: bicalutamide, ketoconazole. Prior to enrollment, patients may have received treatment with abiraterone acetate or enzalutamide for no more than 14 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 definitive radiation therapy or surgery. At least 60 days must have elapsed since completion of definitive radiation therapy or surgery and patient must have only grade 2 or less adverse effects at the time of registration. Enrollment during palliative radiation of ≤ 10 days, or radiation of ≤ 10 days during the duration of the study is allowed.
  • Patients must be able to take oral medication.

Exclusion Criteria:

  • Prior treatment with enzalutamide or abiraterone acetate for > 14 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 SSRIs, SNRIs, and standard dose benzodiazepines at a stable dose, is permitted

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03016741


Contacts
Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Alicia K. Morgans, MD, MPH    312-695-6180      
Principal Investigator: Alicia K. Morgans, MD, MPH         
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: ICC Clinical Trials Information Program    800-811-8480    cip@vanderbilt.edu   
Sponsors and Collaborators
Northwestern University
Investigators
Principal Investigator: Alicia Morgans, M.D., M.P.H. Northwestern University

Responsible Party: Northwestern University
ClinicalTrials.gov Identifier: NCT03016741     History of Changes
Other Study ID Numbers: NU 17U19
STU00206082 ( Registry Identifier: Northwestern University )
NCI-2016-01795 ( Other Identifier: NCI, Clinical Trials Reporting Program )
First Posted: January 11, 2017    Key Record Dates
Last Update Posted: August 16, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Northwestern University:
cognitive function
hormonal therapy
cancer survivorship
dementia
cognitive dysfunction
mild cognitive impairment

Additional relevant MeSH terms:
Carcinoma
Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Prednisone
Triptorelin Pamoate
Abiraterone Acetate
Androgens
Deslorelin
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Cytochrome P-450 Enzyme Inhibitors
Luteolytic Agents
Contraceptive Agents, Female