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Androgen Receptor Directed Therapy on Cognitive Function in Patients Treated With Darolutamide or Enzalutamide (ARACOG)

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ClinicalTrials.gov Identifier: NCT04335682
Recruitment Status : Not yet recruiting
First Posted : April 6, 2020
Last Update Posted : September 1, 2020
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Alliance Foundation Trials, LLC.

Brief Summary:
This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with non-metastatic and metastatic castration-resistant prostate cancer (mCRPC or M0CRPC) treated with darolutamide or enzalutamide. Approximately 132 patients will be enrolled. Eligible patients will be randomized in a 1:1 fashion to treatment with enzalutamide 160 mg orally daily or darolutamide 600 mg orally twice daily, in combination with standard LHRH agonist based treatment. Cognitive assessments will be performed using modules from Cambridge Neuropsychological Test Automated Battery (CANTAB) an internationally recognized software for assessing cognitive function and impairment.

Condition or disease Intervention/treatment Phase
Metastatic Prostate Cancer Prostate Cancer Metastatic Prostate Cancer Castrate Resistant Prostate Cancer Drug: Darolutamide Drug: Enzalutamide Phase 2

Detailed Description:

The goal of the trial is to assess cognitive and quality of life outcomes over the 52-week primary data collection period of the trial. This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with metastatic or non-metastatic CRPC (mCRPC or M0CRPC) treated with darolutamide or enzalutamide. This will be a multicenter trial conducted at 12 sites across the US.

The primary endpoint will be the percent change in the maximally changed cognitive domain by 24 weeks in each study arm. Patients will be stratified by age (<65, 65-80, > 80). Patients will be allowed to cross over from either treatment to the opposite treatment arm at 12 and 24 weeks if they meet any of the cross-over criteria as described in the protocol.

Cognitive assessments will be performed using Cambridge Neuropsychological Test Automated Battery (CANTAB), an internationally recognized software for assessing cognitive function and impairment. Tests available in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual.

Blood samples will be collected for exploratory genomic analyses (AR CAG repeat length, PHS, exosome analysis).

Patients will have the option to opt into an additional separate MRI sub-study. A subset of 40 patients (20 per arm) will undergo fMRI to measure percent signal change in the HP PFC circuit at baseline, 24 and 52 weeks or/and cross-over/end of treatment visit (if applicable).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Randomized Phase II Study of Androgen Receptor Directed Therapy on COGnitive Function in Patients Treated With Darolutamide or Enzalutamide (ARACOG)
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Darolutamide (DARO)
Patients will take DARO at a dose of 600 mg (300 mg ×2 tablets) by mouth twice daily beginning on Day 1, of Week 1. Patients will take DARO throughout planned treatment period or withdrawal of consent or progression of disease requiring change in therapy.
Drug: Darolutamide
Patients randomized to darolutamide.
Other Name: Nubeqa

Active Comparator: Enzalutamide (ENZ)
Patients will take ENZ at a dose of 160 mg PO once daily (QD), beginning on Day 1, of Week 1. Patients will take ENZ throughout planned treatment period or withdrawal of consent or progression of disease requiring change in therapy.
Drug: Enzalutamide
Patients randomized to enzalutamide.
Other Name: Xtandi




Primary Outcome Measures :
  1. Change in the maximally changed cognitive domain [ Time Frame: 24 weeks ]
    To compare the effects of treatment with enzalutamide (ENZ) versus darolutamide (DARO) on the cognitive function of men with non-metastatic and metastatic castration-resistant prostate cancer by comparing the change in the maximally changed cognitive domain utilizing Cambridge Neuropsychological Test Automated Battery [CANTAB] cognitive tests from baseline in patients in each study arm.Tests available in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual.


Secondary Outcome Measures :
  1. Crossover from enzalutamide to darolutamide and darolutamide to enzalutamide [ Time Frame: 52 weeks ]

    Proportion of patients crossing over from each treatment arm based on subjective (self-reported, FACT-Cognitive Function [Version 3], FACT-Cog V3, decline by >10 points from baseline score) cognitive effects.

    • Proportion of patients crossing over from each treatment arm based on objective cognitive effects (the Cambridge Neuropsychological Test Automated Battery [CANTAB] , decline by > 30% from baseline on any cognitive domain).
    • Proportion of patients crossing over from ENZ to DARO based on Timed Up and Go (TUG) times >12 seconds or 12 seconds or increase from baseline by >1 second.
    • Proportion of patient crossing over due to neurologic toxicity (fatigue) with a preference to cross over (ENZ or DARO) or severe neurological toxicity [seizures or posterior reversible encephalopathy syndrome PRES]). Cross over for severe neurologic toxicity is allowed for patients on ENZ only.

  2. Maximally changed cognitive domain [ Time Frame: 52 weeks ]
    Average decline in maximally changed cognitive domain in patients in each arm based on self-reported cognitive tests (Cambridge Neuropsychological Test Automated Battery [CANTAB]). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time. The maximally changed cognitive domain is defined as the domain most changed from baseline in each individual.

  3. Proportion of impaired patients [ Time Frame: 24 weeks ]
    Cumulative proportion of impaired patients in each arm

  4. Proportion of impaired patients [ Time Frame: 52 weeks ]
    Cumulative proportion of impaired patients in each arm

  5. Change in lowest ranking domain [ Time Frame: 24 weeks ]
    Average change in lowest ranking domain Cambridge Neuropsychological Test Automated Battery [CANTAB] questionnaire outcomes at baseline (in a given individual). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.

  6. Change in lowest ranking domain [ Time Frame: 52 weeks ]
    Average change in lowest ranking domain in Cambridge Neuropsychological Test Automated Battery [CANTAB] outcomes at baseline (in a given individual). Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.

  7. Improve in cognitive function after crossover [ Time Frame: 52 weeks ]
    Improvement in cognitive function after crossover from each treatment arm based on Cambridge Neuropsychological Test Automated Battery [CANTAB] modules. Tests in the CANTAB battery include tests of learning and executive function; working memory; visual, verbal and episodic memory; and attention, information and processing time.

  8. Prostate-specific antigen (PSA) progression. [ Time Frame: 104 weeks ]
    Estimation of the probability of PSA progression over time using the cumulative incidence function.

  9. Progression free survival [ Time Frame: 104 weeks ]
    Progression-free survival will be evaluated for each cohort.

  10. Prostate-specific antigen (PSA) response rate [ Time Frame: 24 weeks ]
    Estimation or the proportion PSA responses at 24 weeks (on the basis of a decrease from baseline of ≥ 50%)



Information from the National Library of Medicine

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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

Key inclusion criteria include:

  • Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
  • Progressive disease per PCWG3 criteria
  • Metastatic CRPC or non-metastatic CRPC (M0CRPC)

    • Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 3 PSA rises at least 1 week apart, with the last PSA >2 ng/mL.
    • For mCRPC: metastatic disease documented by standard or novel imaging techniques OR for M0CPRC: no evidence of metastatic disease on standard imaging.
  • Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRHa must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  • Able to complete cognitive testing and patient reported outcome surveys in English.
  • Ability to swallow study tablets whole.
  • Able to provide informed consent.

Key exclusion criteria include:

  • Prior chemotherapy for treatment of CRPC. Patients who received chemotherapy for castrate-sensitive prostate cancer are still eligible provided chemotherapy was completed >6 months prior to study entry.
  • Use of investigational agents for the treatment of prostate cancer within 4 weeks of study entry.
  • Prior usage of ENZ or DARO.
  • Prior use of apalutamide
  • Prior use of investigational agents that act on the androgen axis.
  • Progression during treatment with abiraterone (PSA or radiographic progression). Must have < 12 weeks of abiraterone exposure prior to enrollment if given for treatment of CRPC. If used with radiation for high risk localized hormone sensitive disease, can enroll if no progression of disease during treatment with abiraterone (PSA or radiographic) and >6 months since last exposure to abiraterone.
  • Planned radiation treatment > 21 days during enrollment in the study.
  • Any active, or prior history of, brain metastasis that have not been treated and stabilized.
  • Active or history of seizures or seizure disorder.
  • Prior diagnosis of dementia or other neurologic impairment.
  • Use of chronic opiates (other than stable doses of opioids that in the view of the patient and investigator do not affect cognition).
  • Clinically significant history of falls or risk of falls at baseline (timed up-and-go (TUG) test time of >12 seconds).

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): NCT04335682


Contacts
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Contact: Director Of Project Management 617-525-8627 info@alliancefoundationtrials.org

Locations
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United States, Illinois
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States, 60611
Contact: Alicia Morgans, MD, MPH         
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
Contact: Charles Ryan, MD         
Sponsors and Collaborators
Alliance Foundation Trials, LLC.
Bayer
Investigators
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Principal Investigator: Monica Bertagnolli, MD Alliance Foundation Trials
Publications:

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Responsible Party: Alliance Foundation Trials, LLC.
ClinicalTrials.gov Identifier: NCT04335682    
Other Study ID Numbers: AFT-47
First Posted: April 6, 2020    Key Record Dates
Last Update Posted: September 1, 2020
Last Verified: August 2020

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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
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases