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Effect of a Reduced Dose Enzalutamide in Frail (m)CRPC Patients on Cognitive Side Effects (REDOSE)

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ClinicalTrials.gov Identifier: NCT03927391
Recruitment Status : Recruiting
First Posted : April 25, 2019
Last Update Posted : July 31, 2019
Sponsor:
Information provided by (Responsible Party):
Radboud University

Brief Summary:
Prostate cancer is the most commonly diagnosed cancer among men in Western countries. When the disease recurs as castration-resistant prostate cancer (CRPC) it is associated with a median overall survival of approximately 2 years with significant decrement in quality of life due to additional cancer-specific and treatment-induced morbidity. Palliative agents currently used in the CRPC setting include the 2nd generation hormonal agents abiraterone acetate and enzalutamide but also radium-223, docetaxel and cabazitaxel. Choices for treatment strategies are based on multiple factors such as age, co-morbidity and drug toxicity profile. The side effect profile of enzalutamide is associated with central nervous system (CNS side effects) such as fatigue and depression. The mechanism for these side effects is not yet fully understood, but it was shown in rodent studies that enzalutamide and its active metabolite penetrate into the CNS. This might cause the CNS side effects that were later seen in the phase 1 study where fatigue was found to be a dose-dependent adverse event. After dose reductions the symptoms resolved. This was also found in a retrospective study of Japanese metastatic CRPC (mCRPC) patients (n=345) in which the side effects malaise and nausea decreased remarkably after dose reduction. However, no exposure-response relation was observed in the study of Gibbons et al. Additionally, based on the data of the phase 1 trial of enzalutamide it can be suggested that a minimum trough concentration of 5.0 mg/L could be considered as a target for exposure to enzalutamide. In particular, frail (m)CRPC patients are more prone to develop CNS side effects on enzalutamide. The investigator's hypothesis is that dose reduction to 75% (120mg) can be safely done to treat (m)CRPC in these patients with preserving optimal efficacy and less CNS side effects.

Condition or disease Intervention/treatment Phase
Prostatic Neoplasms, Castration-Resistant Drug: Enzalutamide Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Normal enzalutamide dose versus reduced dose in two patient groups
Masking: Single (Outcomes Assessor)
Masking Description: Outcome assessor does not know the treatment arm
Primary Purpose: Treatment
Official Title: Effect of a Reduced Dose on Cognitive Side Effects of Enzalutamide in Frail (Metastatic) Castration-resistant Prostate Cancer Patients (REDOSE)
Actual Study Start Date : May 30, 2019
Estimated Primary Completion Date : May 1, 2021
Estimated Study Completion Date : December 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Active Comparator: reference (normal) dose
Normal dose of enzalutamide (160mg once daily)
Drug: Enzalutamide
enzalutamide treatment

Experimental: test (reduced) dose
Reduced dose of enzalutamide (120mg once daily)
Drug: Enzalutamide
enzalutamide treatment




Primary Outcome Measures :
  1. To determine the change in the CNS side effect fatigue* in frail (m)CRPC patients treated with a reduced dose of enzalutamide (120mg OD) compared to the standard dose of enzalutamide (160mg OD) after 6 weeks of treatment. [ Time Frame: 6 weeks ]
    *fatigue is measured by the self-reported FACIT-fatigue questionnaire version 4 (Dutch version). Functional Assessment of Chronic Illness Therapy-Fatigue. 13-items are scored on a 5-point scale. All items except items 7 (I have energy) and 8 (I am able to do my usual activities) are reverse-scored before item scores are summed to obtain a total score (range 0-52). Higher scores reflect less fatigue.4 (Dutch version): Functional Assessment of Chronic Illness Therapy-Fatigue. 13-items are scored with a total score ranging 0-52. Higher scores reflect less fatigue.


Secondary Outcome Measures :
  1. To determine the decrease in the CNS side effect fatigue in frail (m)CRPC patients treated with a reduced dose of enzalutamide (120mg OD) compared to the standard dose of enzalutamide (160mg OD) after 12 weeks, and 24 weeks of treatment. [ Time Frame: 12 weeks and 24 weeks ]
    fatigue is measured by the self-reported FACIT-fatigue questionnaire version 4 (Dutch version). Functional Assessment of Chronic Illness Therapy-Fatigue. 13-items are scored on a 5-point scale. All items except items 7 (I have energy) and 8 (I am able to do my usual activities) are reverse-scored before item scores are summed to obtain a total score (range 0-52). Higher scores reflect less fatigue.

  2. To determine the impact of cognition impairment in quality of life in frail (m)CRPC patients treated with a reduced dose of enzalutamide (120mg OD) compared to the standard dose of enzalutamide (160mg OD). [ Time Frame: 6, 12 and 24 weeks ]
    The impact of cognition impairment in quality of life is measured by the self-repored FACT-cog questionnaire. FACT-cog: Functional Assessment of Cancer Therapy - For patients with Cognitive function issues. There are 4 subscale scores (perceived cognitive impairments (range 0-72), impact of perceived cognitive impairments on quality of life (range 0-16), comments from others (range 0-16) and percieved cognitive abilities (range 0-28). All subscale scores are summed to derive a total score. The higher the score, the better quality of life.

  3. To determine cognition impairment in frail (m)CRPC patients treated with a reduced dose of enzalutamide (120mg OD) compared to the standard dose of enzalutamide (160mg OD). [ Time Frame: 6, 12 and 24 weeks ]
    cognition impairment is measured by the MoCA test. Montreal Cognitive Assessment, is a test for cognition. It covers 8 tasks: attention and concentration, executive functions, memory, language, visuospatial abilities, abstract thinking, calculating abilities and orientation. The maximum score is 30 points. The higher the score, the better the cognition is.

  4. To evaluate changes in depression score in frail (m)CRPC patients treated with a reduced dose of enzalutamide (120mg OD) compared to the standard dose of enzalutamide (160mg OD). [ Time Frame: 6, 12 and 24 weeks ]
    Geriatric depression scale 15 (GDS-15): 15 question using an ordinal score (yes/no). Total score: maximum 15 points. A score of 0 to 5 is normal. A score greater than 5 suggests depression.

  5. To correlate exposure (Ctrough) of enzalutamide and n-desmethylenzalutamide to the CNS side effects. [ Time Frame: 6, 12 and 24 weeks ]
    Correlations of Ctrough and CNS side effects

  6. To determine the percentage (%) of subjects that remained on the allocated dose level until the end of the study. [ Time Frame: 6, 12 and 24 weeks ]
    % subjects that without dose reductions or dose increments

  7. To evaluate the effect of dose reduction on treatment efficacy according to prostate cancer working group 3 (PCWG3). [ Time Frame: 6, 12 and 24 weeks ]
    Effect of dose reduction (120mg) on treatment efficacy



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
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Prostate cancer is only prevalent in the male population
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Frailᵃ male patients with prostate cancer who will start treatment with enzalutamide within label
  • Age at least 18 years
  • Patient who are able and willing to give written informed consent prior to screening
  • Patients from whom it is possible to collect blood samples
  • Patients who are willing to answer the questionnaires and test
  • Life expectancy of > 6 months
  • Capable of understanding and answering Dutch tests and questionnaires, as determined by the investigator

ᵃ Frail is defined as:

  • a score on the comprehensive G8 assessment with cut-off ≤14 points and
  • score ≥grade 1 for Central Nervous Disorders according to the Common Toxicity Criteria Adverse Event (CTCAE) criteria, of one of the following: Fatigue, Concentration impairment, cognitive disturbance, amnesia, depressed level of consciousness, memory impairment, hypersomnia.

Exclusion Criteria:

  • change in dose of opioids/sedatives/benzodiazepines during last 2 weeks before study)
  • Use of psychostimulants such as methylphenidate within 1 week of start of study
  • Diagnosed with medical conditions that affect cognition: Dementia, Alzheimer disease, Parkinson's disease, psychiatric disorders that affect cognition other than depression or anxiety complaints related to the disease
  • Active infection or other comorbidities that may contribute to REDOSE, February 2019 Page 7 of 53 fatigue or cognition change within 4 weeks of study entry
  • Clinical relevant anaemia
  • MoCa score <20
  • Hypersensitivity to the active substance or to any of the excipients.

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): NCT03927391


Contacts
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Contact: n van Erp +31243610000 nielka.vanerp@radboudumc.nl

Locations
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Netherlands
CWZ Not yet recruiting
Nijmegen, Netherlands
Contact: Rik Somford, Dr         
Radboudumc Recruiting
Nijmegen, Netherlands
Contact: Nielka van Erp, Dr.         
Sub-Investigator: Inge van Oort, Dr.         
Sub-Investigator: Niven Mehra, Dr.         
Franciscus Gasthuis en Vlietland hospital Recruiting
Rotterdam, Netherlands
Contact: Paul Hamberg, Dr         
Sponsors and Collaborators
Radboud University

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03927391     History of Changes
Other Study ID Numbers: REDOSE
First Posted: April 25, 2019    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Radboud University:
enzalutamide
cognitive side effects
Additional relevant MeSH terms:
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Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases