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

NCT03927391 | Completed Phase 4

• 1 other identifier: REDOSE
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 3

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.

Conditions

Prostatic Neoplasms, Castration-Resistant

Keywords

enzalutamide; cognitive side effects

Outcome Measures

Primary Outcomes (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.

  \*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.

  6 weeks

Secondary Outcomes (7)

• 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.

  12 weeks and 24 weeks

• 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).

  6, 12 and 24 weeks

• 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).

  6, 12 and 24 weeks

• 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).

  6, 12 and 24 weeks

• To correlate exposure (Ctrough) of enzalutamide and n-desmethylenzalutamide to the CNS side effects.

  6, 12 and 24 weeks

Study Arms (2)

reference (normal) dose

ACTIVE COMPARATOR

Normal dose of enzalutamide (160mg once daily)

Drug: Enzalutamide

test (reduced) dose

EXPERIMENTAL

Reduced dose of enzalutamide (120mg once daily)

Drug: Enzalutamide

Interventions

Enzalutamide DRUG

enzalutamide treatment

reference (normal) dose; test (reduced) dose

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Prostate cancer is only prevalent in the male population
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (3)

CWZ

Nijmegen, Netherlands

Location

Radboudumc

Nijmegen, Netherlands

Location

Franciscus Gasthuis en Vlietland hospital

Rotterdam, Netherlands

Location

Related Publications (1)

• Boerrigter E, Overbeek JK, Benoist GE, Somford DM, Hamberg P, Tol J, Scholtes B, Willemsen AECAB, Buffart LM, Kessels RPC, Mehra N, van Oort IM, van Erp NP. A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer. Eur Urol Oncol. 2024 Dec;7(6):1376-1383. doi: 10.1016/j.euo.2024.02.009. Epub 2024 Mar 13.

  PMID: 38485614 RESULT

MeSH Terms

Conditions

Prostatic Neoplasms, Castration-Resistant

Interventions

enzalutamide

Condition Hierarchy (Ancestors)

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Outcome assessor does not know the treatment arm
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Normal enzalutamide dose versus reduced dose in two patient groups

Study Record Dates

• First Submitted: March 29, 2019
• First Posted: April 25, 2019
• Study Start: May 30, 2019
• Primary Completion: January 8, 2024
• Study Completion: January 8, 2024
• Last Updated: June 12, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3)