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

Radboud University Medical Center

Status and phase

Completed

Phase 4

Conditions

Prostatic Neoplasms, Castration-Resistant

Treatments

Drug: Enzalutamide

Study type

Interventional

Funder types

Other

Identifiers

NCT03927391

REDOSE

Details and patient eligibility

About

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.

Enrollment

57 patients

Sex

Male

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.