Effect of a Reduced Dose on Cognitive Side Effects of Enzalutamide in Frail (Metastatic) Castration-resistant Prostate Cancer Patients (REDOSE)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 57
- 试验地点
- 3
- 主要终点
- 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.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Outcome assessor does not know the treatment arm
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
reference (normal) dose
Normal dose of enzalutamide (160mg once daily)
干预措施: Enzalutamide (Drug)
test (reduced) dose
Reduced dose of enzalutamide (120mg once daily)
干预措施: Enzalutamide (Drug)
结局指标
主要结局
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.
时间窗: 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.
次要结局
- To evaluate the effect of dose reduction on treatment efficacy according to prostate cancer working group 3 (PCWG3).(6, 12 and 24 weeks)
- To correlate exposure (Ctrough) of enzalutamide and n-desmethylenzalutamide to the CNS side effects.(6, 12 and 24 weeks)
- 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 percentage (%) of subjects that remained on the allocated dose level until the end of the study.(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 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)