Primary objectives- 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 6 weeks of…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- The primary aim is to show that a reduced dose (120mg OD) results in less
fatigue (measured by the change in FACIT-fatigue subscale score) after 6 weeks
of therapy compared to the standard dose (160mg OD) for frail metastatic
castration resistant prostate cancer patients.
Secondary outcome
- To explore if the change in FACIT-fatigue subscale score is different between
the two arms of the study from start of therapy; an early measurement of
fatigue is performed at 6 weeks, and to explore if there remains a difference
between the two arms from baseline - up untill 6 months of therapy, the
questionnaire is repeated after 6 months of therapy.
- To explore the change in FACIT-cognition subscale score over time: from
baseline to 6 weeks, 12 weeks and 24 weeks after start of therapy between the
two arms of the study (reduced dose vs standard dose)
- To explore the change in GDS-15 subscale score over time: from randomization
to 6 weeks, 12 weeks and 24 weeks after start of therapy between the two arms
of the study (reduced dose vs standard dose)
- To compare the percentage of patients that develop depression (score>5 ) on
GDS-15 questionnaire between the two arms of the study (reduced dose vs
standard dose) over time: after 6 weeks, 12 weeks and 24 weeks months after
start if therapy
- To correlate the change in side effects with plasma concentrations (Ctrough)
of enzalutamide and N-desmethyl enzalutamide
- To evaluate the proportion (%) of patients in control arm (standard dose)
that remain on allocated dose level until the end of the study
- To evaluate treatment efficacy for both arms of the study according to PCWG3
Background summary
Prostate cancer is worldwide the second most commonly diagnosed cancer in men
and also one of the most common causes of death related to cancer for men.
Strategies to block androgen-receptor signaling have formed the backbone of
prostate-cancer therapy since the first description of the hormonal dependence
of this cancer in 1941. Androgen deprivation therapy results in tumor
regression, relief of symptoms and a decrease in the concentration of
prostate-specific antigen (PSA) in most patients. The understanding that
castration resistant prostate cancer remains androgen driven changed the
landscape of treatment for CRPC dramatically. Several hormonal therapy agents
targeted to extragonadal androgen signaling pathways have been developed since
2010. Treatment efficacy was shown by abiraterone acetate and enzalutamide in
patients with mCRPC.. This oral anti-androgen directed therapy allow patients
unfit for chemotherapy to receive an effective though palliative therapy.
Consequently the mCPRC patients treated today have more treatment options and
are a generally older (median age 70) population with a vast amount of
co-morbidities and co-medication. Side effects of these palliative therapies
are important for quality of life of mCRPC patients. Fatigue/asthenia is one of
the most frequently reported side effect of enzalutamide. 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 central
nervous system (CNS). This might be related to the CNS side effects that were
later seen in the phase 1 study where fatigue was found to be a dose-dependent
adverse event. At dosages of 240mg and above an increasing proportion of
patients required dose reductions due to side effects. After dose reductions
the symptoms resolved. This was also found in a retrospective study of Japanese
mCRPC patients (n=345) in which the side effects malaise and nausea decreased
remarkably after dose reduction. Age>75 years was a predictor for side
effects9. Furthermore in the post hoc analysis of the PREVAIL trial, a higher
rate of falls (13.8% vs. 5.6%) was found for elderly patients (>75years)
treated with enzalutamide compared to placebo (19.2% vs. 7.9%) indicating that
enzalutamide has a negative effect on the cognition in elderly. No
exposure-response relation was observed in the study of Gibbons et al.
Additionally, in a phase 1 trial of enzalutamide FDHT PET scans revealed that
enzalutamide substantially displaced FDHT binding with a maximum effect seen at
150mg (corresponding with a Ctrough of 11,4 mg/L) was only minimally higher
than seen at 60mg (corresponding with a Ctrough of 5mg/L)18. This suggests
that androgen receptor binding may be saturated at serum levels of ~5-11,4 mg/L
enzalutamide. Therefore, a minimum trough concentration of 5.0 mg/L could be
considered as a target for exposure to enzalutamide.
Our hypothesis is that there is a relation between enzalutamide and or
N-desmethylenzalutamide concentrations and CNS associated side effects such as
fatigue. In particular, frail (m)CRPC patients are more prone for to develop
CNS side effects on enzalutamide and that dose reduction to 75% (120mg) can be
safely done to treat (m)CRPC in these patients with preserving optimal efficacy.
No prospective trials on the effect of a priori dose reduction on CNS side
effects has been published yet.
We aim to demonstrate that the patients treated at a reduced dose develop less
side effects compared to the patients treated at the standard dose with
maintenance of equivalent efficacy. Thereto, we designed an randomized
controlled study in frail patients with (m)CRPC in whom we would like to
explore if side effects such as fatigue, impaired cognition, worsened
depression are affected by the enzalutamide dose (exposure).
Study objective
Primary objectives
- 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 6 weeks of treatment
Secondary objectives
- 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
- 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) after six weeks,12 weeks and 24 weeks of treatment
- 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) after six weeks, 12 weeks and 24 weeks of treatment
- To correlate exposure (Ctrough) of enzalutamide and N-desmethylenzalutamide
to the measured CNS side effects
- To determine the percentage (%) of subjects that remained on the allocated
dose level until the end of the study
- To evaluate the effect of dose reduction on treatment efficacy according to
PCWG3
* facit-fatigue questionnaire
** facit-cognition questionnaire
*** geriatric depression scale 15 (GDS-15)
Study design
The study is a open label randomised (1:1) controlled phase IV study in 50
(25:25) frail (m)CRPC patients
Intervention
patients who are randomised to arm B of the study receive a reduced doser of
enzalutamide (120mg) vs arm A (standard dose 160mg)
measurement of side effects: fatigue, cognition, depression
Study burden and risks
The risk-classification is assessed as negligible for the patients
participating in this study. Enzalutamide is registered in the Netherlands for
mCRPC patients. No exposure-response relation was observed in the study of
Gibbons et al. Additionally, the phase I trial of enzalutamide showed that
androgen receptor binding may be saturated at serum levels of ~5-11,4 mg/L
enzalutamide, corresponding with 60mg to 150mg. Therefore, the reduced
enzalutamide dose for the frail patients in this study will theoretically not
result in underexposure and thereby suboptimal treatment outcomes, when plasma
concentrations remain >= 5mg/L that was found in the phase I trial of
enzalutamide. Thereto plasma concentrations of enzalutamide and
N-desmethylenzalutamide are measured at 6 weeks, 12 weeks and 24 weeks. The
dose will be adjusted instantly if the exposure is suboptimal (enzalumide
concentration below 5 mg/L
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
- Frail* male patients with prostate cancer who will start treatment with
enzalutamide
(* Frail is defined as a score on the comprehensive G8 assessment with cut-off
<12 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.)
- Age at least 18 years
- Patient who are able and willing to give written informed consent prior to
screening and enrolment
- Patients from whom it is possible to collect blood samples
- Patients who are willing to answer the questionnaires
- Life expectancy of > 6 months
- Capable of understanding and answering Dutch tests and questionnaires, as
determined by the investigator
Exclusion criteria
- Other causes for cognition change (change in dose of
opioids/sedatives/benzodiazepines) during last 2 weeks before study)
- Use of psychostimulantia 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 fatigue or
cognition change within 4 weeks of study entry
- Clinical relevant anaemia
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000779-33-NL |
| CCMO | NL65223.091.18 |