The objective of this trial is to compare standard treatment with radium-223-chloride (proven surivval benefit) with treatment with rhenium-188-HEDP, which is nowadays only used for pain palliation. This trial includes patients with metastatic…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome of the study is the overall survival.
Secondary outcome
Secondary endpoints (main study)
- Time till PSA response
- Time till progression alkaline phosphatase
- Time till clinical progression
- Time till first skeletal related event
- Quality of life (comparison between both treatment arms)
- Pain response
- Incremental cost-effectiveness ratio (ICER); costs Quality Adjusted Life
Year (QALY)
Secondary endpoints (side studies)
- To collect blood samples (ctDNA, platelets and exosomes) for future research
- To determine the predictive value of 18F-DCFPyL PSMA uptake changes on PET/CT
for clinical response (e.g. progression vs. stable or partial metabolic
response) after the first radium-223-chloride or rhenium-188-HEDP therapy
(versus baseline), as defined in the PCWG2 criteria
- To correlate biochemical parameters changes (e.g. PSA, AF) with 18F-FCFPyL
PSMA uptake changes in metastatic lesions, during treatment.
(e.g. PSA, AF) with baseline 18F-DCFPyL PSMA uptake and changes in 18F-DCFPyL
PSMA uptake in tumor lesions during treatment
Background summary
Rhenium-188-HEDP is a bèta-emitting radiopharmacon connected to a
bisphosphonate. This complex will accumulate in osteoblastic bone metastases
after intravenous administration, and give local radiation to the metastases.
Unlike external body radiotherapy, this treatment is also suitable for patients
with multiple bone metastases. At this moment, the bèta-emitting
radiopharmaceuticals are used for their pain palliative effect. The systematic
review of Van Dodewaard et al. shows a relevant pain response in 60-80% of the
patients treated with rhenium-188-HEDP.
Although the effect of rhenium-188-HEDP on survival has not been investigated
yet, some studies suggest a survival benefit as well. Palmedo et al. randomized
58 patients between one or two injections of rhenium-188-HEDP. For both the
progression free survival (7.0 months versus 2.3 months) as for the overall
survival (12.7 versus 7.0 months), a significant benefit was seen for patients
treated with two injections. These data are supported by some retrospective
trials.
For the alfa-emitting radiopharmacon radium-223-chloride, a large phase III
trial comparing radium-233-chloride with placebo has been performed. This trial
showed a significant benefit in overall survival (median overall survival 14.9
months versus 11.3 months).Pain response was not an endpoint in this trial. The
above mentioned review estimates the pain response for radium-223-chloride
around 40-60% of the patients.
Rhenium-188-HEDP has some advantages compared to radium-223-chloride.
Rhenium-188-HEDP can be produced in a generator on site (hospital), which
ensures a fast availability. This 'own production' has a great impact on the
cost; the estimated price for treatment of one patient with rhenium-188-HEDP is
around 5000 euro's, whereas the price for treatment with radium-223-chloride is
around 30.000 euro's. In addition, the burden for patients is lower for
rhenium-188-HEDP as this has to be administered three times with an 8-week
interval (for radium-223-chloride this is six times with an interval of 4
weeks).Finally, the amount of patients with a pain response seems to be higher
for rhenium-188-HEDP.
Study objective
The objective of this trial is to compare standard treatment with
radium-223-chloride (proven surivval benefit) with treatment with
rhenium-188-HEDP, which is nowadays only used for pain palliation. This trial
includes patients with metastatic castration-resistant prostate cancer with
progressive disease after two previous treatment (other than LHRH analogues)
including docetaxel, or inability yo receive other treatments.
Both radiopharmaceuticals will be compared in terms of e.g. overall survival,
pain palliation and quality of life and costs.
Study design
MAIN STUDY
This trial is randomized, open, multicenter phase III trial. Patients will be
1:1 randomized between
- 3 intravenous administrations of rhenium-188-HEDP 40 MBq/Kg (with a maximum
of 3300 MBq) with an 8-weeks interval (experimental arm)
- 6 intravenous administrations of radium-223-chloride 55 kBq/kg, with an
4-week interval (standard treatment)
Prior to start of treatment, a bone scintigraphy and CT-thorax/abdomen will be
performed.
Patients will be stratified according to; including hospital, bone-scan index,
previous treatment with enzalutamide/abiraterone and previous treatment with
docetaxel.
Patients in both study arms will be seen every 4 weeks by their treating
physician, including laboratory tests and the request to fill in 3
questionnaires (VAS, EORTC QLQ 15 and EORTC QLQ BM22).
Treatment will be continued until progressive disease, completion of treatment,
unacceptable toxicity or death, whichever comes first. Follow up will continue
until death (during regular visits).
SIDE STUDIES (optional)
- Additional blood sampling: 3 bloodsamples each time, at 3 different
timepoints (baseline, cycle 3, before cycle 6) Blood collection will take
place during existing blood collection moments.
- Additional scanning: two 18F-DCFPyL PSMA PET/CT scans , at 2 different
timepoints (1 week before cycle 1, 1 week before cycle 2)
Intervention
Administration of 3 intravenous injections of rhenium-188-HEDP 40MBq/kg with an
8-week interval (experimental arm)
Administration of 6 intravenous injections of radium-223-chloride 55 kBq/kg
with a 4-week interval (control arm, standard treatment)
Study burden and risks
MAIN STUDY
Rhenium-188-HEDP group;
- six control visits every 4 weeks (same as standard treatment)
- three administrations of rhenium-188-HEDP (possibly in the Meander Medical
Center in Amersfoort if administration is impossible in the including hospital,
travel expenses will be compensated); 3 times less than standard treatment
- 3 questionnaires every 4 weeks (this is the only additional burden compared
to standard treatment)
Radium-223-chloride (standard treatment)
- six control visits every 4 weeks
- six administrations of radium-223-chloride
- 3 questionnaires every 4 weeks (this is the only additional burden compared
to standard treatment)
The greatest risk of this trial is the possibility that, however unexpected,
there might be no survival benefit of rhenium-188-HEDP.
The most relevant adverse events are of hematological origin. Based on the
literature, we expect a comparable toxicity profile of both
radiopharmaceuticals, so we do not expect any additional risks for the
experimental treatment arm.
SIDE STUDIES (optional)
We don't expect extra burden and/or risk associated with participation to
collect extra blood samples, since the blood sampling will take place during
existing blood collection moments. The burden and risk for the additional scans
are considered minimal. Patients will receive a venous cannula for tracer
injection, which might cause transient intravenous site discomfort or local
hematoma. The total additional radiation burden in this category of patients
(limited life expectancy and already undergo frequent imaging) in this side
study account to 16 mSv, which is in our opinion justified by the future mertis
from the scientic knowledge that can be obtained from this study. The scans
will be performed in VUmc, for this patients will be compensated. Patients will
have no direct benefits from participating in the sides studies. However, extra
blood collection and additional imaging will add to our knowledge for future
prostate cancer research
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
- male, 18 years and older
- histologically confirmed prostate cancer
- bone metastases (*6 lesions) with pathological uptake at bone scintigraphy
- WHO performance status *2
- life expectancy at least 6 months
- castration resistant disease (testosterone level *1.7nmol/L)
- Progression on or after two previous treatments (other than LHRH analogues) including docetaxel), or inability to receive other treatments.
- baseline PSA * 5 ng/ml with evidence of progressively increasing PSA
- symptomatic disease with either regular use of analgesic medication or treatment with external beam radiotherapy within the previous 12 weeks
- adequate renal and hematologic function
- written informed consent
Exclusion criteria
- treatment with chemotherapy within the previous 4 weeks
- treatment with abiraterone and enzalutamide within the previous 5 days
- Previous hemibody external radiotherapy
- systemic radiotherapy with radioisotopes within the previous 24 weeks
- malignant lymhpadenopathy * 3cm in short axis diameter
- presence of visceral metastases
- imminent of established spinal cord compression
- active uncontrolled infections
- history of another malignancy within the last 5 years except adequatly treated basal cell carcinoma of the skin
- any serious uncontrolled concomitant disease
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 | EUCTR2017-000699-27-NL |
| ClinicalTrials.gov | NCT03458559 |
| CCMO | NL61477.029.17 |