The Split Dose Study: Split dose Rhenium-188-HEDP regimen in hormone refractory prostate cancer patients with bone metastases; a phase I toxicity study and phase II efficacy study.

Prostate cancer is currently one of the most common malignancies worldwide.
About 50-70% of patients with prostate cancer present a locally advanced stage
and about 15-30% have bone metastases at the time of diagnosis. Metastatic
disease may also develop after treatment for localized disease. Although a vast
majority of patients initially respond to hormone treatment most, if not all,
patients subsequently relapse and progresses from an androgen-dependent to an
androgen-independent state. Approximately 65% of patients with bone metastases
suffer from bone painand require palliative treatment.
Rhenium-188-HEDP is a radiopharmaceutical that has an affinity for skeletal
tissue and that concentrates in areas of bone turnover secondary to invasion by
tumor. It is used for the treatment of metastatic bone pain.
Repeated administrations with a relatively short interval may lead to an
enhanced effect compared to single treatments alone. Furthermore it is
recognized that the therapeutic effect of radionuclide therapy is increased in
patients with a less advanced stage of their disease. Repeated dosing may have
a better effect on larger metastatic lesions in patients with a more advanced
stage. While most patients who are presented for radionuclide therapy suffer
from an advanced stage of their disease splitting the dose with a short
interval may enhance efficacy.

The primary aim of the phase I part of this trial is to establish the safety of
a split dose regimen of Re-188-HEDP . The primary aim of the phase II part of
this trial is to obtain insight in the efficacy of a split dose regimen of
Re-188-HEDP , as reflected by PSA.
Secondary objectives will be: To determine the biodistribution of Re-188-HEDP;
To study hematological toxicity; To monitor pain; To monitor analgesic
consumption; To monitor quality of life by a HRQOL questionnaire. To monitor
bone metabolism with the measurement of bone markers.

This will be a combined phase I/II, uncontrolled, non-randomized, open-label
study in hormone refractory prostate cancer patients with osteoblastic bone
metastases.

Re-188-HEDP will be administered in a split dose of 18.5 MBq/kg with 2 weeks
interval through an established intravenous (IV) line over a period of 1
minute.15 successive patients will be treated. If a dose limiting toxicity
occurs in at least 2/3 or 2/6 patients the study will be discontinued.
The patients will undergo 2 times total body scintigraphy 6 hours after
administration of re-188-HEDP in week 1 and 3, and urine collection during 8
hours. Blood samples for safety will be taken each week. A blood sample for PSA
measurement will be taken at screening and in weeks 7 and 11. Patients will be
asked to keep a pain and medication diary throughout the study, and to fill out
a HRQOL questionnaire before treatment and in weeks 7 and 11.

The extra burden to the patient consists of:
1 screening visit
2 hospital admissions for treatment with Re-188-HEDP
2 total body scans
2 outpatient visits
12 blood samples for safety and/or PSA
keeping a pain and medication diary during 10 weeks
4 urine samples for bone marker measurement
3 HRQOL questionnaires
The possible risks are related to the side effects of Re-188-HEDP and the
possibility of bruising from blood sampling or intravenous injection.
The radiation dose from Re-188-HEDP (mean dose 1400 mSv) does not form a large
risk to the patient and does not impose any restrictions for medical
investigations or treatments with radiation the patient may need in the future.

The patient may benefit from pain relief.