Clinical trial NCT03458559: Rhenium-188-HEDP vs. Radium-223-chloride in Patients With Advanced Prostate Cancer Refractory to Hormonal Therapy
Official title: Repeated Rhenium-188-HEDP Versus Radium-223-chloride in Patients With Metastatic Castration-resistant Prostate Cancer: The RaRe Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Prostate Cancer Metastatic to Bone
Keywords: Bone metastases
Rhenium-188-HEDP
Radium 223-chloride
Survival
Prostate cancer
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2018-03-08
Enrollment: 402
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized between

* radium-223-chloride intravenously, for a total of 6 administrations (every 4weeks)
* rhenium-188-HEDP intravenously for a total of 3 administratrions (every 8 weeks)
Primary purpose: TREATMENT

Brief summary: Radium-223 chloride is an alpha-emitting radiopharmaceutical with proven survival benefit in patients with castration-resistant prostate cancer metastatic to bone. Beta-emitting radiopharmaceuticals have proven efficacy for palliating malignant bone pain. Nowadays, rhenium-188-HEDP is used in clinical practice for pain relief and palliative care. Several studies suggest that also rhenium-188-HEDP has the potential to improve overall survival. The purpose of this study is to investigate if treatment with rhenium-188-HEDP results in improvement of overall survival compared to treatment with radium-223-chloride.

Detailed description: The main objective of this trial is to compare rhenium-188-HEDP (a beta-emitting radiopharmaceutical) with radium-223-chloride (an alfa-emitting radiopharmaceutical), in patients with castration-resistant prostate cancer metastatic to bone, with overall survival as primary endpoint.

For radium-223-chloride, an overall survival benefit has been proven in a large randomized phase III trial. Although such a trial has never been performed for rhenium-188-HEDP, some trials in literature suggest a survival benefit for rhenium as well.

Rhenium has some advantages compared to radium. Firstly, it is easily available as it can be produced in the hospital. Secondly, the costs of rhenium are significantly lower compared to radium. Lastly, rhenium seems to have a favorable pain response. However, no randomized trials have been performed to confirm this.

Eligibility criteria: Inclusion Criteria:

* Male, 18 years or older
* Histologically confirmed prostate cancer
* Bone metastases (≥ 6 lesions) showing pathological uptake at bone scintigraphy.
* WHO performance status of ≤2
* Life expectancy of at least 6 months
* Castration-resistant disease: serum testosterone level of ≤ 1.7 nmol per liter (≤50 ng per deciliter) after bilateral orchiectomy or during maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist. During study treatment the maintenance androgen-deprivation therapy must be continued.
* Baseline PSA ≥5 ng/ml with evidence of progressively increasing PSA values
* Symptomatic disease with either regular use of analgesic medication or treatment with external-beam radiotherapy for cancer-related bone pain within the previous 12 weeks.
* Progression on or after treatment with docetaxel, or inability to receive docetaxel.
* Adequate renal function (serum creatinine level ≤1.5 x ULN)
* Adequate hematological function defined as absolute neutrophil count ≥ 1.5x10\^9/L and platelet count ≥100x 10\^9/L)
* Written informed consent

Exclusion Criteria:

* Treatment with chemotherapy within the previous 4 weeks
* Continuation of treatment with abiraterone or enzalutamide
* Previous hemibody external radiotherapy
* Systemic radiotherapy with radioisotopes within the previous 24 weeks
* Malignant lymphadenopathy ≥3cm in the short-axis diameter
* Presence of visceral metastases
* Imminent of established spinal cord compression
* Active uncontrolled bacterial, viral or fungal infection
* History of another malignancy within the last five years except adequately treated basal cell carcinoma of the skin
* Organ allografts requiring immunosuppressive therapy.
* Any serious uncontrolled concommitant disease
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule: those conditions should be discussed with the patient before registration in the trial.

Primary outcomes:
measure: Overall survival
timeFrame: Time from randomization until death due to any cause, an average of 18 months
Secondary outcomes:
measure: Time to PSA progression
timeFrame: Time from randomization to the date of a minimum of rising PSA levels, an average of 8 months (PSA measured at baseline and every 4 weeks).
measure: Time to total-ALP progression
timeFrame: Time from randomization to the date of earliest objective evidence of ALP progression, an average of 8 months (ALP measure at baseline and every 4 weeks)
measure: Clinical progression
timeFrame: Time from randomization to the date of first clinical progression, an average of 12 months
measure: Time to first SRE
timeFrame: Time from randomization to the date of first skeletal related events, an average of 12 months
measure: Quality of life
timeFrame: Assessed through study completion, an average of 1 year
measure: Effect on pain
timeFrame: Assessed through study completion, an average of 1 year
measure: Incremental Cost Effectiveness Ratio (IVER)
timeFrame: Assessed through study completion, an average of 1 year
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Alfons JM van den Eertwegh, Prof.dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Palmedo H, Manka-Waluch A, Albers P, Schmidt-Wolf IG, Reinhardt M, Ezziddin S, Joe A, Roedel R, Fimmers R, Knapp FF Jr, Guhlke S, Biersack HJ. Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol. 2003 Aug 1;21(15):2869-75. doi: 10.1200/JCO.2003.12.060.
citation: Biersack HJ, Palmedo H, Andris A, Rogenhofer S, Knapp FF, Guhlke S, Ezziddin S, Bucerius J, von Mallek D. Palliation and survival after repeated (188)Re-HEDP therapy of hormone-refractory bone metastases of prostate cancer: a retrospective analysis. J Nucl Med. 2011 Nov;52(11):1721-6. doi: 10.2967/jnumed.111.093674. Epub 2011 Oct 5.
citation: Jong JM, Oprea-Lager DE, Hooft L, de Klerk JM, Bloemendal HJ, Verheul HM, Hoekstra OS, van den Eertwegh AJ. Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review. Eur Urol. 2016 Sep;70(3):416-26. doi: 10.1016/j.eururo.2015.09.005. Epub 2015 Sep 19.