Radium-223 in Patients With Hormone Refractory Prostate Cancer (HRPC) and Skeletal Metastases

• Estimation of whole-body retention of radioactivity at each imaging time post-injection [ Time Frame: 1 week ] [ Designated as safety issue: No ]
• Radiation Dosimetry: Estimation of the individual organ uptake/retention of radioactivity at each time-point post injection [ Time Frame: 1 week ] [ Designated as safety issue: No ]
• Estimate retention of administered radioactivity in blood [ Time Frame: 2 days ] [ Designated as safety issue: No ]
• Estimation of elimination of radioactivity in urine and faeces [ Time Frame: 2 days ] [ Designated as safety issue: No ]
• Radiation Dosimetry: Calculation of estimated absorbed radiation dose to target organs [ Time Frame: 1 week ] [ Designated as safety issue: No ]
• Pharmacokinetics [ Time Frame: 1 week ] [ Designated as safety issue: No ]

• Imaging: Comparison of the biodistribution and dosimetry after the first and second injection [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]
• Safety: Adverse events [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• Safety: Laboratory variables; serum biochemistry and haematology [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• Safety: Vital signs (systolic/diastolic blood pressure, respiratory rate, heart rate and body temperature) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
• Safety: ECG (12 leads) [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
• Safety: Physical examination [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

• Imaging: • Comparison of the biodistribution and dosimetry after the 1. and 2. injection • Comparison of the biodistribution and dosimetry of the study drug between different patients • Change in metabolic activity in bone metastases
• Safety: • Adverse events • Laboratory variables • Vital signs • ECG (12 leads) • Physical examination
• PSA response: • PSA decline, defined as number of patients with a confirmed ≥ 50% reduction in PSA level after treatment with respect to the pre-injection PSA level. • The time to PSA progression after PSA response.
• Survival: Survival data will be collected at 6 and 12 months after first injection.

The purpose of this study is to evaluate the biodistribution, radiation dosimetry, pharmacokinetics and safety of the investigational radioisotope Radium-223, Alpharadin, in men with prostate cancer and bone metastases that no longer respond to hormonal treatment

This is an open-label, biodistribution, radiation dosimetry, pharmacokinetic, safety and efficacy study of Alpharadin treatment. The treatment consists of at least two intravenous administrations of Alpharadin.

The target population is patients with asymptomatic or symptomatic (e.g. bone pain) hormone refractory prostate cancer, with documented skeletal metastases.

The study is designed to investigate safety, biodistribution, radiation dosimetry and pharmacokinetics of two separate IV administrations of Alpharadin (100 kBq/kg b.w.) separated by six weeks.

Furthermore, the secondary objectives of the study are:

• To evaluate treatment response (antitumor effect in osteoblastic bone metastases) of Alpharadin treatment consisting of two injections of activity 100 kBq/kg b.w. 6 weeks apart
• To evaluate long-term radiation toxicity
• Survival data will be collected at 6 and 12 months after the first injection

• Hormone Refractory Prostate Cancer
• Bone Metastases

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of the prostate.

2. Hormone refractory with evidence of rising PSA:

   • Patient must be maintained on androgen ablation therapy with LHRH agonist (stable dose for at least 8 weeks prior to study entry), or have undergone bilateral orchiectomy
   • Serum testosterone level is required to be </=50 ng/dl

   • Patients who have received prior antiandrogen drug therapy:

     • Flutamide, nilutamide or cyproterone acetate must have stopped at least four weeks prior to study drug administration and progression, as defined by rising PSA as defined below, must have been demonstrated since cessation;
     • Bicalutamide must have stopped at least six weeks prior to study drug administration and progression, as defined by rising PSA as defined below, must have been demonstrated since cessation

   • PSA progression

     • Progressive rise in PSA, defined as two consecutive increases in PSA documented over a previous reference value (measure 1). The first increase in PSA (measure 2) should occur at a minimum of 1 week from the reference value (measure 1). This increase in PSA should be confirmed (measure 3) after a minimum of 1 week. If the confirmatory PSA value (measure 3) is less than the previous value, the patient will still be eligible provided the next PSA measure (measure 4) is found to be greater than the second PSA value (measure 2).
3. Skeletal metastases confirmed by bone scintigraphy within the last 6 weeks
4. Performance status: ECOG 0-2
5. Life expectancy: >/= 6 months

6. Laboratory requirements:

   • Neutrophil count >/= 1.5 x 109/L
   • Platelet count >/= 100 x109/L
   • Haemoglobin >/= 95 g/L
   • Total bilirubin level within normal institutional limits
   • ASAT and ALAT </= 2,5 times upper institutional limit of the normal range
   • S-Creatinine </= 1,5 times upper institutional limit of the normal range
7. The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow-up visits and examination
8. Able and willing to give written informed consent.

Exclusion Criteria:

1. Has received an investigational drug within 4 weeks prior to the administration of radium-223, or is scheduled to receive one during the treatment and post-treatment period
2. Has received chemo-, immunotherapy, or external radiotherapy within the last 4 weeks prior to administration of study drug, or has not recovered from adverse events due to agents administered more than 4 weeks earlier
3. More than one regimen of previous cytotoxic chemotherapy
4. Has received prior hemibody external radiotherapy
5. Has a need for immediate external radiotherapy
6. Has received systemic radiotherapy with radium-223, strontium-89, samarium-153, rhenium-186 or rhenium-188 for the treatment of bony metastases within the last year prior to administration of study drug.
7. Has started treatment with bisphosphonates less than 3 months prior to administration of study drug. Patients are allowed to be on bisphosphonates provided patient is on a stable dose for >/= 12 weeks before administration of study drug.
8. Patients who are </= 4 weeks (6 weeks for bicalutamide) post withdrawal of antiandrogen therapy
9. Patients who have started or stopped systemic steroids, within a week prior to study drug administration, or are expected to be subject to changes in the systemic steroid medication
10. Other currently active (relapse within the last 3 years) malignancy (except non-melanoma skin cancer) that are not prostate cancer metastases
11. Visceral (e.g. liver, lung) metastases from prostate cancer as assessed by abdominal/ pelvic CT or chest radiograph within six weeks before administration of study drug;
12. Lymph node metastases with short-axis diameter greater than 2 cm.
13. Bulky loco-regional disease

14. Any other serious illness or medical condition, for example:

    • any uncontrolled infection
    • any patient who has clinical heart failure severe enough to cause marked limitation of activity, and who is only comfortable at rest; or any patient who has heart failure more severe than this (NYHA Heart Failure Class III or IV).
    • Crohns disease or ulcerative colitis