A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases (ENTHUSE M1)

• Progression Free Survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 31 months ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation until clinical progression of disease, where progression is defined, using RECIST, as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline, using the Kaplan-Meier method
• Time to Use of Opiates [ Time Frame: From date of randomization until use of opiates for disease-related symptoms for a duration ≥1 week, assessed up to 31 months ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation until use of opiates for disease-related symptoms for a duration ≥1 week using the Kaplan-Meier method
• Incidence of Skeletal Related Events [ Time Frame: From date of randomization until occurrence of a skeletal related event, assessed up to 31 months ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation until occurrence of a skeletal related event, where skeletal related event is defined as the first occurrence of a pathological fracture, a vertebral compression fracture not related to trauma, prophylactic surgery or radiation for impending fracture or spinal cord compression, or a spinal cord compression, using the Kaplan-Meier method.
• Bone Metastases Formation [ Time Frame: Patients were assessed every 12 weeks ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation to appearance of ≥4 new bone lesions using the Kaplan-Meier method
• Health Related Quality of Life [ Time Frame: Patients were assessed at every visit ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation until deterioration of Health related Quality of Life using the Kaplan-Meier method, where deterioration is defined as a change from baseline of less than or equal to -6 points in Total FACT-P score maintained for 2 consecutive visits.
• Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: Patients were assessed every 12 weeks ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation to first PSA value >50% higher than baseline of at least 5ng/ml seen in at least 2 consecutive PSA values at least 2 weeks apart using the Kaplan-Meier method.
• Time to Pain Progression [ Time Frame: Patients were assessed every 12 weeks ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation to first assessment of an increased pain event, where increased pain event is defined as the first of a patient requiring opiate medication for duration of ≥1 week for pain due to prostate cancer metastasis, pain due to metastasis that has an increase in the worst pain item of the Brief Pain Inventory (BPI) from baseline to a minimum score of 5 with no decrease in analgesic use, or pain due to metastasis requiring radionuclide therapy, radiation therapy or surgery.
• Time to Initiation of Chemotherapy [ Time Frame: Patients were assessed every 12 weeks ] [ Designated as safety issue: No ]
  Median time (in months) from randomisation to first administration of any chemotherapy using the Kaplan-Meier method
• Pharmacokinetic Characteristics of ZD4054 [ Time Frame: PK samples were performed at randomisation, Week 4, Week 8 and Week 12 ] [ Designated as safety issue: No ]

• Progression free survival [ Time Frame: study visits and assessments every 4 weeks for first 12 weeks then every 12 weeks ]
• Tolerability and safety profile of ZD4054 [ Time Frame: Assessed at each visit ]
• Time to use of opiates
• Incidence of skeletal related events [ Time Frame: Assessed at each visit ]
• Bone metastases formation
• Health Related Quality of Life [ Time Frame: Assessed every visit ]
• Time to prostate-specific antigen (PSA) progression
• Time to pain progression
• Time to initiation of chemotherapy
• Pharmacokinetic characteristics of ZD4054 [ Time Frame: Assessed at each visit ]

Enthuse M1 is a large phase III clinical trial studying the safety and efficacy of ZD4054 (Zibotentan) in patients with hormone resistant prostate cancer and bone metastases.

• This clinical trial will test if the Endothelin A Receptor Antagonist ZD4054 (Zibotentan) can improve survival compared with placebo.
• ZD4054(Zibotentan) is a new type of agent, which is thought to slow tumour growth and spread by blocking Endothelin A receptor activity. This trial will look at the effects of ZD4054 (Zibotentan) in hormone resistant prostate cancer patients with bone metastases.
• All patients participating in this clinical trial will receive existing standard prostate cancer treatments in addition to trial therapy.
• Half the patients will receive ZD4054 (Zibotentan), and half the patients will receive placebo in addition to standard prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may slow the progression of the tumour.
• No patients will be deprived of standard prostate cancer therapy.

• Drug: ZD4054
  ZD4054 10 mg oral tablet once daily
  Other Name: Zibotentan
• Drug: Placebo
  Matching placebo oral tablet once daily

• Experimental: ZD4054
  ZD4054 10 mg oral tablet once daily
  Intervention: Drug: ZD4054
• Placebo Comparator: Placebo
  Matching Placebo, oral tablets once daily
  Intervention: Drug: Placebo

Inclusion Criteria:

Patients who answer TRUE to the following criteria may be eligible to participate in this trial.

1. Confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate) that has spread to the bone (bone metastases)
2. Increasing Prostate Specific Antigen (PSA) over a one month period
3. No pain, or mild pain from prostate cancer
4. Currently receiving treatment with surgical or medical castration

Exclusion Criteria:

Patients who answer TRUE to the following may NOT eligible to participate in this trial.

1. Currently using opiates based pain killers)
2. Previous treatment with chemotherapy (paclitaxel, docetaxel, and mitoxantrone)
3. Suffering from heart failure or had a myocardial infarction within last 6 months
4. A history of epilepsy or seizures