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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III Trial to Test the Efficacy of ZD4054(Zibotentan), an Endothelin A Receptor Antagonist, Versus Placebo in Patients With Hormone Resistant Prostate Cancer (HRPC) and Bone Metastasis Who Are Pain Free and Mildly Symptomatic.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ZD4054
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who answer TRUE to the following criteria may be eligible to participate in this trial. Confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate) that has spread to the bone (bone metastases) Increasing Prostate Specific Antigen (PSA) over a one month period No pain, or mild pain from prostate cancer 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. Currently using opiates based pain killers) Previous treatment with chemotherapy (paclitaxel, docetaxel, and mitoxantrone) Suffering from heart failure or had a myocardial infarction within last 6 months A history of epilepsy or seizures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZD4054<br>ZD4054 10 mg oral tablet once daily | Drug: ZD4054<br>* ZD4054 10 mg oral tablet once daily<br>* Other names: Zibotentan;|
| Placebo Comparator: Placebo<br>Matching Placebo, oral tablets once daily | Drug: Placebo<br>* Matching placebo oral tablet once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Median time (in months) from randomisation until death using the Kaplan-Meier method | From date of randomization until date of death, assessed up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | 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 | 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 | 
| Time to Use of Opiates | Median time (in months) from randomisation until use of opiates for disease-related symptoms for a duration ≥1 week using the Kaplan-Meier method | From date of randomization until use of opiates for disease-related symptoms for a duration ≥1 week, assessed up to 31 months | 
| Incidence of Skeletal Related Events | 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. | From date of randomization until occurrence of a skeletal related event, assessed up to 31 months | 
| Bone Metastases Formation | Median time (in months) from randomisation to appearance of ≥4 new bone lesions using the Kaplan-Meier method | Patients were assessed every 12 weeks | 
| Health Related Quality of Life | 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. | Patients were assessed at every visit | 
| Time to Prostate-specific Antigen (PSA) Progression | 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. | Patients were assessed every 12 weeks | 
| Time to Pain Progression | 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. | Patients were assessed every 12 weeks | 
| Time to Initiation of Chemotherapy | Median time (in months) from randomisation to first administration of any chemotherapy using the Kaplan-Meier method | Patients were assessed every 12 weeks | 
| Pharmacokinetic Characteristics of ZD4054 |  | PK samples were performed at randomisation, Week 4, Week 8 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelin A, Hormone Resistant Prostate Cancer, Endothelin A Receptor Antagonist, Endothelin A antagonist