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

• ClinicalTrials.gov Identifier: NCT00554229
• Recruitment Status: Completed
• First Posted: November 6, 2007
• Results First Posted: May 31, 2012
• Last Update Posted: February 8, 2016
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: November 2, 2007
• First Posted Date: November 6, 2007
• Results First Submitted Date: April 26, 2012
• Results First Posted Date: May 31, 2012
• Last Update Posted Date: February 8, 2016
• Study Start Date: November 2007
• Actual Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 29, 2012)

Overall Survival [ Time Frame: From date of randomization until date of death, assessed up to 32 months ]

Median time (in months) from randomisation until death using the Kaplan-Meier method

• Original Primary Outcome Measures (submitted: November 2, 2007): Overall survival [ Time Frame: study visits and assessments every 4 weeks for first 12 weeks then every 12 weeks ]

Current Secondary Outcome Measures (submitted: August 29, 2012)

• 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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]

Original Secondary Outcome Measures (submitted: November 2, 2007)

• 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 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases
• Official Title: 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.

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

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

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 29, 2012): 896
• Original Estimated Enrollment (submitted: November 2, 2007): 580
• Actual Study Completion Date: August 2011
• Actual Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Hungary, India, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Serbia, Singapore, South Africa, Sweden, Switzerland, Taiwan, United Kingdom, United States
• Removed Location Countries: Former Serbia and Montenegro

Administrative Information

• NCT Number: NCT00554229
• Other Study ID Numbers: D4320C00014; 2007-003227-20 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Not Provided
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Martin Gleave, MD, FRCSC, FACS; The Prostate Centre at Vancouver General Hospital
• Principal Investigator: Joel B Nelson, MD; University of Pittsburgh

• PRS Account: AstraZeneca
• Verification Date: April 2012