A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer (ENTHUSE M1C)

• ClinicalTrials.gov Identifier: NCT00617669
• Recruitment Status: Completed
• First Posted: February 18, 2008
• Results First Posted: May 31, 2012
• Last Update Posted: September 10, 2012
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: January 24, 2008
• First Posted Date: February 18, 2008
• Results First Submitted Date: April 26, 2012
• Results First Posted Date: May 31, 2012
• Last Update Posted Date: September 10, 2012
• Study Start Date: January 2008
• Actual Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 26, 2012)

Overall Survival [ Time Frame: Patients were followed for survival up to 40 months ]

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

• Original Primary Outcome Measures (submitted: February 6, 2008): Overall survival [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]

Current Secondary Outcome Measures (submitted: September 4, 2012)

• Progression Free Survival [ Time Frame: Patients were followed for progression up to 40 months ]
  Median time (in months) from randomisation until clinical progression of disease using the Kaplan-Meier method. 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
• Incidence of Skeletal Related Events [ Time Frame: While receiving docetaxel study visits were aligned with its administration ie every 3weeks, after 12 weeks and completion of docetaxel therapy every 12 weeks (up to 40 months) ]
  Median time (in months) from randomisation until occurrence of a skeletal related event using the Kaplan-Meier method, 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.
• Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: While receiving docetaxel study visits were aligned with its administration ie every 3weeks, after 12 weeks and completion of docetaxel therapy every 12 weeks (up to 40 months) ]
  Median time (in months) from randomisation until 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: While receiving docetaxel study visits were aligned with its administration ie every 3weeks, after 12 weeks and completion of docetaxel therapy every 12 weeks (up to 40 months) ]
  Median time (in months) from randomisation until date of first assessment of increased pain using the Kaplan-Meier method, 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.
• Pain Response [ Time Frame: While receiving docetaxel study visits were aligned with its administration ie every 3weeks, after 12 weeks and completion of docetaxel therapy every 12 weeks (up to 40 months) ]
  Number of patients with a pain response, defined as a decrease in brief pain inventory questionnaire (BPI) of at least 2 points from baseline or a decrease in opiate use of 25% from baseline.
• Health Related Quality of Life [ Time Frame: While receiving docetaxel study visits were aligned with its administration ie every 3weeks, after 12 weeks and completion of docetaxel therapy every 12 weeks (up to 40 months) ]
  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.
• PSA Response [ Time Frame: While receiving docetaxel study visits were aligned with its administration ie every 3weeks, after 12 weeks and completion of docetaxel therapy every 12 weeks (up to 40 months) ]
  PSA response defined as >50% decrease in serum PSA values from baseline seen in at least 2 consecutive PSA values at least 2 weeks apart.

Original Secondary Outcome Measures (submitted: February 6, 2008)

• Progression free survival [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• Tolerability and safety profile of ZD4054 [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• Incidence of skeletal related events [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• Time to prostate-specific antigen (PSA) progression [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• Time to pain progression [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• Pain response [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• Health Related Quality of Life [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]
• PSA response [ Time Frame: while receving docetaxel study visits will be aligned with its adminstration ie every 3 weeks, after 12 weeks and completion of docetaxel therapy study may be every 12 weeks ]

• 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) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer
• Official Title: A Phase III, Randomised, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of 10 mg ZD4054 (Zibotentan) in Combination With Docetaxel in Comparison With Docetaxel in Patients With Metastatic Hormone-resistant Prostate Cancer

Brief Summary

Enthuse M1C is a large phase III clinical trial studying the safety and efficacy of ZD4054 (Zibotentan) in combination with docetaxel (Taxotere) in patients with metastatic hormone resistant prostate cancer (HRPC).

This clinical trial will test if the Endothelin A Receptor Antagonist ZD4054 (Zibotentan) can further improve survival compared with docetaxel alone.

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 compared with docetaxel.

All patients participating in this clinical trial will receive docetaxel chemotherapy, which is a commonly used chemotherapy to treat prostate cancer in addition to other existing prostate cancer therapies.

Half the patients will receive ZD4054 (Zibotentan), and half the patients will receive placebo in addition to docetaxel and other prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may further 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: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• Drug: Docetaxel
  intravenous infusion given every three weeks
  Other Name: Taxotere®
• Drug: ZD4054
  10 mg oral once daily dose
  Other Name: Zibotentan
• Drug: Placebo
  placebo oral tablet once daily

Study Arms

• Active Comparator: Placebo + Docetaxel
  placebo oral tablet once daily + docetaxel intravenous infusion every 3 weeks
  Interventions:

  • Drug: Docetaxel
  • Drug: Placebo
• Experimental: ZD4054 + Docetaxel
  ZD4054 10 mg oral tablet once daily + docetaxel intravenous infusion every 3 weeks
  Interventions:

  • Drug: Docetaxel
  • Drug: ZD4054

• Publications *: Fizazi K, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, Nathan FE, McIntosh S, Pemberton K, Moul JW. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013 May 10;31(14):1740-7. doi: 10.1200/JCO.2012.46.4149. Epub 2013 Apr 8. Erratum In: J Clin Oncol. 2014 Oct 20;32(30):3461. Fizazi, Karim S [Corrected to Fizazi, Karim].

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 4, 2012): 1494
• Original Estimated Enrollment (submitted: February 6, 2008): 1044
• Actual Study Completion Date: July 2011
• Actual Primary Completion Date: May 2011 (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.

• Confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate) that has spread to the bone (bone metastasis)
• Increasing Prostate Specific Antigen (PSA), collected within one year of enrollment
• Currently receiving treatment with surgical or medical castration

Exclusion Criteria:

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

• Previous treatment with chemotherapy (paclitaxel, docetaxel, and mitoxantrone). Prior targeted cancer therapies are permitted if received during a previous clinical trial.
• Suffering from heart failure or had a myocardial infarction within last 6 months
• 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, Brazil, Canada, Czech Republic, Finland, France, Germany, Hungary, India, Italy, Korea, Republic of, Netherlands, Peru, Poland, Portugal, Romania, Russian Federation, Serbia, South Africa, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
• Removed Location Countries: Norway, Singapore

Administrative Information

• NCT Number: NCT00617669
• Other Study ID Numbers: D4320C00033
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Thomas Morris, BSc, MB BCh, MRCP, FFPM, ZD4054 Medical Science Director, AstraZeneca
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Karim Fizazi, MD, PhD; Gustave Roussy, Cancer Campus, Grand Paris
• Principal Investigator: Judd W Moul, MD, FACS; Duke University

• PRS Account: AstraZeneca
• Verification Date: April 2012