Prostate Cancer
Conditions
Keywords
Hormone Resistant Prostate Cancer, Endothelin A Receptor Antagonist, Endothelin A, Endothelin A antagonist
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.
Interventions
DRUGZD4054
ZD4054 10 mg oral tablet once daily
DRUGPlacebo
Matching placebo oral tablet once daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Use of Opiates | 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 | 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 | 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 | 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. |
| Progression Free Survival | 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 Pain Progression | 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 | 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 | PK samples were performed at randomisation, Week 4, Week 8 and Week 12 | — |
| Time to Prostate-specific Antigen (PSA) Progression | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, India, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Russia, Serbia, Singapore, South Africa, South Korea, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
896 patients with hormone-resistant prostate cancer patients and bone metastasis were recruited between 20th November 2007 and 13th February 2009.
Pre-assignment details
302 of the 896 enrolled patients were not randomised to treatments groups as they failed screening.
Participants by arm
| Arm | Count |
|---|---|
| ZD4054 ZD4054 10 mg oral tablet once daily | 299 |
| Placebo Placebo oral tablet once daily | 295 |
| Total | 594 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 71 | 39 |
| Overall Study | Lost to Follow-up | 3 | 6 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Randomised but no treatment received | 1 | 0 |
| Overall Study | Reason not otherwise captured, eg; death | 119 | 140 |
| Overall Study | Withdrawal by Subject | 29 | 37 |
Baseline characteristics
| Characteristic | ZD4054 | Placebo | Total |
|---|---|---|---|
| Age, Continuous Overall | 70.2 Years STANDARD_DEVIATION 7.8 | 70.9 Years STANDARD_DEVIATION 8.6 | 70.5 Years STANDARD_DEVIATION 8.2 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 299 Participants | 295 Participants | 594 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 257 / 298 | 221 / 295 |
| serious Total, serious adverse events | 98 / 298 | 105 / 295 |
Outcome results
Primary
Overall Survival
Median time (in months) from randomisation until death using the Kaplan-Meier method
Time frame: From date of randomization until date of death, assessed up to 32 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Overall Survival | 24.5 months |
| Placebo | Overall Survival | 22.5 months |
Secondary
Bone Metastases Formation
Median time (in months) from randomisation to appearance of ≥4 new bone lesions using the Kaplan-Meier method
Time frame: Patients were assessed every 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Bone Metastases Formation | 15.1 Months |
| Placebo | Bone Metastases Formation | 11.9 Months |
Secondary
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.
Time frame: Patients were assessed at every visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Health Related Quality of Life | 5.5 Months |
| Placebo | Health Related Quality of Life | 5.5 Months |
Secondary
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.
Time frame: From date of randomization until occurrence of a skeletal related event, assessed up to 31 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Incidence of Skeletal Related Events | 18.4 Months |
| Placebo | Incidence of Skeletal Related Events | 17.1 Months |
Secondary
Pharmacokinetic Characteristics of ZD4054
Time frame: PK samples were performed at randomisation, Week 4, Week 8 and Week 12
Secondary
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
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Progression Free Survival | 6.2 Months |
| Placebo | Progression Free Survival | 6.5 Months |
Secondary
Time to Initiation of Chemotherapy
Median time (in months) from randomisation to first administration of any chemotherapy using the Kaplan-Meier method
Time frame: Patients were assessed every 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Time to Initiation of Chemotherapy | 11.4 Months |
| Placebo | Time to Initiation of Chemotherapy | 10.6 Months |
Secondary
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.
Time frame: Patients were assessed every 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Time to Pain Progression | 9.0 Months |
| Placebo | Time to Pain Progression | 8.4 Months |
Secondary
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.
Time frame: Patients were assessed every 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Time to Prostate-specific Antigen (PSA) Progression | 5.6 Months |
| Placebo | Time to Prostate-specific Antigen (PSA) Progression | 5.6 Months |
Secondary
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
Time frame: From date of randomization until use of opiates for disease-related symptoms for a duration ≥1 week, assessed up to 31 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZD4054 | Time to Use of Opiates | 16.7 Months |
| Placebo | Time to Use of Opiates | 14.8 Months |