E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hormone-refractory prostate cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062904 |
E.1.2 | Term | Hormone-refractory prostate cancer |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To determine the effect of ZD4054 on overall survival compared to placebo 2. To assess the effect of ZD4054 on progression free survival compared to placebo
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E.2.2 | Secondary objectives of the trial |
1. To investigate the tolerability and safety profile of ZD4054 2. To investigate the effect of ZD4054 on time to prostate-specific antigen (PSA) progression compared to placebo 3. To assess the effects of ZD4054 on Health-related Quality of Life (HRQOL) compared to placebo 4. To investigate the effect of ZD4054 on time to symptomatic progression compared to placebo
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Provision of informed consent 2.Male, aged 18 years or older 3.Histological or cytological confirmation of adenocarcinoma of the prostate 4.No evidence of metastatic disease, local recurrence or pelvic lymph node disease on: -CT scan of chest -CT scan or MRI of abdomen/pelvis -Bone scan (In the event that bone scans cannot be performed due to a Technetium 99(Tc-99) radioisotope shortage, please see section 4.6.6.1) Patients with prostate cancer involving the pelvic lymph nodes are acceptable providing that: a. In the opinion of the investigator the patient is not a candidate for local/salvage therapy b. Only a single lymph node is enlarged in which case there is no size limit OR if there are multiple enlarged lymph nodes then they must be ≤2cm in size (based on short axis measurement). c. There is no lymph node disease above the aortic bifurcation Patients with evidence of local disease progression or recurrence that the Investigator would normally treat with local therapy are excluded. A patient can be enrolled as long as any residual prostatic disease in the pelvis that was present at the initiation of castration therapy has not changed significantly and would not normally be treated by local therapy by the Investigator. 5. Biochemical progression of prostate cancer, defined as at least 2 stepwise increases in a series of any 3 PSA values collected while the patient is castrate. The 3 PSA values selected do not need to be consecutive, and do not need to include the most recent PSA collected at or prior to study enrolment but must meet the following criteria: b. There must be at least 14 days between each of the 3 PSA values, and each must be collected no more than 1 year before enrolment into the study c. The last PSA value in the series of 3 must be either an increase of ≥25% of the first PSA or an absolute increase of ≥10 ng/mL over the first PSA d. The last PSA value in the series of 3 must be ≥1.2 ng/mL in patients who have had a radical prostatectomy and ≥5 ng/mL in all other patients a. Each of the 3 PSA values must be collected whilst the patient is under medical castration or is surgically castrated 6. Continuously medically castrated with stable treatment for at least 8 weeks prior to study randomisation or surgically castrated. Acceptable medical castration includes luteinising hormone-releasing hormone analogues (LHRHa), estradiol, estramustine or other estrogen based preparations. Anti-androgens can be taken in conjunction with medical castration. Serum testosterone must be ≤2.4nmol/L (70ng/dL) at enrolment despite method of castration. 7.World Health Organisation (WHO) performance status 0 – 1 8.Life expectancy of 6 months or more. For inclusion in the genetic research, patients must fulfil the following criterion: 1.Provision of informed consent for genetic research. If a patient declines to participate in the genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent to participate. |
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E.4 | Principal exclusion criteria |
1.Current use (from the time that written informed consent is given) of any opiates, with the exception of opiates taken PRN for non-disease-related symptoms 2.Definitive therapy to treat the patient’s primary prostate cancer (prostatectomy, radiotherapy, cryotherapy) within 3 months prior to study entry 3.Prior cytotoxic chemotherapy (such as paclitaxel, docetaxel and mitoxantrone) for the treatment of recurrent prostate cancer (prior estramustine therapy is allowed), Prior targeted cancer therapies, such as EGF, EGFR, VEGF and VEGFR, or immune cell therapy, are only permitted if the patient received them during participation in a previous clinical trial. 4.Use of intravenous bisphosphonates within 6 weeks prior to start of study treatment. Oral bisphosphonates for prevention and/or treatment of osteoporosis are permitted. Oral bisphosphonate dose must be stable for a minimum of 4 weeks prior to starting study treatment. Intravenous bisphosphonates are permitted after disease progression, however dose must be stable within trial 5.Use of potent CYP450 inducers (such as phenytoin, rifampicin, carbamazepine and phenobarbitone, St John’s Wort) within 2 weeks prior to start of study treatment. Dexamethasone will be allowed if the investigator feels it is necessary but is encouraged to use a different form of steroid treatment wherever possible 6.Use of systemic retinoids within 2 weeks prior to starting study treatment 7.Have received investigational drug in another clinical study of anticancer therapy, within 4 weeks prior to starting study treatment 8.Prior therapy with endothelin receptor antagonists or family history of hypersensitivity to endothelin antagonists 9.History of past or current epilepsy, epilepsy syndrome, or other seizure disorder 10.Stage II, III or IV cardiac failure (classified according to New York Heart Association (NYHA) classification) or myocardial infarction within 6 months prior to study entry 11.QT interval corrected for heart rate (by Bazett’s correction) (QTcB) >470 msec 12.Previous history or presence of another malignancy, other than prostate cancer treated squamous/basal cell carcinoma of the skin, or melanoma that has been fully excised with no signs of residual disease or recurrence at the time of study enrolment, within the last 5 years 13.In the opinion of the investigator, any evidence of severe or uncontrolled systemic disease (eg, currently unstable or uncompensated respiratory, cardiac, hepatic or renal disease) or evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study 14.Haemoglobin (Hb) <9 g/dL. Concomitant use of erythropoietin or blood transfusions is allowed 15.Serum bilirubin greater than 1.5 times the upper limit of normal (ULN). This will not apply to patients with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician 16.Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times the ULN 17.Creatinine clearance of <50 mL/minute, determined using the Cockcroft-Gault equation or by 24-hour creatinine clearance 18.Patients who have been previously randomised in this study cannot be re-randomised. Patients who fail to meet the inclusion/exclusion criteria may be reconsidered once for participation in the study.19.Involvement in the planning and conduct of the study (ICON and AstraZeneca staff or staff at the study site). The following are regarded as exclusion criteria for genetic research: 1.The patient has undergone a previous bone marrow transplant 2.The patient has undergone a whole blood transfusion in the preceding 90 days.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival, defined as time to death (from randomisation) from any cause Progression free survival defined as the time from randomisation until documentation of progressive metastatic disease. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 400 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |