E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
hormone-resistant prostate cancer |
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MedDRA Classification |
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 |
To determine the effect of ZD4054 in combination with docetaxel on overall survival compared with docetaxel; overall survival defined as time to death (from randomisation) from any cause |
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E.2.2 | Secondary objectives of the trial |
To assess/investigate the: *Effect of ZD4054 in combination with docetaxel on progression free survival at 6 and 12 months compared with docetaxel. *Safety and tolerability profile of ZD4054 in combination with docetaxel compared with docetaxel *Effect of ZD4054 in combination with docetaxel on skeletal-related events compared with docetaxel. * Effect of ZD4054 in combination with docetaxel on time to prostate-specific antigen (PSA) progression compared to docetaxel *Effects of ZD4054 in combination with docetaxel on time to pain progression compared with docetaxel *Effects of ZD4054 in combination with docetaxel on pain response compared to docetaxel *Effect of ZD4054 in combination with docetaxel on Health-related Quality of Life (HRQoL) compared with docetaxel. *Effect of ZD4054 in combination with docetaxel on PSA response compared to docetaxel.
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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.Documented evidence of bone metastasis on bone scan. Patients must have disease involvement <75% of the spine, pelvis and ribs in the anteroposterior (AP) or posteroanterior (PA) view. Patients with £3 lesions seen on bone scan will require a CT scan, MRI or x-ray to confirm 5.Biochemical progression of prostate cancer, documented while the patient is castrate: -Biochemical progression is defined as at least 2 stepwise increases in PSA over a period of ≥1 month (values do not need to be consecutive but 2 values that have increased since the previous highest value are required) with at least 14 days between each measurement irrespective of assay or laboratory -Historical values may be used -The last PSA must be an increase of ≥50 % of the first PSA value of the 3 values or an absolute increase of ≥10 ng/mL over the initial PSA -The final PSA value must be ≥1.2 ng/mL in patients who have had a radical prostatectomy and ≥ 5ng/mL in all other patients 6.Surgically castrated or continuously medically castrated with serum testosterone £2.4 nmol/L (70 ng/dL). 7.World Health Organisation (WHO) performance status 0 – 1 (see Appendix E). 8.Life expectancy of 3 months or more. For inclusion in the genetic component of the study, 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.Radiotherapy to bone lesion or prostatic bed within 4 weeks of starting study treatment 2.Prior cytotoxic chemotherapy (such as paclitaxel, docetaxel and mitoxantrone) for the treatment of recurrent prostate cancer (prior estramustine therapy is allowed), as well as other targeted cancer therapies (such as EGF, EGFR, VEGF and VEGFR) 3.Systemic radionuclide therapy (ie, strontium chloride Sr89, 186Relabeled HEDP, or 153Sm-EDTMP pentasodium) within 12 weeks of starting study treatment 4.Use of potent CYP450 inducers (such as phenytoin, rifampicin, carbamazepine, phenobarbitone, St John’s Wort) within 2 weeks of starting study treatment. Dexamethasone is a known inducer of CYP2D6 and CYP3A4 but is acceptable for this study when used as part of the standard docetaxel regime 5.Use of systemic retinoids within 2 weeks of starting study treatment 6.Have received investigational drug in another clinical study of anti-cancer therapy, within 4 weeks of starting study treatment 7.Prior therapy with endothelin receptor antagonists or family history of hypersensitivity to endothelin antagonists 8.Acute or evolving spinal cord compression or neurological symptoms or signs consistent with this. If a patient has neurologic symptoms, an MRI must be performed that demonstrates no impending or actual spinal cord compression. Stable, previously treated patients are allowed 9.Symptomatic peripheral neuropathy of CTCAE grade 2 or higher 10.Known or suspected central nervous system metastases. 11.History of past or current epilepsy, epilepsy syndrome, or other seizure disorder 12.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 13.QT interval corrected for heart rate eg, by Bazett’s correction >470 msec 14.Previous history or presence of another malignancy within the preceding 5 years except treated squamous/basal cell carcinoma of the skin 15.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 16.Absolute Neutrophil Count (ANC) <1.5 x 109/L (1,500/mm3); haemoglobin (Hb) <9 g/dL; platelet count <100 x 109/L (100,000/mm3). Concomitant use of erythropoietin or blood transfusions is allowed 17.Serum bilirubin >1.5 times the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of haemolysis or hepatic pathology), who will be allowed in consultation with their physician 18.Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times the ULN or 5 times the ULN in the presence of liver metastases 19.Creatinine clearance of <50 mL/minute, determined using the Cockcroft-Gault equation or by 24-hour creatinine clearance 20.Patients who discontinue after randomisation cannot be re-enrolled. Patients who fail to meet the inclusion/exclusion criteria may be reconsidered once for participation in the study. Patients who are re-enrolled must be re-consented and will be assigned a new enrolment number 21.Involvement in the planning and conduct of the study (applies to ICON and AstraZeneca staff or staff at the study site). The following are regarded as an 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. Restrictions: 1.Patients taking bisphosphonates must be on a stabilized dose for 4 weeks or more prior to starting study treatment and should remain on the same dose whilst taking part in the study. Bisphosphonate therapy, if infused, must be administered at least 1 week before bone scans are performed 2.Medically castrated patients must remain on castration therapy throughout the study and must have been on stable treatment for a minimum of 8 weeks prior to starting study treatment. The castration therapy dose must also remain stable during the study 3.Patients should avoid using CYP450 inducers (such as phenytoin, rifampicin, carbamazepine, phenobarbitone, St John’s Wort) during the study as they may lower ZD4054 plasma concentrations. Dexamethasone may be taken when used as part of the standard docetaxel regime 4.Avoid pro-creative sex from receiving first dose of ZD4054 until 4 months after receiving the last dose of ZD4054. All patients, if sexually active and not surgically sterile, should practice reliable methods of birth control to prevent pregnancy (eg, spermicidal foam and condoms) during the study. Patients should not donate sperm for the same time period as above.
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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 |
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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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |