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    EudraCT Number:2007-003224-38
    Sponsor's Protocol Code Number:D4320C00015
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2008-03-20
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2007-003224-38
    A.3Full title of the trial
    A Phase III, Randomised, Placebo-controlled, Double-blind Study to Assess the Efficacy and Safety of Once-daily Orally Administered ZD4054 10 mg in Non-metastatic Hormone-resistant Prostate Cancer Patients
    Studio di Fase III randomizzato, in doppio cieco e controllato verso placebo, per valutare l efficacia e la sicurezza di una singola somministrazione orale giornaliera di ZD4054 10 mg in pazienti con tumore della prostata ormone resistente non metastatico
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD4320C00015
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorASTRAZENECA
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZibotentan
    D.3.2Product code ZD4054
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeZD4054
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D. medicinal product typeNon Applicabile
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-metastatic Hormone-resistant Prostate Cancer Patients
    pazienti con tumore della prostata ormone resistente non metastatico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10036911
    E.1.2Term Prostate cancer recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the effect of ZD4054 on overall survival compared to placebo To assess the effect of ZD4054 on progression free survival compared to placebo
    Determinare l effetto di ZD4054 sulla sopravvivenza complessiva, rispetto al placebo Valutare l effetto di ZD4054 sulla sopravvivenza senza progressione, rispetto al placebo
    E.2.2Secondary 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
    1.Valutare la tollerabilita` e il profilo di sicurezza di ZD4054 2.Valutare l effetto di ZD4054 sul tempo alla progressione dell antigene prostatico specifico (PSA),rispetto al placebo 3.Valutare gli effetti di ZD4054 sulla qualita` della vita correlata alla salute (HRQOL),rispetto al placebo 4.Valutare l effetto di ZD4054 sul tempo alla progressione sintomatica,rispetto al placebo
    E.2.3Trial contains a sub-study No
    E.3Principal 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 on:  CT scan of chest (CT scan only to be performed if clinically indicated i.e. if lung metastases are suspected)  CT scan or MRI scan of the 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 Patients with prostate cancer involving the pelvic lymph nodes are acceptable providing that:  In the opinion of the investigator the patient is not a candidate for local/salvage therapy  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).  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:  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  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  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  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.
    1. Rilascio del consenso informato 2. Maschi di 18 anni di eta` o piu` 3. Conferma istologica o citologica della presenza di adenocarcinoma della prostata 4. Nessuna evidenza di patologia ossea, recidiva localizzata o malattia a carico dei linfonodi pelvici, come emerso da:  TAC toracica  TAC o RM addominale/pelvica  Scintigrafia Nel caso in cui la scintigrafia ossea non possa essere eseguita a causa di carenza del radio-isotopo Tecnezio 99(Tc-99), fare riferimento alla sezione Pazienti con tumore alla prostata con coinvolgimento dei linfonodi pelvici sono accettabili a condizione che: - Secondo il parere dello sperimentatore il paziente non sia un candidato per una terapia locale/di salvataggio - Solo un singolo linfonodo sia aumentato, nel qual caso non vi e limite di dimensione O molteplici linfonodi siano aumentati e in tal caso devono risultare di una dimensione `‰¤2cm (basandosi sulla misura dell asse minore) - Non vi sia interessamento dei linfonodi sopra la biforcazone aortica Sono esclusi pazienti con evidenza di progressione locale della malattia o recidiva che lo sperimentatore desidera trattare con terapia locale. Un paziente puo` essere arruolato se qualsiasi malattia prostatica residua nella pelvi che era presente all inizio della terapia di castrazione non e` cambiata in maniera significativa e non sarebbe normalmente trattata dallo sperimentatore tramite terapia locale. 5. Progressione biochimica del cancro alla prostata , definita come almeno due incrementi successivi in una serie di 3 valori di PSA misurati quando il paziente e` in castrazione. I 3 valori di PSA selezionati non devono necessariamente essere consecutivi e non e` necessario che includano i valori di PSA piu` recenti misurati prima o al momento dell arruolamento, purche` i seguenti criteri siano soddisfatti: - devono essere trascorsi almeno 14 giorni tra ciascuno dei 3 valori di PSA, ed ogni valore deve essere stato ottenuto non prima di 1 anno dall arruolamento nello studio - l ultimo valore di PSA nella serie di 3 deve rappresentare o un aumento del 25% rispetto al primo valore di PSA o un aumento assoluto `‰¥10 ng/mL rispetto al primo valore di PSA. - L ultimo valore di PSA nella serie di 3 deve essere `‰¥1.2 ng/mL in pazienti che hanno subito prostatectomia radicale e `‰¥5 ng/mL in tutti gli altri pazienti - Ognuno dei 3 valori di PSA deve essere ottenuto mentre il paziente e` in castrazione medica o e` chirurgicamente castrato 6. Pazienti sotto castrazione medica continua con trattamento stabile per almeno 8 settimane prima della randomizzazione nello studio oppure chirurgicamente castrati. Le modalita` di castrazione medica accettabili includono analoghi dell ormone di rilascio dell ormone luteinizzante (LHRHa), estradiolo, estramustina o altre preparazioni a base estrogenica. Anti-androgeni possono essere assunti in concomitanza della terapia di castrazione. Il testosterone sierico deve essere &lt; o uguale2.4 nmol/L (70 ng/dL) all arruolamento, a prescindere dal metodo di castrazione. 7. Stato funzionale 0 1 secondo l Organizzazione Mondiale della Sanita` (OMS) 8. Aspettativa di vita pari a 6 mesi o piu`.
    E.4Principal 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 (eg, by Bazett s correction) >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.
    1. Uso corrente (dalla data del rilascio del consenso informato scritto) di qualunque oppiaceo, fatta eccezione per quelli assunti secondo necessita` (PRN), per sintomi non correlati alla patologia in studio 2. Terapia radicale per il tumore prostatico primario del paziente (prostatectomia, radioterapia, crioterapia), nei 3 mesi precedenti l ingresso nello studio 3. Pregressa chemioterapia citotossica (es. con paclitaxel, docetaxel e mitoxantrone) per il trattamento di recidive del tumore della prostata (e` consentita una terapia precedente con estramustina), nonche` altre terapie oncologiche mirate (es. EGF, EGFR, VEGF e VEGFR) 4. Uso di bifosfonati per endovena nelle 6 settimane precedenti l inizio del trattamento in studio. E` ammessa l assunzione di bifosfonati per via orale a scopo preventivo e/o per il trattamento dell osteoporosi. La dose orale deve mantenersi stabile per almeno 4 settimane prima dell avvio del trattamento in studio. E` consentito assumere bifosfonati per endovena in seguito a progressione della patologia, purche` la dose venga mantenuta stabile durante lo studio 5. Uso di potenti induttori del CYP450 (come fenitoina, rifampicina, carbamazepina, fenobarbitone, Erba di San Giovanni) entro le 2 settimane precedenti l inizio dell assunzione del trattamento in studio. Il desametasone e` consentito se ritenuto necessario a giudizio dello sperimentatore, tuttavia dove possibile si incoraggia l uso di un diverso trattamento steroideo. 6. Uso di retinoidi sistemici entro 2 settimane dall inizio dell assunzione del trattamento in studio 7. Assunzione di farmaci sperimentali all interno di altri studi clinici su terapie contro il cancro, nelle 4 settimane precedenti l inizio della somministrazione del trattamento in studio 8. Pregressa terapia con antagonisti recettoriali dell endotelina, o anamnesi familiare di ipersensibilita` agli antagonisti dell endotelina 9. Anamnesi di epilessia, sindrome epilettica o altro disturbo convulsivo, pregressi o correnti 10. Insufficienza cardiaca di grado II, III o IV (classificata in base alla scala della New York Heart Association (NYHA)) oppure infarto del miocardio nei 6 mesi precedenti l ingresso nello studio 11. Intervallo QT corretto per frequenza cardiaca (mediante correzione di Bazett) (QTcB) &gt;470 msec 12. Precedente storia o presenza di un altro tumore maligno diverso dal carcinoma prostatico, o dal carcinoma squamoso/basale della pelle trattato, o da melanoma che e` stato completamente exciso senza segni di malattia residua o di recidiva al momento dell arruolamento nello studio, entro gli ultimi 5 anni.13. A giudizio dello sperimentatore, evidenza di patologia sistemica severa o incontrollata (es. paziente con patologie respiratorie, cardiopatie, patologie epatiche o renali correntemente instabili o scompensate), oppure evidenza di altro disturbo clinico o esito di laboratorio di portata significativa che renda indesiderabile la partecipazione del paziente allo studio 18. Pazienti che sono stati precedentemente randomizzati in questo studio non possono essere randomizzati una seconda voltaPazienti che non rientravano inizialmente nei criteri d inclusione/esclusione possono essere riconsiderati una volta per la partecipazione allo studio.
    E.5 End points
    E.5.1Primary 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
    Sopravvivenza generale, definita come tempo dalla morte (a partire dalla randomizzazione) per qualunque causa. Sopravvivenza libera da progressione definita come tempo dalla randomizzazione fino a progressione documentata di metstasi
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned21
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA400
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months62
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months62
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 784
    F.4.2.2In the whole clinical trial 1507
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-04-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-03-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2011-02-07
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