| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| AG-013736 (axitinib) is indicated for the treatment of patients with metastatic renal cell cancer (mRCC) following failure of one prior systemic first-line therapy |
| AG 013736 (axitinib) e' indicato per il trattamento di pazienti con adenocarcinoma renale metastatico (mRCC) dopo fallimento di una precedente terapia sistemica di prima linea. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Compare the Progression-Free Survival (PFS) of patients with mRCC receiving AG-013736 (axitinib) vs sorafenib following failure of one prior systemic first-line regimen containing one or more of the following: sunitinib, bevacizumab + IFN ±, temsirolimus, or cytokine(s). |
| • Confrontare la Sopravvivenza Libera da Progressione (PFS) di pazienti con mRCC che ricevono AG 013736 con la PFS di pazienti con mRCC trattati con sorafenib, dopo fallimento di una precedente terapia sistemica di prima linea basata sulla somministrazione di uno o piu` dei seguenti farmaci: sunitinib, bevacizumab + IFN ±, temsirolimus, o citochine. |
|
| E.2.2 | Secondary objectives of the trial |
| Compare the Overall Survival (OS) of patients in each arm; • Compare the Objective Response Rate (ORR) of patients in each arm; • Evaluate the safety and tolerability of AG-013736; • Estimate the Duration of Response (DR) of patients in each arm; Compare the kidney specific symptoms, and health status of patients in each arm as measured by the FACT-Advanced Kidney Cancer Symptom Index (FKSI), and EuroQol-5D (EQ-5D). |
| • Confrontare la Sopravvivenza Globale (OS) dei pazienti in ogni braccio di trattamento; • Confrontare la Percentuale di Risposta Obiettiva (ORR) dei pazienti in ogni braccio di trattamento; • Valutare la sicurezza e la tollerabilita` di AG 013736; • Stimare la Durata della Risposta (DR) dei pazienti in ogni braccio di trattamento; • Confrontare i sintomi specifici del rene e lo stato di salute dei pazienti in ogni braccio di trattamento secondo FACT Advanced Kidney Cancer Symptom Index (FKSI).ed il questionario sulla qualita` della vita EuroQol-5D (EQ 5D). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOGENETIC:
Vers:1
Date:2008/02/28
Title:
Objectives:
|
FARMACOGENETICA:
Vers:1
Data:2008/02/28
Titolo:MOLECULAR PROFILING SUPPLEMENT
SAMPLES FOR PFIZER'S EXPLORATORY RESEARCH BIOBANK
AXITINIB (AG-013736) AS SECOND LINE THERAPY FOR METASTATIC RENAL
CELL CANCER: AXIS TRIAL
Obiettivi:The primary objective of this additional research component is to collect, store, and use
samples to investigate possible associations between genomic and metabonomic variation:
• in relation to response to the study drugs, and
• in relation to characteristics of the disease/condition under study in the associated clinical
trial, and related conditions.
|
|
| E.3 | Principal inclusion criteria |
| 1. Histologically or cytologically confirmed renal cell cancer with a component of clear cell subtype, with metastasis. 2. Evidence of unidimensionally measurable disease (ie, >/=1 malignant tumor mass that can be accurately measured in at least 1 dimension >/= 20 mm with conventional computerized tomography [CT] scan or Magnetic Resonance Imaging [MRI], or >/=10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable. 3. Must have progressive disease per RECIST (version 1.0) after one prior systemic first-line regimen for metastatic renal cell cancer. The prior regimen must have contained one or more of the following: sunitinib, bevacizumab + IFN ±, temsirolimus, or cytokine(s). 4. Adequate organ function as defined by the following criteria: - absolute neutrophil count (ANC) >/=1500 cells/mm3; - platelets >/=75,000 cells/mm3. - Hemoglobin >/=9.0 g/dl. - AST and ALT </=2.5 x upper limit of normal (ULN), unless there are liver metastases in which case AST and ALT </=5.0 x ULN; - Total bilirubin </=1.5 x ULN; - Serum creatinine </=1.5 x ULN or calculated creatinine clearance >/=60 mL/min; - Urinary protein <2+ by urine dipstick. If dipstick is >/=2+ then a 24-hour urine collection can be done and the patient may enter only if urinary protein is <2 g per 24 hours. 5. Male or female, age >/=18 years. 6. ECOG performance status of 0 or 1. 7. Life expectancy of >/=12 weeks. 8. At least 2 weeks since the end of prior systemic treatment (4 weeks for bevacizumab + IFN ±), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 3.0 grade </=1 or back to baseline except for alopecia or hypothyroidism. 9. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be </=140 mm Hg, and the baseline diastolic blood pressure readings must be </=90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible. |
| 1. Carcinoma renale metastatico istologicamente o citologicamente confermato con componente a cellule chiare. 2. Evidenza di malattia unidimensionalmente misurabile (es, 1 o piu` masse tumorali maligne accuratamente misurabili in almeno una dimensione >/= 20 mm mediante convenzionale tomografia computerizzata [TAC] o Risonanza Magnetica [RM], o >/=10 mm mediante TAC spirale utilizzando un algoritmo di ricostruzione contiguo di 5 mm o piu` piccolo). Lesioni ossee, ascite, carcinomatosi peritoneale o lesioni miliari, , effusioni pleuriche o pericardiche, linfangite della cute o del polmone, lesioni cistiche o lesioni irradiate non sono considerate misurabili. 3. Progressione della malattia per RECIST dopo una precedente terapia sistemica di prima linea per il carcinoma renale metastatico Il trattamento di prima linea deve essersi basato sulla somministrazione di uno o piu` dei seguenti farmaci: sunitinib, bevacizumab + IFN ±, temsirolimus o citochina/e. 4. Adeguata funzionalita` d`organo definita in base ai seguenti criteri: - Conta assoluta dei neutrofili (ANC) >/=1500 cellule/mm3; - Piastrine >/=75,000 cellule/mm3; - Emoglobina >/=9.0 g/dl; - AST e ALT </= 2.5 x il limite superiore normale (ULN); salvo metastasi epatiche per le quali di AST e ALT possono essere </=5.0 x ULN; - Bilirubina totale </=1.5 x ULN; - Creatinina sierica </=1.5 x ULN o cleareance della creatinina >/=60 mL/min; - Proteinuria <2+ mediante dipstick. Se la proteinuria e` >/=2+ puo` essere raccolto un campione di urina delle 24 ore ed il paziente sarebbe eleggibile solo se la proteinuria e` <2 g per 24 ore; 5. Maschi o femmine, eta` minima 18 anni; 6. ECOG performance status 0 o 1; 7. Aspettativa di vita >/=12 settimane; 8. Almeno 2 settimane dalla fine del precedente trattamento sistemico (4 settimane per bevacizumab + IFN ±), dalla radioterapia o da una procedura chirurgica con risoluzione di tutta la tossicita` correlata al trattamento ad un grado </=1 secondo la classificazione NCI CTCAE v.3.0 o con risoluzione al basale eccetto per l`alopecia o ipotiroidismo; 9. Nessuna evidenza di una pre-esistente ipertensione non controllata come dimostrato da due misurazioni della pressione arteriosa da effettuarsi al basale ad 1 ora di distanza l`una dall`altra. La sistolica al basale deve essere </=140 mmHg; la diastolica al basale deve essere </=90 mmHg. Pazienti con ipertensione controllata con terapia antiipertensiva sono eleggibili; |
|
| E.4 | Principal exclusion criteria |
| 1. Prior treatment of mRCC with more than one systemic first-line regimen. 2. Patients treated with any neoadjuvant or adjuvant systemic therapy. 3. Major surgery <4 weeks or radiation therapy <2 weeks of starting the study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated. 4. Gastrointestinal abnormalities including: - inability to take oral medication; - requirement for intravenous alimentation; - prior surgical procedures affecting absorption including total gastric resection; - treatment for active peptic ulcer disease in the past 6 months;- active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; - malabsorption syndromes. 5. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine). 6. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St.John s wort). 7. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed. 8. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis. 9. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment. 10. Any of the following within the 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism. 11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. 12. History of a malignancy (other than renal cell cancer) except those treated with curative intent for skin cancer (other than melanoma), in situ breast or in situ cervical cancer, or those treated with curative intent for any other cancer with no evidence of disease for 2 years. 13. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol. 14. Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 6 months after discontinuing study treatment The definition of effective contraception should be in agreement with local regulation and based on the judgment of the principal investigator or a designated associate. 15. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study |
| 1.Precedente trattamento del mRCC con piu` di una terapia sistemica di prima linea; 2.Pazienti trattati con una qualsiasi terapia neoadiuvante o adiuvante sistemica; 3.Interventi di chirurgia maggiore entro 4 settimane o radioterapia entro 2 settimane dall`inizio del trattamento in studio.E` consentita una precedente radioterapia palliativa per lesioni metastatiche, ammesso che ci sia almeno una lesione misurabile che non sia stata irradiata. 4.Anomalie gastrointestinali includendo: - incapacita` di assumere il farmaco per via orale; - necessita` di alimentarsi per via endovenosa; - precedenti procedure chirurgiche riguardanti l`assorbimento inclusa la totale resezione gastrica; - terapia per ulcera peptica nei precedenti 6 mesi; - emorragie gastrointestinali in atto, non correlate al tumore, evidenziate da ematemesi, ematochezia o melena nei precedenti 3 mesi senza evidenza di risoluzione documentata da endoscopia o colonscopia; - disturbi da malassorbimento alimentare; 5.Assunzione in corso o prevista di farmaci noti come potenti inibitori del CYP3A4 (es, succo di pompelmo, verapamil, ketoconazolo, miconazolo, itraconazolo, eritromicina, telitromicina, claritromicina, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdina); 6.Assunzione in corso o prevista di farmaci noti come potenti induttori del CYP3A4 o del CYP1A2 (es, carbamazepina, desametasone, felbamato, omeprazolo, fenobarbital, fenitoina, amobarbitale, nevirapina, primidone, rifabutin, rifampin, and Erba di San Giovanni); 7.Necessita` di una terapia anticoagulante con antagonisti della vitamina K per via orale.E` consentito l`uso di basse dosi di anticoagulanti per il mantenimento della pervieta` dell`accesso venoso centrale o per la prevenzione di trombosi venosa profonda.E` consentito anche l`uso di eparina a basso peso molecolare; 8.Disordini convulsivi attivi o evidenza di metastasi cerebrali, compressione della corda spinale, meningite carcinomatosa; 9.Un disturbo medico non controllato grave o un`infezione attiva che potrebbe ostacolare la somministrazione del trattamento in studio; 10.Una delle seguenti patologie entro i 12 mesi precedenti l`inizio del trattamento in studio: infarto del miocardio, angina non controllata, bypass coronario/arteria periferica, insufficienza cardiaca congestizia sintomatica, accidente cerebrovascolare o attacco ischemico transiente e 6 mesi per trombosi venosa acuta o embolia polmonare; 11.Infezione documentata da virus dell`immunodeficienza umano (HIV) o AIDS conclamato; 12.Storia di un tumore maligno (diverso dal carcinoma renale) eccetto quelli trattati con intento curativo nell`ambito dei tumori della pelle (diversi dal melanoma), carcinoma mammario in situ o carcinoma della cervice uterina in situ o quelli trattati con intento curativo nell`ambito di qualsiasi altro tumore con nessuna evidenza di malattia per 2 anni; 13.Demenza o stato mentale significativamente alterato che impedirebbe la comprensione od il rilascio del consenso informato e la compliance con i requisiti del protocollo; 14.Gravidanza o allattamento.Donne e uomini in eta` fertile non disposti o non in grado di utilizzare metodi contraccettivi adeguati per impedire la gravidanza durante lo studio e nei 6 mesi successivi all`interruzione del trattamento in studio.La definizione di metodo contraccettivo efficace e` in accordo con la normativa locale e basata sul giudizio dello sperimentatore principale o di un collega designato; 15.Altre patologie gravi acute o croniche di tipo fisico o psichiatrico, o alterazioni dei valori di laboratorio tali da aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco sperimentale, da interferire con l`interpretazione dei risultati dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 20 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 25 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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