E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients affected by untreated metastatic renal cell carcinoma with bone involvement |
Pazienti affetti da carcinoma renale metastatico non trattato con almeno una localizzazione ossea di malattia |
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E.1.1.1 | Medical condition in easily understood language |
Patients with untreated metastatic renal cancer with bone metastases |
Pazienti con tumore renale metastatico con metastasi ossee e che non hanno mai ricevuto una terapia |
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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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073251 |
E.1.2 | Term | Clear cell renal cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To evaluate the efficacy of first line therapy with Pazopanib, in terms of progression free survival (PFS), in patients with metastatic renal cell carcinoma with bone involvement |
Valutare l'efficacia della terapia di I linea con Pazopanib, in termini di sopravvivenza libera da progressione (PFS), in pazienti con carcinoma del rene metastatico con metastasi ossee |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of the first line treatment with Pazopanib. To evaluate pain and quality of life of patients, by means of specific questionnaries. Exploratory objectives: to study the effect of Pazopanib on bone turnover markers |
Valutare la sicurezza e la tollerabilità del trattamento di I linea con Pazopanib. Valutare, attraverso specifici questionari, il dolore e la qualità di vita dei pazienti. Obiettivi esploratori: studiare gli effetti del trattamento con Pazopanib sui markers del turnover osseo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written informed consent - Age = 18 and = 80 years - ECOG Performance Status: 0-1-2 - Life expectancy =24 weeks - Diagnosis of predominantly clear cell RCC - Risk score (Heng criteria): favorable or intermediate - No previous systemic treatment for Renal Cell Carcinoma - Documented metastatic disease (CT scan or MRI) with at least two bone metastasis (non pretreated with radiotherapy). Lesions could be measurable or not according with RECIST criteria v.1.1. -Laboratory requirements: Neutrophils =1.5 x 109/L, Platelets =100 x 109/L, and Haemoglobin =10g/dL; Total bilirubin =1.5 time the upper-normal limits (UNL) of the Institutional normal values except for patients affected by Gilbert’s syndrome; AST (SGOT) and/or ALT (SGPT) =2.5 x UNL, or =5 x UNL in case of liver metastases; alkaline phosphatase =2.5 x UNL, =5 x UNL in case of liver metastases, =10 x UNL in case of bone metastases - Patients should be compliant to study protocol procedures - Patients could receive a bone targeted agents after the first two cycles of Pazopanib treatment; the preferred drug is denosumab (due to best renal safety) - Patients that will receive bone targeted agents must have baseline dental scan and dental examination (and after every 6 months) - Patients of childbearing age should use contraceptive methods during the study
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- Consenso informato scritto firmato, prima dell’avvio di qualunque procedura associata allo studio - Età: anni =18 e =80 - ECOG Performance Status 0-1-2 - Aspettativa di vita di almeno 24 settimane - Diagnosi istologica (sul tumore primitivo o su un sito metastatico) di carcinoma renale con istologia a predominanza a cellule chiare - Classe di rischio (in accordo con i criteri di Heng): buona-intermedia - Nessun trattamento sistemico precedente per la malattia metastatica - Malattia metastatica documentata misurabile o non misurabile secondo criteri RECIST (versione 1.1) con la presenza di almeno due lesioni ossee metastatiche (non precedentemente radio trattate) - Esami di laboratorio compatibili con le seguenti caratteristiche: o Neutrofili = 1.5 x 109/L, Piastrine = 100 x 109/L, ed Emoglobina = 10g/dL; Bilirubina totale =1.5 volte i limiti normali superiori (UNL) del range di normalità istituzionale (UNL) eccetto che per i pazienti affetti da sindrome di Gilbert; AST (SGOT) e/o ALT (SGPT) = 2.5 x UNL, o = 5 x UNL in caso di metastasi epatiche; fosfatasi alcalina = 2.5 x UNL, = 5 x UNL in caso di metastasi epatiche, = 10 x UNL in caso di metastasi ossee - I pazienti devono essere complianti per il trattamento ed il follow up - I pazienti possono ricevere una terapia bone-targeted che deve pero’ essere iniziata dopo almeno 2 cicli di terapia con Pazopanib; il farmaco raccomandato è il denosumab (in considerazione del migliore profilo di tossicità renale) - I pazienti che ricevono terapia bone-targeted devono avere una ortopantomografia e una valutazione odontoiatrica specialistica al basale e ogni 6 mesi - I pazienti in età fertile devono utilizzare metodi contraccettivi come descritto nel protocollo per tutta la durata dello studio
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E.4 | Principal exclusion criteria |
- Previous systemic treatment for mRCC - Non-clear-cell histology - Poor prognosis as defined by Heng criteria - History of malabsorption syndrome - Pregnant or breastfeeding women - Concomitant cardiac disorders: cardiac failure NYHA> 2; Acute coronary syndrome or myocardial infarction or severe or unstable angina within the last 6 months as well as uncontrolled hypertension (= 160/90) - Uncontrolled diabetes - Patients with single bone lesion that could receive curative treatment (radiotherapy or surgery) - Known central nervous system (CNS) metastases other than stable, treated brain metastases. Subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging for at least 3 months following prior treatment (radiotherapy or surgery) - Other cancer within the previous 5 years (except for in situ skin carcinoma, superficial bladder Ta, Tis, T1 and carcinoma of the cervix or every cancer with curative treatment within 5 years) - Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or active hepatitis B or C - Surgery, chemotherapy, or other anti-cancer therapy within 4 weeks prior to enrollment in the study - Intravenous bisphosphonate or denosumab for bone metastasis, when started in the 3 months period before study inclusion - Planned radiation therapy or surgery to bone must be before 2 weeks to study enrollment - Radiotherapy during the study (except palliative radiotherapy) - Inability to swallow tablets or capsules
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- Precedente trattamento sistemico per carcinoma renale metastatico - Istologia di carcinoma renale “non a cellule chiare” - Classe di rischio “infausta” secondo i criteri di Heng - Anamnesi positiva per sindrome da malassorbimento - Donne gravide o in allattamento - Comorbidità cardiologica concomitante: scompenso cardiaco NYHA>2; sindrome coronarica acuta, infarto del miocardio, angina severa o instabile nei 6 mesi precedenti oppure ipertensione incontrollata (valori pressori = 160/90) - Diabete scompensato - Pazienti con metastasi ossea singola che potrebbe ricevere un trattamento a finalità curativa (chirurgia/radioterapia ablativa) - Metastasi cerebrali, eccetto se già trattate e radiologicamente stabili. I pazienti con metastasi cerebrali precedentemente trattate sono arruolabili se la malattia è radiologicamente stabile da almeno 3 mesi - Altre patologie oncologiche negli ultimi 5 anni (eccetto per carcinoma in situ, carcinoma vescicale superficiale Ta-Tis-T1, carcinoma della cervice uterina o altre forme tumorali trattate radicalmente negli ultimi 5 anni) - Soggetti con positività per il virus HIV o epatiti A o B in forma attiva - Chirurgia, chemioterapia o altre terapie antitumorali nelle 4 settimane che precedono l’inizio del trattamento in trial - Terapia con agenti bone targeted (acido zoledronico o denosumab) se iniziati 3 mesi prima dell’ingresso nello studio - Trattamenti loco regionali (chirurgia/radioterapia) eccetto se effettuati almeno 2 settimane prima dell’inizio del trattamento in studio - Radioterapia durante il corso dello studio (eccetto che per finalità palliativa) - Impossibilità a deglutire ed assumere compresse
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS) |
Sopravvivenza libera da progressione (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the start of the first line treatment with Pazopanib until disease progression or death from any cause |
Tempo dall'inizio del trattamento di prima linea con Pazopanib alla progressione di malattia o decesso per qualsiasi causa |
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E.5.2 | Secondary end point(s) |
Study treatment safety and tolerability according to the NCI-CTCAE version 4.03 ; Incidence of Skeletal Related Events (SREs) ; Time to pain progression and pain response according to the Brief Pain Inventory–Short Form (BPI-SF) ; Quality of live according to the NCCN-FACT FKSI-19 and EORTC QLQ-C30 questionnaires; The exploratory objectives of this study are to evaluate the effects of Pazopanib on Bone turnover markers, as follows: 1) Total alkaline phosphatase (ALP) will be measured by standard automated analytical procedures. 2) Bone alkaline phosphatase (BAP) level will be measured by measured by precipitation with wheat germ lectin or electrophoresis-precipitation. 3) Serum ß-C-terminal telopeptide of type I collagen (CTx) will be measured by (ELISA) or radioimmunoassay (RIA). 4) Procollagen type I propeptides (PINP) (ELISA) 5) Tartrate-resistant acid phosphatase (TRAcP) (ELISA) 6) Osteoprotegerin (OPG) (ELISA) 7) Receptor activator of nuclear factor kappa-B ligand (RANKL) (ELISA)
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Sicurezza e tollerabilità del farmaco in studio in accordo ai criteri NCI-CTCAE versione 4.03; Incidenza di eventi scheletrici correlati (SREs) ; Valutazione del dolore effettuata con la scala del Brief Pain Inventory; Valutazione della qualità della vita effettuata tramite i questionari NCCN-FACT FKSI-19 e EORTC QLQ-C30; Endponit esplorativi: Analisi degli effetti di Pazopanib sui markers di turnover osseo, quali: 1) Fosfatasi alcalina totale (ALP) 2) Fosfatasi alcalina ossea Bone alkaline phosphatase (BAP) 3) Serum ß-C-terminal telopeptide of type I collagen (CTx) (ELISA and RIA) 4) Procollagen type I propeptides (PINP) (ELISA) 5) Tartrate-resistant acid phosphatase (TRAcP) (ELISA) 6) Osteoprotegerin (OPG) (ELISA) 7) Receptor activator of nuclear factor kappa-B ligand (RANKL) (ELISA)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From the date of signature of informed consent until 30 days after the last dose of study drug ; During treatment period and follow-up; At baseline, at day 1 of each treatment cycle and at the end of the treatment (EOT visit) until the end of study period; At baseline, at day 1 of each treatment cycle and at the end of the treatment (EOT visit) until the end of study period; At baseline, month 2, first tumour radiological evaluation as per protocol and at disease progression |
Dalla firma del consenso informato fino a 30 giorni dopo l'ultima dose di farmaco; Durante il trattamento e il follow-up; Al basale, al giorno 1 di ogni ciclo di trattamento, alla visita di fine trattamento fino alla conclusione del periodo di follow-up; Al basale, al giorno 1 di ogni ciclo di trattamento, alla visita di fine trattamento fino alla conclusione del periodo di follow-up; Al basale, mese 2, alla prima rivalutazione strumentale della malattia e alla progressione di malattia. |
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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 | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 |
Studio a braccio singolo |
Single arm clinical trial |
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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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 15 |
E.8.5 | The trial involves multiple Member States | No |
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 | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
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 | 2 |
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 |