| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non small cell lung cancer |
| Carcinoma polmonare non a piccole cellule |
|
| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 |
| The objective of this phase III study is to compare the efficacy of sorafenib in combination with gemcitabine and cisplatin versus placebo with gemcitabine and cisplatin for first-line treatment of patients with stage IIIB (with effusion) or Stage IV NSCLC. The primary efficacy objective is to compare overall survival (OS) in NSCLC patients with non-squamous cell carcinoma histology treated with gemcitabine, cisplatin and sorafenib to patients treated with gemcitabine, cisplatin and placebo. |
| L'obiettivo di questo studio di Fase III e` quello di confrontare l'efficacia di sorafenib in associazione con gemcitabina e cisplatino in confronto al trattamento con placebo con gemcitabina e cisplatino per il trattamento di prima linea di pazienti affetti da NSCLC di Stadio IIIB (con versamento) o di Stadio IV. L'obiettivo di efficacia primaria e` confrontare l'OS dei pazienti con NSCLC con carcinoma ad istologia non squamocellulare trattati con gemcitabina, cisplatino e sorafenib con quella dei pazienti trattati con gemcitabina, cisplatino e placebo. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary efficacy objectives will include progression-free-survival (PFS), tumor responses and patient reported outcomes (PRO). |
| L'obiettivo di efficacia secondaria includera` il PFS,la risposta del tumore e la valutazione dell'esito della terapia riferito dal paziente. |
|
| 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:
Date:
Title:
Objectives:
LIFE QUALITY:
Vers:
Date:
Title:
Objectives:
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FARMACOGENETICA:
Vers:
Data:
Titolo:
Obiettivi:
QUALITA DELLA VITA:
Vers:
Data:
Titolo:
Obiettivi:
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| E.3 | Principal inclusion criteria |
| •Age > 18 years old •Stage IIIB (with cytologically confirmed malignant pleural or pericardial effusion) or Stage IV histological or cytological confirmation of NSCLC. (thoracentesis or pericardiocentesis is not necessary if a biopsy of the original tumor is available to confirm diagnosis of NSCLC). •Patients with at least one measurable lesion. Lesions must be measured by CT-scan or MRI (Magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST, see Appendix 10.3) •Life expectancy of at least 12 weeks •Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of first dose: •Hemoglobin ³ 9.0 g/dl (³ 5.6 mmol/l) •Absolute neutrophil count (ANC) ³ 1,500/mm3 •Platelet count ³ 100,000/l •Total bilirubin £ 1.5 x upper limit of normal •ALT and AST £ 2.5 x upper limit of normal (£ 5 x upper limit of normal for patients with liver involvement of their cancer) •Alkaline phosphatase £ 4 x upper limit of normal •PT-INR (international normalized ratio of PT) /PTT < 1.5 x upper limit of normal •Serum Creatinine ≤ 1.5 times the upper limit of normal. •Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to performing any study specific procedures. •ECOG Performance Status of 0 or 1 |
| • Eta' > 18 anni • Stadio IIIB di NSCLC (con versamento pleurico o pericardico maligno confermato citologicamente) o Stadio IV di NSCLC confermato istologicamente o citologicamente (non e' necessaria una toracentesi od una pericardiocentesi se e' disponibile una biopsia del tumore originale per confermare la diagnosi di NSCLC). • Pazienti con almeno una lesione misurabile. Le lesioni devono essere misurate mediante una TAC od una MRI (Imaging mediante Risonanza Magnetica) secondo i Criteri di Valutazione della Risposta nei Tumori Solidi (RECIST) • Aspettativa di vita di almeno 12 settimane • Adeguata funzione midollare, epatica e renale valutata secondo i seguenti requisiti di laboratorio, da eseguire entro 7 giorni prima dell'inizio della prima dose: • Emoglobina ³ 9,0 g/dl (³ 5,6 mmol/l) • Conta neutrofila assoluta (ANC) ³ 1.500/mm3 • Conta piastrinica ³ 100.000/l • Bilirubina totale £ 1,5 volte il limite superiore della norma • ALT e AST £ 2,5 volte il limite superiore della norma (£ 5 volte il limite superiore della norma per pazienti con interessamento epatico del loro tumore) • Fosfatasi alcalina £ 4 volte il limite superiore della norma • PT-INR (International Normalized Ratio della PT)/PTT < 1,5 volte il limite superiore della norma • Creatininemia <1,5 volte il limite superiore della norma • Capacita' di intendere e volonta' di firmare un consenso informato scritto. Un consenso informato scritto deve essere ottenuto prima di eseguire qualsiasi procedura specifica dello studio. • Performance Status secondo l'ECOG di 0 o 1 |
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| E.4 | Principal exclusion criteria |
| •History of cardiac disease: congestive heart failure >NYHA (New York Heart Association) class 2; active CAD (Coronary artery disease), MI (Myocardial Infarction) more than 6 months prior to study entry is allowed; cardiac arrhythmias requiring anti-arrhythmic therapy beta blockers or digoxin are permitted or uncontrolled hypertension. •History of HIV (Human immunodeficiency virus) infection or chronic hepatitis B or C •Active clinically serious infections (> grade 2 NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0) •Patients with seizure disorder requiring medication (such as steroids or anti-epileptics) •Known brain metastasis. Patients with neurological symptoms should undergo a CT scan/MRI of the brain to exclude brain metastasis. •History of organ allograft •Patients with evidence or history of bleeding diathesis or coagulopathy •Patients undergoing renal dialysis •Cancer other than NSCLC within 5 years prior to start of study treatment EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, or superficial bladder tumors [Ta (Noninvasive tumor), Tis (Carcinoma in situ) & T1 (Tumor invades lamina propria)] •Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. •Thrombotic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months •Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug •Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug •Serious, non-healing wound, ulcer, or bone fracture •Uncorrected dehydration •Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate. •Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results •Known or suspected allergy to the investigational agent or any agent given in association with this trial •Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study •Patients unable to swallow oral medications •Any malabsorption condition Excluded therapies and medications, previous and concomitant: •Any prior systemic anticancer therapy including cytotoxic therapy, targeted agents, experimental therapy, adjuvant, or neo-adjuvant therapy for NSCLC •Concomitant use of nephrotoxic drugs, ototoxic drugs, anticonvulsant, anti-gout treatment •Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section) •Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug (bronchoscopy is allowed) •Granuloctye colony stimulating factor (GCSF) or Granulocyte macrophage colony stimulating factor (GMCSF), within 3 weeks of study entry (these growth factors may be used during the study thereafter). •Therapeutic anticoagulation with vitamin K antagonists such as warfarin, or with heparins or heparinoids. Low dose warfarin (1 mg po qd) is permitted if the INR (International normalized ratio) is < 1.5. Low-dose aspirin is permitted (≤ 81 mg daily). •Investigational drug therapy outside of this trial during or within 4 weeks of study entry |
| • Anamnesi di insufficienza cardiaca congestizia di classe 2 > secondo la NYHA; coronaropatia in atto IM avvenuto piu' di 6 mesi prima che sia consentita l'inclusione nello studio; aritmia cardiaca che richieda una terapia anti-aritmica; i beta-bloccanti o la digossina sono permessi per l'ipertensione non controllata. • Anamnesi di infezione da HIV (Human Immunodeficiency Virus) o di epatite cronica B o C • Infezioni in atto clinicamente serie in atto (> grado 2 secondo NCI-CTCAE) • Pazienti con disturbi convulsivi che richiedano un trattamento (ad esempio steroidi od anti-epilettici) • Nota metastasi cerebrale. • Anamnesi di eterotrapianto d'organo • Pazienti con evidenze od anamnesi di diatesi emorragica o coagulopatia • Pazienti sottoposti a dialisi renale • Tumori diversi dal NSCLC verificatisi 5 anni prima di iniziare il trattamento in studio TRANNE carcinoma cervicale in situ, carcinoma delle cellule basali trattato o tumori vescicali superficiali [Ta (tumore non-invasivo), Tis (Carcinoma in situ) e T1 (il tumore invade la lamina propria)] • ipertensione non controllata definita pressione sistolica >150 mmHg o pressione diastolica > 90 mmHg, nonostante un trattamento medico ottimale. • Eventi trombotici od embolici, come eventi cerebrovascolare comprendenti attacchi ischemici transitori negli ultimi 6 mesi • Emorragie polmonari/eventi emorragici > Grado 2 CTCAE entro 4 settimane dalla prima dose del farmaco in studio • Eventuali altre emorragie/eventi emorragici > Grado 3 CTCAE entro 4 settimane dalla prima dose del farmaco in studio • Ferita grave non cicatrizzata, ulcera o frattura ossea • Disidratazione non corretta • Pazienti gravide o che allattano. • Abuso di sostanze stupefacenti, affezioni mediche, psicologiche o sociali che possano interferire con la partecipazione del paziente allo studio o con la valutazione dei risultati dello studio • Allergia nota o sospettata al farmaco in studio o ad eventuali farmaci somministrati in associazione in questo studio • Eventuali condizioni che rendano instabile o che potrebbero mettere in pericolo la sicurezza del paziente e la sua compliance allo studio • Pazienti incapaci di deglutire i farmaci orali • Eventuali affezioni da malassorbimento • Eventuale terapia antitumorale sistemica comprendente la terapia citotossica, farmaci mirati, terapia sperimentale, terapia adiuvante o neo-adiuvante per NSCLC • Impiego concomitante di farmaci nefrotossici, ototossici, trattamento anticonvulsivante e antigottoso • Radioterapia durante lo studio o entro 3 settimane dall'inizio della somministrazione del farmaco in studio. (Sara' consentita una radioterapia palliativa) • Interventi di grande chirurgia, biopsia aperta o danno traumatico significativo entro 4 settimane dalla prima dose del farmaco in studio (e' consentita la broncoscopia) • Fattore stimolante le colonie dei granulociti (GCSF) o Fattore stimolante le colonie di granulociti-macrofagi (GMCSF), entro 3 settimane dall'inclusione nello studio (in seguito questi fattori di crescita possono essere utilizzati durante lo studio). • Terapia anticoagulante con antagonisti della vitamina K come warfarina, o con eparine od eparinoidi. Warfarina a basso dosaggio (1 mg per os una volta al giorno) e' permessa se l'INR (International Normalized Ratio) e' < 1,5. E' permessa l'aspirina a basso dosaggio (≤ 81 mg al giorno). Terapia con un farmaco sperimentale al di fuori di questo studio o durante od entro 4 settimane dall'inclusione nello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy analysis will be based on patients with non-squamous cell histology for the primary as well as the secondary efficacy variables. The primary efficacy variable is overall survival (OS). One-sided alpha of 0.025 will be used for OS analysis. Overall survival is defined as the time (days) from randomisation to death due to any cause. Patients alive at the time of analysis will be censored at their last contact date. In addition to the final analysis of OS, which will be performed at the end of the study, two futility interim analyses of OS are planned during the study. These will be based on the projected number of events in non-squamous cell carcinoma patients. The first futility analysis of OS is planned to take place when approximately 182 deaths are observed (that is, after one third of the total number of events). The second futility analysis of OS is planned to take place when approximately 363 deaths are observed (that is, after two thirds of the total number of events). The futility analyses will be performed based on ruling out a 20% increase in OS. There is no planned early stopping for efficacy. The final efficacy analysis of OS will be performed when approximately 544 deaths in non-squamous cell carcinoma patients occur. The final efficacy boundary will be calculated separately from the futility analyses, which will make the futility and final efficacy analyses independent of each other, hence non-adherence to the futility boundary does not inflate the overall false positive rate, alpha, to over 0.025 (one-sided). Additionally, as no early stopping for efficacy is planned, the alpha level for the final OS analysis will remain at 1-sided 0.025. |
| L`analisi di efficacia primaria si basera` su pazienti con istologia tumorale non squamosa per le variabili di efficacia sia primaria che secondaria. La variabile di efficacia primaria e` la OS. L'obiettivo OS avra` l'alfa primaria totale di 0.025 ad una coda |
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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 | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 14 |
| 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 | 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 | 36 |
| 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 | 36 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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