E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NSCLC is the description of a malign development of body tissues from cells in the Bronchia / Lungs where larger cells are visible per microscope. |
NSCLC è l’acronimo che si rifericse allo svilupparsi di tessuti maligni a partire dalle cellule dei Bronchi/Polmoni dove le cellule più grandi sono visibili al microscopio |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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 compare overall survival of subjects who have been randomized to receive ipilimumab at 10mg/kg to that of subjects receiving pemetrexed at 500mg/m2. |
confrontare la sopravvivenza complessiva dei soggetti assegnati in modalità random al gruppo ipilimumab in dose da 10 mg/kg (Braccio A) con quella dei soggetti assegnati al gruppo pemetrexed in dose da 500 mg/m2 (Braccio B). |
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E.2.2 | Secondary objectives of the trial |
To compare progression free survival by mWHO and to evaluate best overall response rate (BORR) |
confrontare la sopravvivenza libera da progressione (PFS) in base ai criteri mWHO e valutare il miglior tasso di risposta complessiva (BORR). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent: a) Willing and able to provide informed consent 2) Target Population: a) Subjects with NSCLC of predominantly non-squamous histology documented by histology or cytology from brushing, washing or needle aspiration of a defined lesion but not from sputum cytology alone b) Subjects must present with Stage IV or Recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer (IASLC) classification) c) Subjects must have received 4 cycles of a platinum-based chemotherapy regimen consisting of carboplatin or cisplatin combined with docetaxel, paclitaxel, vinorelbine, gemcitabine, or pemetrexed. Previous treatment with cetuximab or bevacuzimab is allowed provided these drugs are stopped at least 3 weeks prior to randomization. d) Subjects must have stable disease or better following the 4 cycles of platinum-based chemotherapy e) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at study entry. f) Accessible for treatment and follow-up. Subjects enrolled in this trial must be treated at the participating centers 3) Age and Reproductive Status: a) Men and Women >/= 18 years of age b) Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of ipilimumab in such a manner that the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP c) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product d) Women must not be breastfeeding |
1)Consenso informato scritto e firmato •Volontà e capacità del paziente di dare il proprio consenso 2)Popolazione in studio: •Soggetti con NSCLC ad istologia prevalentemente squamosa documentata, per via istologica o citologica, tramite brushing, washing o aspiratazione con ago di una determinata lesione tramite sola istologia dell’espettorato. •I soggetti devono avere un NSCLC di stadio IV o recidivante (secondo i criteri della 7a classificazione dell’Associazione Internazionale per lo Studio del Cancro al Polmone (IASLC)). •I soggeti devono aver ricevuto 4 cicli di chemioterapia, basata sull’impiego di platino, e consistente nella somministrazione di carboplatino o cisplatino combinati con docetaxel, paclitaxel, vinorelbine, gemcitabine, o pemetrexed. E’ accettato il pregresso trattamento con cetuximab o bevacuzimab a condizione che la somministrazione di tali farmaci sia stata interrotta almeno 3 settimane prima della randomizzazione. •I soggetti devono presentare patologia stabile o un miglioramento a seguito dei 4 cicli di chemioterapia basata sull’impiego di platino. •Punteggio ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1 al momento dell’arruolamento •Disponibilità a sottoporsi al trattamento ed al follow up. I soggetti arruolati in questo studio devono essere trattati ai centri partecipanti. 3)Età anagrafica e condizione riproduttiva: •uomini e donne di età >/= 18 anni •donne in grado di avere figli (WOCBP) e uomini devono utilizzare un metodo contraccettivo accettabile per evitare gravidanze durante lo studio e fino a 12 settimane dopo l’ultima dose di ipilimumab, in maniera da minimizzare il rischio di gravidanza. Si veda la sezione 3.3.3 per la definiziione di WOCBP •WOCBP devono sottoporsi ad un test di gravidanza su sangue o urine con esito negativo (sensibilità minima 25 IU/L o unità equivalenti di HCG) entro 72 ore dalla prima assunzione di farmaco sperimentale. •Le donne non devono essere in allattamento |
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E.4 | Principal exclusion criteria |
1) Target Disease Exceptions: a) Brain metastases unless stable with no evidence of progression on scans for at least 30 days, non-symptomatic, and not requiring treatment with steroids b) Malignant pleural effusion that is recurrent despite appropriate supportive care c) Known to have an EGFR activating mutation and/or an ALK mutation d) Have previously been treated with a tyrosine kinase inhibitor (eg., erlotinib, gefintinib, etc) e) Previously been treated with more than 4 cycles of chemotherapy for recurrent/stage IV lung cancer 2) Medical History and Concurrent Diseases: a) Documented history of severe autoimmune or immune mediated symptomatic disease that required prolonged (more than 2 months) systemic immunosuppressive (ie, steroids) treatment such as: i) Ulcerative colitis and Crohn’s di sease ii) Rheumatoid arthritis, systemic progressive sclerosis (scleroderma) iii) Systemic Lupus Erythematosus iv) Autoimmune vasculitis (eg, Wegener’s Granulomatosis) b) Subjects with history of motor neuropathy considered of autoimmune origin (eg, Guillain Barré Syndrome) c) Subjects with a history of toxic epidermal necrolysis (TEN) d) Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent or completing questionnaires e) Serious uncontrolled medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive protocol therapy f) Prior malignancy, active within 5 years, except for locally curable cancers that have been apparently cured and need no subsequent therapy, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast g) HIV, Hepatitis B, or Hepatitis C infection based on testing performed during the CA184124 screening period h) Subjects with >/= Grade 1 peripheral neuropathy 3) Physical and Laboratory Test Findings: a) Inadequate hematologic function defined by: i) Absolute neutrophil count (ANC) < 1,500/mm3, or ii) Platelet count < 100,000/mm3; or iii) Hemoglobin level < 9 g/dL b) Inadequate hepatic function as defined by either: i) Total bilirubin level >/=2.5 times the upper limit of normal (ULN); ii) AST and ALT levels >/= times the ULN or >/= times the ULN if liver metastases are present c) Inadequate renal function defined as calculated creatinine clearance < 45 ml/min based on the standard Cockroft and Gault formula 4) Prohibited Treatments and/or Therapies: a) Chronic use of immuno-suppressive drugs (ie, corticosteroids used in the management of cancer or non-cancer related illnesses). Use of corticosteroids are allowed if used as premedication for chemotherapy administration or on study management of an AE b) Any non-oncology vaccine therapy, including flu vaccine, used for prevention of infectious disease for up to 4 weeks prior to or after any dose of study drug c) Any immunotherapy for the treatment of cancer d) Prior treatment with any inhibitor or agonist of T-cell co-stimulation e) Unable to interrupt treatment with aspirin or non steroidal inflammatory drugs f) Unable to take folic acid and vitamin B12 5) Sex and Reproductive Status: a) Sexually active fertile men not using effective birth control if their partners are WOCBP. 6) Other Exclusion Criteria: a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
1 - Eccezioni alla patologia in studio : a) Presenza di metastasi cerebrali a meno che non siano stabili senza evidenza di progressione sulla base delle TAC effettuate negli ultimi 30 giorni, asintomatiche, e che non richiedono trattamento con steroidi. b) Stravaso pleurico maligno ricorrente nonostante il trattamento con le cure opportune. c) Presenza confermata di una mutazione attivante dell’EGFR e/o una mutazione a carico dell’ALK d) Precedente trattamento con un inibitore della tirosin chinasi (erlotinib, gefintinib, ecc..) e) Precedente trattamento con più di 4 cicli di chemioterapia per cancro ai polmoni recidivante/di IV stadio 2 – Anamnesi e patologie concomitanti a) Storia clinica documentata di grave malattia sintomatica autoimmune o immuno-mediata che ha richiesto un trattamento prolungato (per più di due mesi) con un immunosoppressore sistemico, come ad esempio : i – colite ulcerosa e morbo di Crohn ii – Artrite reumatoide, sclerosi progressiva sistemica (scleroderma) iii – Lupus erimatoso sistemico iv – vasculite autoimmune b) b) Soggetti con storia clinica di necrolisi epidermica tossica (TEN) c) Demenza, alterazione degli stati mentali, o qualsiasi condizione psichiatrica che impedirebbe la comprensione o l’interpretazione del consenso informato o il completamento dei questionari d) Gravi disturbi medici non controllati che, nell’opinione dello sperimentatore, potrebbero indebolire la capacità del soggetto di assumere il farmaco previsto dal protocollo f) Pregresso tumore maligno, attivo negli ultimi 5 anni, ad eccezione di tumori locali curabili che sono stati apprentemente curati e che non necessitano di ulteriori trattamenti, come ad esempio il tumore alle cellule basali o squamose della pelle, il tumore superficiale alla vescica o il carcinoma in situ della cervice o della mammella. f) Saranno esclusi i pazienti con specifiche patologie autoimmuni preesistenti, anamnesi di patologie neuromotorie di origine autoimmune o di necrolisi epidermica tossica (TEN), metastasi cerebrali (ad eccezione di quelle stabili, con assenza di progressione alla scansione da almeno 30 giorni e assenza di sintomi, che non richiedono trattamento steroideo) o mutazioni attivanti nei geni EGFR e/o ALK. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival will be defined as the time from the date of randomization until the date of death. For those subjects who have not died, OS will be censored on the last date the subject was known to be alive. |
confrontare la sopravvivenza complessiva sarà definitia come il periodo di tempo dalla data di randomizzazione fino al decesso. Per i soggetti che non sono deceduti, la sopravvivenza complessiva verrà calcolata considerando la data in cui si ha avuto la più recente conferma che il paziente era in vita. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final analysis occurs when we reach 132 deaths. There is an IA at 99 deaths. |
l’analisi finale verrà effettuata quando saranno raggiunti 132 decessi. Sarà prevista un’analisi ad interim al raggiungimento dei 99 decessi. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are progression-free survival and best overall response rate per mWHO criteria. • Progression-free survival is defined as the time between the event of disease progression per mWHO criteria or death and the randomization date. If the subject did not progress or die, he/she will be censored at the last tumor assessment date. • The BORR will be defined as the number of subjects whose best overall response per mWHO criteria was CR or PR, divided by the total number of subjects in the all randomized subjects data set |
La sopravvivenza libera da progressione è definita come il periodo di tempo che intercorre tra il manifestarsi della progressione, secondo i criteri mWHO, o il decesso, e la data randomizzazione. Se il soggetto non manifesta progressione o non muore, verrà considerata la data dell’ultima valutazione sullo stato del tumore. La BORR verrà definitia come il numero di soggetti la cui migliore risposta complessiva, in base ai criteri mWHO, era CR (complete response) o PR (partial response), suddiviso per il numero totale dei soggetti contenuti nel database di tutti i soggetti randomizzati. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis occurs when we reach 132 deaths. There is an IA at 99 deaths |
l’analisi finale verrà effettuata quando saranno raggiunti 132 decessi. Sarà prevista un’analisi ad interim al raggiungimento dei 99 decessi. |
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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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
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 | No |
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 |
Russian Federation |
United States |
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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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Final analysis occurs when we reach 132 deaths |
l’analisi finale verrà effettuata quando saranno raggiunti 132 decessi. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 38 |
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 | 38 |
E.8.9.2 | In all countries concerned by the trial days | 0 |