| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV/Recurrent Non-Small Cell Lung Cancer |
| Cancro polmonare non a piccole cellule |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stage IV/Recurrent Non-Small Cell Lung Cancer |
| Cancro 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 | 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) |
|
| 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) |
|
| 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 (OS) of subjects with Stage IV/recurrent NSCLC of squamous histology who have been randomized to ipilimumab in addition to aclitaxel and carboplatin versus placebo in addition to paclitaxel and carboplatin. |
| Comparare la sopravvivenza globale (OS) dei soggetti con NSCLC a cellule squamose in stadio IV o ricorrente, randomizzati a una terapia con ipilimumab associato a paclitaxel e carboplatino con la OS di soggetti randomizzati a un trattamento con placebo associato a paclitaxel e carboplatino. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare Overall Survival in all randomized subjects who received at least one dose of blinded study therapy (OS2), Progression-Free survival (PFS) per mWHO and Best Overall Response Rate (BORR) per mWHO between the two treatment arms |
| Confrontare la sopravvivenza complessiva in tutti i soggetti randomizzati che hanno ricevuto almeno una dose di terapia sperimentale in cieco (OS2), la sopravvivenza senza progressione (PFS) per i criteri mWHO e il miglior tasso di risposta generale (BORR) per i criteri mWHO tra i due bracci di trattamento. |
|
| 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 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) At least 1 measurable tumor lesion, as defined by mWHO criteria, that is not located in a previously irradiated area d) Eastern Cooperative Oncology Group (ECOG) performance status `‰¤ 1 at study entry e) 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) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 8 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 |
| I soggetti devono essere maggiorenni ed in grado di esprimere il loro consenso per iscritto, se di sesso femminile potenzialmente fertili e sessualmente attivi devono usare un metodo efficace di contraccezione per tutta la durata dello studio e per otto settimane dopo aver ricevuto l`€™ultima dose d`€™ipilimumab, devono fornire un test di gravidanza negativo (siero o urine) entro 72 ore dall`€™inizio del trattamento e non devono essere in fase di allattamento. I soggetti devono essere affetti da NSCLC ad istologia a predominanza squamosa, documentato tramite spazzolato, lavaggio o ago-aspirazione di una lesione definita, ma non dalla sola citologia dell`€™espettorato. I soggetti devono presentare NSCLC a stadio IV o ricorrente (classificazione IASLC), devono avere almeno una lesione tumorale misurabile (criteri mWHO) non localizzata in un`€™area precedentemente irradiata, devono avere un performance status <=1 all`€™entrata nello studio ed essere accessibili a trattamenti e follow-up. I soggetti arruolati in questa sperimentazione devono essere trattati nei centri partecipanti. |
|
| E.4 | Principal exclusion criteria |
| 1) Target Disease Exceptions a) Brain metastases b) Malignant pleural effusion that is recurrent despite appropriate supportive care 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 disease 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-Barre` 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 positive or active Hepatitis B or active Hepatitis C infection h) Prior systemic therapy for lung cancer including vaccines and other targeted therapies i) Prior radiation therapy or loco-regional surgeries are allowed if performed at least 3 weeks prior to the date of entry into the lead-in phase i) Subjects with `‰¥ Grade 2 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 `‰¥ 2.5 times the ULN or `‰¥ 5 times the ULN if liver metastases are present c) Inadequate renal function defined as calculated creatinine clearance < 50 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 used for prevention of infectious disease (for up to 4 weeks prior to or after any dose of blinded study drug) c) Any immunotherapy for the treatment of cancer d) Prior treatment with any inhibitor or agonist of T-cell co-stimulation 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 |
| I soggetti non devono presentare: metastasi cerebrali, effusione plurale maligna ricorrente nonostante le cure, anamnesi di malattie auto-immuni importanti che abbiano richiesto piu` di 2 mesi di trattamento con immunosoppressivi, quali coliti ulcerative e morbo di Chron, artrite reumatoide, sclerosi progressiva sistemica, Lupus Erythematosus sistemico, vasculiti autoimmuni, anamnesi di neuropatie motorie considerate di origine autoimmune o di necrolisi epidermale tossica. I soggetti non devono essere dementi, presentare uno stato mentale alterato o qualsiasi condizione psichiatrica che potrebbe impedire il rilascio del consenso o il completamento dei questionari; non devono altresi` essere affetti da malattie che secondo l`€™opinione dello Sperimentatore possano riflettersi sulla capacita` da parte del soggetto di ricevere la terapia. I soggetti non devono aver presentato tumori maligni in precedenza, entro 5 anni, ad eccezione delle forme di cancro curabile localmente che sono state apparentemente curate senza la necessita` di ulteriori terapie, come il cancro della pelle a cellule squamose o basale, il cancro superficiale della vescica o il carcinoma in situ della cervice o del seno; non devono essere positivi per HIV, epatite B o C; non devono aver effettuato terapie sistemiche per il cancro ai polmoni (es:vaccini); inoltre non devono presentare neuropatia periferica di grado>=2. I soggetti non devono presentare funzioni ematologiche inadeguate (conta assoluta dei neutrofili < 1.500/mm3, piastrine < 100.000/ mm3, emoglobina< 9g/dL), funzioni epatiche inadeguate (bilirubina totale >=2.5 ULN, AST e ALT >= 2.5 ULN o >= 5 ULN se metastasi epatiche presenti, funzioni renali inadeguate (clearance creatinina < 50 ml/min). Sono esclusi i soggetti che facciano uso di farmaci immunosoppressivi (l`€™uso di corticosteroidi e` permesso solo come premedicazione prima della somministrazione di chemioterapia o per trattare eventi avversi), che abbiano seguito terapie vacciniche non oncologiche per la prevenzione di malattie infettive, o immunoterapie per il cancro o trattamenti precedenti con inibitori o agonisti della co-stimolazione delle cellule T. Sono esclusi dallo studio soggetti fertili di sesso maschile sessualmente attivi che non usino un efficace metodo di contraccezione se la loro compagna e` una donna sessualmente attiva e fertile. I soggetti che siano stati prigionieri o che siano obbligatoriamente detenuti per il trattamento di una malattia psichiatrica o fisica. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety Assessments: All subjects who receive at least 1 dose of study treatment (ipilimumab, placebo, paclitaxel or carboplatin) will be evaluated for safety parameters. Efficacy Assessments: All randomized subjects will be evaluated for efficacy analyses. 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. Progression Free Survival (PFS) defined by mWHO and BORR by mWHO are secondary endpoints. Radiologic Assessments: CT/MRI imaging of the chest and abdomen is required at screening and every 6 weeks in the induction phase (from date of first blinded study drug dose) and every 12 weeks in the maintenance phase until confirmed progressive disease (PD). Subjects who demonstrate PD at the week 7 tumor assessment will not be randomized into the study. Brain scan at screening is required to rule out the presence of brain metastases. |
| 1) Valutazioni di sicurezza: Tutti i soggetti che ricevono almeno 1 dose del medicinale di studio (ipilimumab, placebo, paclitaxel o carboplatino) saranno sottoposti a una valutazione dei parametri di sicurezza. 2) Valutazioni d'efficacia: Tutti i soggetti randomizzati saranno sottoposti ad analisi d'efficacia. La sopravvivenza globale (OS) sara' definita come l'intervallo tra la data della randomizzazione e la data di morte. Per i soggetti ancora in vita, l'OS sara' registrata con l'ultima data in cui il soggetto risultava essere in vita. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Radiologic Assessments: CT/MRI imaging of the chest and abdomen is required at screening and every 6 weeks in the induction phase (from date of first blinded study drug dose) and every 12 weeks in the maintenance phase until confirmed progressive disease (PD). Subjects who demonstrate PD at the week 7 tumor assessment will not be randomized into the study. Brain scan at screening is required to rule out the presence of brain metastases. |
| Tutti i soggetti randomizzati saranno sottoposti ad analisi d'efficacia. La sopravvivenza globale (OS) sara' definita come l'intervallo tra la data della randomizzazione e la data di morte. Per i soggetti ancora in vita, l'OS sara' registrata con l'ultima data in cui il soggetto risultava essere in vita. |
|
| E.5.2 | Secondary end point(s) |
| - Overall Survival in All Randomized Subjects who Received at Least One Dose of Blinded Study Therapy (OS2) - Progression-Free Survival (PFS) per mWHO - Best Overall Response Rate (BORR) per mWHO between the two treatment arms. |
| La sopravvivenza complessiva in tutti i soggetti randomizzati che hanno ricevuto almeno una dose di terapia sperimentale in cieco (OS2), la sopravvivenza senza progressione (PFS) per i criteri mWHO e il miglior tasso di risposta generale (BORR) per i criteri mWHO tra i due bracci di trattamento mWHO sono gli endpoints secondari. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| - Time from date of randomization until the date of death - Radiologic Assessments: CT/MRI imaging of the chest and abdomen is required at screening and every 6 weeks in the induction phase (from date of first blinded study drug dose) and every 12 weeks in the maintenance phase until confirmed progressive disease (PD). Subjects who demonstrate PD at the week 7 tumor assessment will not be randomized into the study. Brain scan at screening is required to rule out the presence of brain metastases. |
| -Tempo dalla data di randomizzazione alla data di morte -Valutazioni radiologiche: la diagnostica per immagini TC/RMI del torace e dell`€™addome e' obbligatoria allo screening e ogni 6 settimane nella fase di induzione (dalla data della prima dose di farmaco assunto in cieco), e ogni 12 settimane nella fase di mantenimento fino alla conferma di progressione della malattia (PD). Soggetti che dimostrino PD nel corso della valutazione del tumore alla settimana 7non saranno arruolati. Si richiede una scansione cerebrale allo screening per escludere la presenza di metastasi al cervello. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 125 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Colombia |
| Hong Kong |
| Israel |
| Korea, Democratic People's Republic of |
| Korea, Republic of |
| Mexico |
| Peru |
| Russian Federation |
| Singapore |
| South Africa |
| Switzerland |
| Taiwan |
| Thailand |
| United States |
|
| 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
|
| Approximately 3 years (36 months) are estimated to be required to observe the necessary number of events for full information on the primary endpoint of overall survival. For more info about follow-up see protocol study |
| Approximately 3 years (36 months) are estimated to be required to observe the necessary number of events for full information on the primary endpoint of overall survival. For more info about follow-up see protocol study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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 |
Print
