| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| progressive well differentiated thoracic neuroendocrine tumors |
| tumore neuroendocrino ben differenziato del torace in progressione |
|
| E.1.1.1 | Medical condition in easily understood language |
| progressive well differentiated thoracic neuroendocrine tumors |
| tumore neuroendocrino ben differenziato del torace in progressione |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007282 |
| E.1.2 | Term | Carcinoid tumour pulmonary |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062476 |
| E.1.2 | Term | Neuroendocrine tumor |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037342 |
| E.1.2 | Term | Pulmonary carcinoid tumor |
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068115 |
| E.1.2 | Term | Metastatic carcinoid tumour |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068118 |
| E.1.2 | Term | Metastatic carcinoid tumor |
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052399 |
| E.1.2 | Term | Neuroendocrine tumour |
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055108 |
| E.1.2 | Term | Thymic cancer metastatic |
| 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 evaluate the efficacy of Lanreotide Autogel (ATG) 120 mg in combination with Temozolomide (TMZ) in subjects with unresectable advanced neuroendocrine tumours of the lung or thymus (typical and atypical carcinoids according to the WHO 2004 criteria) as Disease Control Rate (DCR) at 9 months, according to RECIST criteria v 1.1. |
| Valutare l’efficacia di Lanreotide Autogel (ATG) 120 mg in combinazione con Temozolomide (TMZ) in soggetti con tumore neuroendocrino avanzato non-resecabile del polmone o del timo (carcinoide tipico e atipico secondo i criteri WHO 2004) in termini di tasso di controllo di malattia (Disease Control Rate o DCR) a 9 mesi, in accordo ai criteri RECIST v 1.1. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess, according to RECIST criteria v 1.1: Progression Free Survival;Time to Response;Duration of Response;Time to Progression;Best Overall response;Objective Response Rate; Disease Control Rate at 12 months;The influence of typical carcinoids and atypical carcinoids on the Disease Control Rate at 9 months;
• To assess the biochemical response (CgA plasma levels);To assess NSE) and CgA biomarkers levels prognostic and predictive value;To assess the prognostic value of biomarkers expression (immunohistochemistry assay SSTR2, Ki67 and MGMT status in tissue obtained from paraffin embedded primary tumour surgery specimens or biopsies) for PFS, Overall Response Rate (ORR), and DCR;
• To assess the correlation of the central assessment of tumor radiological response and the local one.
• To assess safety profile of Lanreotide ATG 120 mg in combination with TMZ in terms of AEs/SAEs,vital signs,physical examination,gallbladder evaluation,laboratory abnormalities, concomitant medications. |
• Valutare, in accordo ai criteri RECIST v 1.1: Sopravvivenza libera da progressione;Tempo alla risposta;Durata della risposta;Tempo alla progressione;Miglior risposta complessiva;Frequenza di risposte obiettive;Tasso di controllo di malattia a 12 mesi;Effetto del carcinoide tipico o del carcinoide atipico sul tasso di controllo di malattia a 9 mesi.
• Valutare la risposta biochimica attraverso i livelli plasmatici di CgA; Determinare il valore prognostico e predittivo di NSE e CgA;Determinare il valore prognostico dell’espressione di alcuni biomarcatori(SSTR2, Ki67 e MGMT)su blocchetti di tessuto paraffinato, o biopsie, in termini di PFS, Tasso complessivo di risposte, e DCR;Determinare la correlazione tra la risposta radiologica valutata centralmente e quella valutata localmente;
• Valutare il profilo di sicurezza di Lanreotide ATG 120 mg in combinazione con TMZ in termini di AE/SAE,segni vitali,esame fisico,valutazione della cistifellea,anomalie di laboratorio, terapie concomitanti |
|
| 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 |
| non disponibile-Wed Dec 02 00:00:00 CET 2015-substudy ATLANT: title not yet available- evaluations of activity of O6-Methylguanine-DNA methyltransferasi (MGMT) |
| non disponibile-Wed Dec 02 00:00:00 CET 2015-Sottostudio-ATLANT : titolo non ancora disponibile-Valutazione dell’attività dell’ O6-Methylguanine-DNA methyltransferasi (MGMT) |
|
| E.3 | Principal inclusion criteria |
1) Provision of written Informed Consent prior to any study related procedures;
2) Adult subjects (male or female) ≥ 18 years old ;
3) WHO Performance status ≤ 2;
4) Histological documented unresectable advanced (locally or metastatic) well or moderately differentiated neuroendocrine tumors of the lung or thymus (typical and atypical carcinoids according to the WHO 2004 criteria);
5) Imaging documented progression within 12 months before screening visit (V1), according to RECIST criteria v 1.1;
6) Measurable disease, as defined by RECIST criteria v 1.1, on a CT scan performed at screening visit (V1);
7) Octreoscan or Ga68-DOTA-TATE/TOC/NOC-PET-TC within 12 months before screening visit (V1);
8) Adequate liver, renal and bone marrow function, as defined below:
a. Adequate bone marrow function
Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L
Platelets ≥ 100 × 109/L
Hemoglobin > 9 g/dL
b. Adequate liver function
Total serum bilirubin ≤ 2.0 × ULN (exception for Gilbert disease)
International Normalized Ratio (INR) < 1.5
ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN, in subjects with liver metastases)
c. Adequate renal function
Serum creatinine ≤ 1.5 × ULN
9) Willing and able to comply with study restrictions and willing to return to the clinic for the required visits during the study period and for the follow up evaluation as specified in the protocol.
10) Female subjects of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 6 months after participation in the study. Acceptable methods of contraception include double barrier method [i.e. condom and occlusive cap (diaphragm or cervical/vault caps)] with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.
11) Male subjects with female partners of childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 6 months after participation in the study.
|
1) Consenso Informato scritto prima di intraprendere qualsiasi procedura specifica dello studio;
2) Pazienti adulti, maschi e femmine, di età ≥ a 18 anni;
3) WHO Performance status ≤ 2;
4) Diagnosi di tumore neuroendocrino avanzato (localmente avanzato o metastatico), non resecabile, istologicamente confermato, ben o moderatamente differenziato del polmone o del timo (carcinoide tipico e atipico secondo i criteri WHO 2004);
5) Progressione di malattia documentabile con referto radiologico eseguito nei 12 mesi prima delle visita di screening (V1), in accordo ai criteri RECIST v 1.1;
6) Malattia misurabile, come da criteri RECIST v 1.1, sulla base di una TAC effettuata alla visita di screening(V1);
7) Octreoscan o Ga68-DOTA-TATE/TOC-PET-TC effettuata nei 12 mesi prima della visita di screening (V1);
8) Funzione epatica, renale e midollare adeguata, come da parametri di seguito elencati:
a. Funzione midollare adeguata
Conta assoluta dei Neutrofili (ANC) ≥ 1.5 × 109/L
Piastrine ≥ 100 × 109/L
Emoglobina > 9 g/dL
b. Funzione epatica adeguata
Serum bilirubina sierica totale ≤ 2.0 × ULN (tranne in presenza di malattia
di Gilbert)
International Normalized Ratio (INR) < 1.5
ALT e AST ≤ 2.5 × ULN (≤ 5 × ULN, in soggetti con metastasi epatiche)
c. Funzione renale adeguata
Creatinina sierica ≤ 1.5 × ULN
9) Disposto ed in grado aderire alle limitazioni dello studio e disposto a ritornare in ospedale per le visite richieste per tutto il corso dello studio e per le valutazioni di follow up secondo protocollo.
10) Soggetti di sesso femminile potenzialmente fertili (non sterilizzate chirurgicamente o in post-menopausa da almeno due anni) devono usare un metodo contraccettivo valido e devono acconsentire ad utilizzare questo metodo per l’intera durata dello studio e per i 6 mesi successivi. Metodi di contraccezione accettati includono un metodo di doppia barriera (ad es. preservativo e diaframma o cappuccio cervicale) con spermicida, intrauterine dispositivo intrauterino (IUD), o contraccettivo steroideo (orale, transdermico, a impianto, e ad iniezione) insieme ad un metodo di barriera.
Soggetti di sesso maschile con partner potenzialmente fertile devono usare un metodo contraccettivo valido e devono acconsentire ad utilizzare questo metodo per l’intera durata dello studio e per i 6 mesi successivi.
|
|
| E.4 | Principal exclusion criteria |
1) History of hypersensitivity to the IMPs or drugs with a similar chemical structure or any excipient used in the formulation.
2) Any known contraindications to CT scan.
3) Poorly differentiated neuroendocrine carcinoma and mixed NET tumours, according to WHO 2004 criteria.
4) Neuroendocrine tumours other than lung or thymus.
5) Non-neuroendocrine thymic neoplasm.
6) Treated with systemic therapies (chemotherapy, interferon-alpha, somatostatin analogues, molecular target therapies) within 1 month prior to screening visit (V1).
7) Treated with a number of systemic therapy lines > 3 prior to screening visit (V1), and any of the following:
a. for chemotherapy no more than 1 line prior to V1;
b. for somatostatin analogue no more than 1 line therapy, considered as treatment lasting more than 6 months, prior to V1;
c. no therapy with TMZ prior to V1.
8) Received a prior therapy with Peptide Receptor Radionuclide Therapy (PRRT) within 6 months prior to screening visit (V1).
9) Sign of recurrence of prior malignancies, or concomitant malignancies, or malignancies requiring active treatment within the last 3 years, other than the investigated disease, with the exception of previous basal cell skin cancer and previous cervical carcinoma in situ or neoplasm radically resected within 3 years prior to screening visit (V1).
10) Undergone major surgery/surgical therapy for any cause within 3 months prior to screening visit (V1).
11) Received external palliative radiotherapy within the last month prior to screening visit (V1).
12) Received locoregional therapies (TAE, TACE, TARF) and SIRT within 3 months prior to screening visit (V1).
13) Presence of symptomatic brain metastasis.
14) Unstable angina pectoris, symptomatic congestive heart failure (NYHA Class III or IV), serious uncontrolled cardiac arrhythmia or a history of myocardial infarction ≤ 6 months prior to screening visit (V1).
15) Active or uncontrolled severe infection or known history of HIV seropositivity.
16) Previous Pneumocistis Carini Pneumonitis infection.
17) Liver cirrhosis, chronic active or persistent hepatitis, HCV and HBV positive test in presence of active disease clinical evidence.
18) Active bleeding diathesis, including abnormal coagulation (PT or APTT greater than 30% above ULN).
19) Uncontrolled diabetes mellitus as defined by HbA1c ≥ 8%, despite adequate therapy. Subjects with history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
20) History of cholelithiasis or cholelithiasis found at screening visit (V1).
21) Any current or prior medical condition that may interfere with the conduct of the study.
22) Hypersensitivity to dacarbazine (DTIC).
23) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
24) Treated with any other IMP within 1 month prior to screening visit (V1).
25) Likely to require treatment during the study with drugs that are not permitted by the study protocol.
26) Female subject pregnant or lactating. A pregnancy test will be performed at the start of the study for all female subjects of childbearing potential (i.e. not surgically sterile or 2 years postmenopausal).
27) Male subject who is planning a sperm donation during the entire study participation and at least 6 months after the last study drug administration.
28) History of, or known current, problems with substance or alcohol abuse.
29) Any mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
30) Abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject’s safety
|
1) Anamnesi di ipersensibilità ai farmaci in studio o a farmaci con una struttura chimica simile o ad alcuno degli eccipienti presenti nella formulazione.
2) Nota controindicazione alla TAC.
3) Carcinomi neuroendocrini scarsamente differenziati e tumori neuroendocrini misti, secondo i criteri WHO 2004.
4) Tumori neuroendocrini con origine diversa da polmone e timo.
5) Neoplasia non-neuroendocrina del timo.
6) Trattati con terapie sistemiche (chemioterapia, interferone-alfa, analoghi della somatostatina, terapie a target molecolare) nel mese precedente la visita di screening (V1).
7) Trattati con un numero di linee terapeutiche sistemiche > 3 prima della visita di screening (V1), e qualsiasi delle seguenti:
a. per la chemioterapia non più di 1 linea prima della V1;
b. per gli analoghi della somatostatina non più di 1 linea terapeutica;
c. nessuna terapia con TMZ prima della V1.
8) Terapia radiometabolica (PRRT) nei 6 mesi prima della (V1).
9) Segni di ricomparsa di un precedente tumore maligno, o tumore maligno concomitante, o tumore maligno che abbia richiesto trattamento attivo negli ultimi 3 anni, diverso dalla malattia oggetto di studio, ad eccezione di precedente carcinoma basocellulare o precedente carcinoma in situ della cervice o neoplasia radicalmente resecata nei tre anni antecedenti la (V1).
10) Intervento chirurgico maggiore/chirurgia a scopo curativo per qualsiasi causa nei 3 mesi antecedenti la visita di screening (V1).
11) Radioterapia esterna palliativa nell’ultimo mese prima della (V1).
12) Terapie locoregionali (TAE, TACE, TARF) e SIRT nei 3 mesi prima della (V1).
13) Presenza di metastasi cerebrali sintomatiche.
14) Angina pectoris instabile, scompenso cardiaco congestizio sintomatico (Classe NYHA III o IV), aritmia cardiaca seria non controllata o storia di infarto miocardico ≤ 6 mesi prima della (V1).
15) Infezione non-controllata o severa, o anamnesi nota di sieropositività all’HIV.
16) Precedente infezione da Pneumocistis Carini Pneumonitis.
17) Cirrosi epatica, epatite cronica attiva o persistente, test positivo per HCV e HBV in presenza di evidenza clinica di malattia attiva.
18) Diatesi emorragica in sanguinamento attivo, con indici di coagulazione anormali (PT o APTT con valore ≥ 30% ULN).
19) Diabete mellito non controllato definito da HbA1c ≥ 8%, nonostante la terapia. Soggetti con anamnesi di glicemia alterata a digiuno o diabete mellito (DM) potrebbero essere inclusi; tuttavia il livello di glucosio nel sangue e il trattamento antidiabetico devono essere monitorati strettamente durante lo studio, e aggiustati ove necessario.
20) Storia di colelitiasi o colelitiasi riscontrata alla (V1).
21) Qualsiasi terapia in corso, o antecedente, che possa interferire con la conduzione della studio.
22) Ipersensibilità alla dacarbazina (DTIC).
23) Rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento glucosio-galattosio.
24) Trattamento con altri farmaci sperimentali nel mese antecedente la (V1).
25) Che possano necessitare di terapie durante lo studio con farmaci non ammessi dal protocollo di studio.
26) Soggetti di sesso femminile in stato di gravidanza o in allattamento. Un test di gravidanza sarà effettuato all’inizio dello studio per tutte le pazienti di sesso femminile potenzialmente fertili (non sterilizzate chirurgicamente o in post-menopausa da almeno due anni).
27) Soggetti di sesso maschile non devono pianificare donazione di sperma durante l’intera partecipazione allo studio e almeno 6 mesi dopo l’ultima somministrazione di farmaco.
28) Anamnesi o attuali problemi di abuso di sostanze stupefacenti o alcool.
29) Qualsiasi condizione mentale che renda il soggetto non in grado di comprendere la natura, lo scopo e le possibili conseguenze dello studio, e/o evidenza di atteggiamento non collaborativo.
Anomalie al basale, qualsiasi altra condizione clinica o referto di laboratorio, che nell’opinione dello sperimentatore possa mettere a repentaglio la sicurezza del soggetto.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response of subjects to the study combination therapy, 9 months after first treatment administration. Responders are subjects showing disease control rate (DCR) according to RECIST criteria v 1.1, defined as objective response or stability of the disease. They include: CR (complete response), PR (partial response) or SD (stable disease). |
| Risposta dei soggetti al trattamento di combinazione in studio a 9 mesi dalla prima somministrazione di farmaco. I soggetti che rispondono sono soggetti che mostrano controllo di malattia (DCR)secondo i criteri RECIST v 1.1, definito come risposta obiettiva o stabilità di malattia. Questa definizione include: risposta completa (CR), risposta parziale (PR) o stabilità di malattia (SD). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 9 months after first treatment administration. |
| 9 mesi dalla prima somministrazione di farmaco |
|
| E.5.2 | Secondary end point(s) |
Safety:
• Occurrence of adverse events (AEs) by CTCAE v 4.03 (June 14, 2010) from informed consent and throughout the study.
• Standard haematology and biochemistry test results at each study visit.
• Vital signs (assessment of blood pressure (BP), heart rate (HR) and body weight in kg) measurements at each study visit.
• Physical examination at each study visit.
• Concomitant medication usage throughout the study.
• Electrocardiogram (ECG), Echocardiography at visits 1, 9 and 16.
• Gallbladder Echography at Visit 1, 9 and 16.
|
Tollerabilità:
. Incidenza di eventi avversi (AEs) secondo CTCAE v 4.03 (14 Giugno 2010) dalla firma del consenso informato per tutto il corso dello studio.
• Risultati dei test ematologici e biochimici standard ad ogni visita.
• Misurazione dei segni vitali (valutazione di pressione sanguigna (BP), battito cardiaco (HR) e peso in kg) ad ogni visita.
• Esame fisico ad ogni visita.
• Terapie concomitanti impiegate nel corso dello studio.
• Elettrocardiogramma (ECG), Ecocardiografia alle visite 1, 9 e 16.
• Ecografia della cistifellea alle visite 1, 9 e 16. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| during all study treatment period. For ECG, Echocardiography and Gallbladder Echography at baseline, , 24 and 52 weeks |
| tutto lo studio, per le valutazioni ECG, ecocardiografia e eco alla cistifellea al basale, 24 e 52 settimane |
|
| 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 | 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Studio multicentrico a singolo braccio di associazione tra Lanreotide 120 mg e TMZ |
| Multicentre study, single arm, of combination Lanreotide 120 mg and TMZ |
|
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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