| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Elderly Patients with Advanced Non-Small-Cell Lung Cancer |
| Pazienti anziani affetti da carcinoma polmonare non a piccole cellule in stadio avanzato/metastatico. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Elderly Patients with Advanced Non-Small-Cell Lung Cancer |
| Pazienti anziani con tumore del polmone metastatico |
|
| 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 | 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) |
|
| 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 primary endpoint is OS (determined from the date of randomization). |
| • Mettere a confronto la sopravvivenza globale fra soggetti anziani con carcinoma polmonare non a piccole cellule (NSCLC) in stadio avanzato/metastatico sottoposti a chemioterapia di I linea personalizzata sulla base del profilo genetico del tumore primario, definito per mezzo della reazione a catena della polimerasi quantitativa in tempo reale (qRT-PCR) su campioni in paraffina, e soggetti anziani sottoposti a chemioterapia standard di I linea nella modalità stabilita dal ricercatore. |
|
| E.2.2 | Secondary objectives of the trial |
a) PFS at 6 months (determined from the date of randomization).
b) Treatment response (according to RECIST 1.1).
c)To determine the feasibility of treatment selection based on pharmacogenomic parameters in previously untreated patients with advanced NSCLC in a multi-institutional randomized setting.
d)To describe the toxicity in patients treated with and without assignment of chemotherapy based on gene expression. |
•Mettere a confronto la percentuale di sopravvivenza libera da progressione fra soggetti anziani affetti da NSCLC in stadio avanzato/metastatico sottoposti a chemioterapia di I linea personalizzata sulla base del profilo genetico del tumore primario e soggetti anziani sottoposti a chemioterapia standard di I linea nella modalità stabilita dal ricercatore.
•Valutare la risposta al trattamento
•Valutare la fattibilità del trattamento di I linea la cui scelta è basata su criteri di farmacogenomica.
•Valutare la tossicità del trattamento |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histologically confirmed NSCLC of adenocarcinoma, squamous cell carcinoma, large cell [53][68] carcinoma, or NSCLC not otherwise specified (NOS). For the purposes of this trial all patients that are not categorically called as squamous cell carcinoma will be referred to as non-squamous NSCLC. Patients with suspected NSCLC may enroll prior to the diagnostic biopsy in order to obtain both the diagnostic and molecular analysis-required specimen during the same procedure.
4.1.2 Willing to undergo a biopsy to enable precise histologic determination and customization of chemotherapy if necessary
4.1.3 Stage IV NSCLC by the AJCC Staging Manual 7th edition (2010)
4.1.4 Measurable or evaluable disease by RECIST 1.1[53][68]
4.1.5 Age 70 years
4.1.6 Performance Status 0 or 1 (by ECOG criteria)
4.1.7 Adequate bone marrow function as evidenced by the following (assessed within 21 days of study registration ):
Absolute neutrophil count > 1,500/mm3
Platelet count 100,000/mm3
Hemoglobin > 9.0 gm/dL
4.1.8 Normal prothrombin time (PT) and activated prothrombin time with thromboplastin and kaolin (APTT)
4.1.9 Serum creatinine 1.5 x UNL (assessed within 21 days of study registration)
4.1.10 Adequate liver function as evidenced by the following (assessed within 21 days of study registration):
Total bilirubin must be within normal limits
AST (SGOT) and ALT (SGPT) 2.5 x UNL
Alkaline Phosphatase 4 x UNL
4.1.11 Serum calcium 1.1 x UNL
4.1.12 Signed informed consent document (ICD)
4.1.13 Men with partners in the childbearing age group must use effective contraception while on treatment and for 6 months thereafter.
4.1.14 Previous surgery for NSCLC (more than 30 days before study registration) is allowed but 4.1.3 and 4.1.4 must be present
4.1.15 Previous radiotherapy is allowed if:
(i) The time between completion of RT and initiation of study treatment is at least 7 days,
(ii) The patient has fully recovered from all toxic effects, and
(iii) At least one target lesion or evaluable disease is outside the radiation field.
4.1.16 Previous chemotherapy is allowed if the last dose was administered equal to or greater than 12 months ago. This chemotherapy must have been given in an adjuvant or neoadjuvant mode prior to or after a curative intent surgical resection for a NSCLC. Patient should be previously untreated for metastatic disease.
4.1.17 Patients with stable brain metastases will be allowed to enroll. At the time of screening, a CT scan or MRI of the brain is only required if clinically indicated. Stable brain metastasis is defined as no progression of brain metastases 14 days after conclusion of definitive treatment as documented by a CT scan or MRI of the brain. |
| Tutti i pazienti devono presentare evidenza istologica di carcinoma polmonare non a piccole cellule di stadio avanzato/metastatico (classificato come tale in base ai parametri sanciti dall'American Joint Committee on Cancer Staging Manual [AJCC], 7a edizione, 2010) ed avere materiale biologico sufficiente per le analisi molecolari o accettare l’esecuzione di un ulteriore esame diagnostico per il reperimento del tessuto. I pazienti devono essere di età ≥ ai 70anni; devono avere performance status secondo la scala ECOG pari a 0-1 e sottoscrivere di propria volontà un consenso informato. Devono avere almeno una lesione misurabile secondo i criteri RECIST 1.1. ed adeguata funzione d’organo. E’ concessa una precedente chirurgia per il tumore polmonare (se eseguita più di 30 giorni prima dell’entrata nello studio) e una chemioterapia sistemica con intento adiuvante o neoadiuvante se conclusa almeno 12 mesi prima dall’inserimento in protocollo; o radioterapia se completata almeno 7 giorni prima dall’inizio della chemioterapia. I pazienti con metastasi cerebrali stabili (definite come assenza di progressione 14 giorni dopo la conclusione di un trattamento locale documentato da TC o RM dell’encefalo) possono essere inclusi in protocollo. L’analisi mutazionale di EGFr è mandatoria: i pazienti positivi alla mutazione dell’ esone 20 (T790M, D770) di EGFr, in assenza di mutazioni degli esoni 18,19 o 21 o che abbiano stato mutazionale di EGFr non codificabile possono essere inclusi nel protocollo. |
|
| E.4 | Principal exclusion criteria |
4.2.1 Prior systemic chemotherapy or immunotherapy for advanced NSCLC.
4.2.2 Prior malignancies, except:
Cured non-melanoma skin cancer,
Curatively treated in situ carcinoma of the cervix, or
Any other curatively treated malignancy with no evidence of disease recurrence for at least 2 years.
4.2.3 Presence of uncontrolled brain or leptomeningeal metastases.
4.2.4 Peripheral neuropathy or hearing loss of neural origin equal to or greater than grade 2 by CTCAE v4.0 except if due to trauma
4.2.5 Other serious illness or medical condition, including but not limited to:
Congestive heart failure;
Myocardial infarction within 6 months;
Significant neurologic or psychiatric disorders that would impact study participation as judged by the treating physician or study chair;
Infection requiring I.V. antibiotics;
Tuberculosis with ongoing therapy at study entry,
Superior vena cava syndrome, except if controlled with radiation (see 4.1.15);
Active peptic ulcer disease;
Unstable diabetes mellitus;
Any contraindication to high dose corticosteroid therapy such as herpes simplex, herpes zoster, hepatitis, or other disease.
4.2.6 Hypercalcemia requiring therapeutic intervention (see 4.1.11).
4.2.7 Clinically significant ascites and/or pericardial effusion.
4.2.8 Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80.
4.2.9 Concurrent treatment with other investigational drugs.
4.2.10 Patients known to harbor sensitizing EGFR mutations in exons 18, 19 and 21. Patients with resistance mutation in exon 20 will be allowed to enroll i.e. T790M and D770. The rare patient who has both a resistance mutation and a sensitizing mutation at the diagnoses will be excluded in the protocol.
4.2.11 Patients whose tissue submission is not of adequate size to perform molecular testing will be excluded. Please see section 5.3.2 for details regarding adequate tissue samples sizes. Sites will be notified if there is insufficient tissue to conduct the molecular analysis.
4.2.12 Patients known to have translocations of ALK will also be excluded; however, testing for ALK translocation prior to study entry is not mandated. |
sono esclusi i pazienti che hanno sofferto di patologie oncologiche precedenti, fatta eccezione per i carcinomi cutanei non-melanoma, i carcinomi in situ della cervice o altre forme tumorali dalle quali il paziente dovrà, tuttavia, risultare libero da almeno 2 anni prima dell'arruolamento, nonché i pazienti affetti da metastasi cerebrali o leptomeningee non controllate. Non sono ammessi, inoltre, i pazienti che soffrano di neuropatia periferica o di disturbi dell’udito ≥ grado II, definiti come tali secondo i comuni criteri di tossicità (classificati sulla base dei criteri di tossicità per gli eventi avversi, versione 4.0, stabiliti dal National Cancer Institute - CTCAE v. 4.0), di disturbi cardiaci gravi quali infarto miocardico occorso nell'arco degli ultimi 6 mesi, scompenso cardiaco, diabete mellito non controllato, disturbi psichiatrici e neurologici gravi, sindrome della vena cava non radio trattata, ulcera peptica in fase attiva, infezioni in fase attiva o tubercolosi in trattamento, epatite, herpes simplex o herpes zoster che controindichino l’utilizzo di corticosteroidi ad alte dosi, ipercalcemia maligna, soffusione pericardica o versamento ascitico clinicamente significativi. Sono esclusi i pazienti con una storia di grave ipersensibilità a Docetaxel o ai prodotti contenenti Polisorbato 80.
I pazienti positivi alla mutazione di EGFr negli esoni 18,19 o 21 saranno esclusi dallo studio.
I pazienti con traslocazione di ALK saranno esclusi dal protocollo, tuttavia l’analisi non è mandatoria
I pazienti con materiale biologico inadeguato o insufficiente per eseguire le analisi molecolari saranno esclusi dallo studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is OS (determined from the date of randomization). |
| Sopravvivenza totale (definita come l'intervallo che intercorre fra la data della randomizzazione e la data del decesso). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Approximately 60 months |
| Approssimativamente 60 mesi |
|
| E.5.2 | Secondary end point(s) |
a) PFS at 6 months (determined from the date of randomization).
b) Treatment response (according to RECIST 1.1).
2.2.1 To determine the feasibility of treatment selection based on pharmacogenomic parameters.
2.2.2 To describe the toxicity in patients treated with and without assignment of chemotherapy based on gene expression. |
Sopravvivenza libera da progressione (definita come l'intervallo che intercorre fra la data della randomizzazione e la data del primo insuccesso terapeutico [progressione o decesso]).
Tasso di risposte (valutato secondo criteri RECIST 1.1.).
Fattibilità del trattamento di I linea la cui scelta è basata su criteri di farmacogenomica e dunque sull’esecuzione di biopsie tumorali il cui materiale sia disponibile per le analisi molecolari.
Tossicità (classificata sulla base dei CTCAE v. 4.0). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Approximately 60 months |
| Approssimativamente 60 mesi |
|
| 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 | Yes |
| 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 | 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 | 18 |
| 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 | 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
|
| death of the last patient in follow up phase |
| decesso dell'ultimo paziente in follow up |
|
| 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 | 60 |
| E.8.9.1 | In the Member State concerned days | 0 |
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