E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non Small Cell Lung Cancer |
Tumore Polmonare Non a Piccole Cellule |
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E.1.1.1 | Medical condition in easily understood language |
Lung Cancer |
Tumore Polmonare |
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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 | 16.1 |
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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of AZD9291 by assessment of Objective Response Rate (ORR) |
Valutare l’efficacia di AZD9291 secondo la valutazione del Tasso di Risposta Oggettivo |
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E.2.2 | Secondary objectives of the trial |
To further assess the efficacy of AZD9291 in terms of:
- Progression Free Survival (PFS)
- Duration of Response (DoR)
- Disease Control Rate (DCR)
- Tumour shrinkage
- Overall Survival (OS)
To assess the safety and tolerability profile of AZD9291.
To investigate the effect of AZD9291 on QTc interval after oral dosing to NSCLC patients.
To assess the impact of AZD9291 on patients’ disease-related symptoms and health related quality of life (HRQoL).
To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550).
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Valutare ulteriormente l’efficacia di AZD9291 in termini di:
• sopravvivenza libera da Progressione (PFS)
• durata della Risposta (DoR)
• tasso di controllo della malattia (DCR)
• riduzione della dimensione del tumore
• sopravvivenza globale (OS)
Valutare il profilo di sicurezza e tollerabilità di AZD9291
Studiare l’effetto di AZD9291 sull’intervallo QTc dopo l’assunzione per via orale in pazienti con NSCLC
Valutare l’impatto di AZD9291 sui sintomi della malattia e la qualità della vita (HRQoL) collegata alla salute dei pazienti
Caratterizzare la farmacocinetica (PK) di AZD9291 e i rispettivi metaboliti (AZ5104 and AZ7550)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Locally advanced/metastatic NSCLC.
Radiological documentation of disease progression following 1st line EGFR TKI treatment or following minimum prior therapy with an EGFR TKI and platinum-containing doublet chemotherapy.
Confirmation the tumour harbours EGFR and T790 mutation.
WHO status 0-1; min life expectancy of 12 weeks.
At least one measurable lesion at baseline by CT/MRI.
Females of child-bearing potential using contraception; negative pregnancy test.
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• tumore Polmonare Non a Piccole Cellule Localmente Avanzato o Metastatico localmente avanzato o metastatico
• documentazione radiologica di progressione della malattia dopo trattamento in prima linea con EGFR TKI o a seguito di una precedente terapia con almeno un EGFR TKI combinata con chemioterapia a base di platino.
• conferma che il tumore ha mutazione EGFR e T790
• stato WHO 0-1
• aspettativa di vita minima di 12 settimane.
• almeno una lesione che misurabile tramite TAC / Risonanza Magnetica al basale
• donne in età fertile che utilizzano metodi di contraccezione;
• test di gravidanza negativo.
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E.4 | Principal exclusion criteria |
Treatment with an EGFR-TKI within 8 days of study entry; any cytotoxic chemotherapy, investigational agents or other anticancer drugs within 14 days of study entry; previous treatment with AZD9291 (or 3rd generation TKIs); major surgery within 4 weeks; radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks; current treatment with potent inhibitors of CYP2C8 and potent inhibitors/inducers of CYP3A4.
Unresolved toxicities from prior therapy.
Unstable spinal cord compression/brain metastases.
Severe/uncontrolled systemic diseases, including uncontrolled hypertension, bleeding diatheses or infection.
Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection.
Cardiac disease.
Past history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
Inadequate bone marrow reserve or organ function.
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• trattamento con EGFR-TKI entro 8 giorni dall’ inizio dello studio
• qualsiasi chemioterapia citotossica, agenti sperimentali o altri farmaci antitumorali entro 14 giorni dall’ inizio dello studio
• precedente trattamento con AZD9291 (o con un TKI di terza generazione
• chirurgia maggiore entro 4 settimane
• radioterapia per più del 30 % del midollo osseo o con un' ampio campo di radiazione entro 4 settimane dalla prima dose del trattamento in studio
• attuale trattamento con potenti inibitori del CYP2C8 e potenti inibitori / induttori del CYP3A4.
• tossicità non risolte dalla terapia precedente.
• compressione instabile del midollo osseo o metastasi al cervello
• qualsiasi evidenza di malattie sistemiche gravi / incontrollate, inclusa ipertensione non controllata, diatesi emorragica attiva o infezioni.
• nausea e vomito refrattari, malattie gastrointestinali croniche, incapacità di ingoiare il prodotto così formulato o precedente resezione intestinale che potrebbe precludere l’adeguato assorbimento di AZD9291.
• patologia cardiaca.
• storia precedente di malattia polmonare interstiziale, malattia polmonare interstiziale indotto da farmaco-indotta, polmonite da radiazioni che ha richiesto trattamento con steroidi, o qualsiasi evidenza di malattia polmonare interstiziale clinicamente attiva
• Inadeguata riserva di midollo osseo o funzione degli organi
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR according to RECIST 1.1 by an Independent Central Review (ICR).
Sensitivity analysis of ORR using investigators assessments of RECIST.
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• ORR secondo i criteri Recist 1.1 valutato da un Indipendent Central Review (ICR)
• Analisi di sensibilità della ORR tramite l’ utilizzo delle valutazioni RECIST fatte dagli Sperimentatori
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 6 weeks relative to first dose until disease progression |
ogni 6 settimane relativo alla prima dose fino a progressione di malattia |
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E.5.2 | Secondary end point(s) |
PFS, DoR, DCR according to RECIST 1.1 using assessments performed by an ICR.
Sensitivity analysis of PFS, DoR, DCR, tumour shrinkage using investigators assessments of RECIST.
Description of OS.
Adverse events (graded by CTCAE v4)
- Clinical chemistry, haematology and urinalysis
- Vital signs, Physical Examination, Weight
- Digital ECG
- WHO Performance Status
QT interval by digital ECG
EORTC QLQ-C30
EORTC QLQ LC13
PK exposure parameters: (Cmax) (Css max), (tmax),(tss max), (AUC(0-24)),(AUCss), (Css min), (CLss/F) (RAC)
The ratio of metabolite to AZD9291 will also be calculated.
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• PFS, DoR, DCR secondo i criteri Recist 1.1 utilizzando le valutazioni fatte dall’ Indipendent Central Review (ICR)
• Analisi di sensitività di PFS, DoR, DCR e riduzione delle dimensioni del tumore sulla base delle valutazioni Recist degli Sperimentatori
• Descrizione della OS
• Eventi Avversi (secondo i gradi CTCAE v4):
o chimica clinica, ematologia e analisi delle urine
o segni vitali, esame fisico, peso
o ECG digitale
o stato della performance secondo l’ OMS
• intervallo QT tramite ECG digitale
• EORTC QLQ-C30
• EORTC QLQ LC13
• parametri farmacocinetici: (Cmax) (Css max), (tmax), (tss max), (AUC(0-24)), (AUCss), (Css min), (CLss/F) (RAC)
• rapporto del metabolita rispetto a AZD9291
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy every 6 weeks, Safety and Health related quality of life throughout study, PK exposure Cycles 1 to 3. |
efficacia ogni 6 settimane, sicurezza e qualità della vita durante tutto lo studio, farmacocinetica nei cicli 1 e 3 |
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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 | Yes |
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 | Yes |
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 | 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 | 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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 0 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Canada |
Italy |
Japan |
Hong Kong |
Korea, Republic of |
Spain |
Taiwan |
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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the last visit of the last subject undergoing the study |
ultima visita dell' ultimo paziente in studio |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |