| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with EGFRm+/T790M, locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR-TKI |
| Pazienti con EGFRm+/T790M, affetti da NSCLC localmente avanzato o metastatico la cui malattia ¿ in progressione dopo precedente terapia con EGFR-TKI |
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| E.1.1.1 | Medical condition in easily understood language |
| lung cancer Patients progressed after a previous chemotherapy |
| Pazienti affetti da tumore al polmone in progressione dopo una precedente terapia |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062042 |
| E.1.2 | Term | Lung neoplasm |
| 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 investigate the tolerability of AZD9291 when given orally to a real life population of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), who have progressed after prior therapy with an Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) agent. |
| Valutare la tollerabilit¿ di AZD9291 quando somministrato per via orale a pazienti affetti da NSCLC localmente avanzato o metastatico, a seguito di progressione dopo precedente terapia con EGFR-TKI. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate patients' perception of symptomatic Adverse Events (AEs) when under continuous treatment with AZD9291, and to compare it to physicians evaluation, being the medical evaluation performed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
To assess changes in Quality of life, depression, sleep quality and distress of advanced NSCLC patients undergoing continuous treatment with AZD9291.
To further investigate the anti tumour activity of AZD9291 by evaluation of duration of response, disease control rate, tumour shrinkage, progression free survival (PFS) using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, through local review of radiological examinations performed during the study.
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Valutare la percezione da parte dei pazienti degli eventi avversi (AEs) in corso di trattamento con AZD9291 e confrontarla con la medesima valutazione effettuata da parte del personale medico di riferimento, attraverso l¿utilizzo dei "Common Terminology Criteria for Adverse Events" (CTCAE), versione 4.0.
Valutare i cambiamenti nella qualit¿ di vita, nella deflessione del tono dell¿umore, nella qualit¿ del sonno e nel distress emotivo dei pazienti affetti da NSCLC in stadio avanzato in corso di trattamento con AZD9291.
Indagare inoltre l¿attivit¿ antitumorale di AZD9291 attraverso la valutazione della durata della risposta, il tasso di controllo della malattia, la riduzione del volume tumorale, la sopravvivenza libera da progressione (PFS), attraverso rivalutazioni radiologiche periodiche effettuate durante lo studio secondo precise timelines, utilizzando i ¿Response Evaluation Criteria in Solid Tumours¿ (RECIST), versione 1.1.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures.
2. Male or female, aged at least 18 years.
3. Histological or cytological confirmation diagnosis of NSCLC.
4. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy (IIIB and IV stages, according to the UICC TNM 7th edition)
5. Radiological documentation of disease progression after a previous continuous treatment with a EGFR-TKI (e. g. Gefitinib, Erlotinib, Afatinib). In addition other lines of therapy may have been given. All patients must have documented radiological progression after the last treatment administered prior to enrolling in the study.
6. Patients must fulfil one of the following:
• Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
• OR
• Must have experienced clinical benefit from EGFR-TKI, according to the Jackman criteri (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI
7. Patients must have confirmation of tumour T790M mutation positive status from a biopsy sample taken after confirmation of disease progression on treatment with EGFR-TKI. Biopsy samples will be locally analysed.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
9. At least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT or MRI at baseline and follow up visits.
10. Patients must have adequate verbal comprehension skills for answering to the surveys provided by the investigator during the study.
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1. Ottenimento del consenso informato prima di qualsiasi procedura studio-specifica.
2. Uomini o donne, che abbiano almeno 18 anni di età.
3. Diagnosi citologica o istologica di NSCLC.
4. NSCLC in stadio localmente avanzato o metastatico, non suscettibile di trattamento chirurgico ad intento curativo o radioterapia (stadi IIIB e IV, in accordo alla 7° edizione della stadiazione UICC TNM)
5. Progressione di malattia documentata radiologicamente dopo precedente trattamento con EGFR-TKI (es. Gefitinib, Erlotinib, Afatinib). Altre linee di trattamento sono concesse. Tutti i pazienti devono presentare una progressione di malattia documentata radiologicamente dopo l’ultimo trattamento oncologico effettuato prima dell’arruolamento nello studio.
6. I pazienti devono soddisfare una delle seguenti condizioni:
• conferma che il tumore esprima una mutazione a carico del gene EGFR associata a sensibilità al trattamento con EGFR-TKI (incluse la mutazione G719X, la delezione dell’esone 19, le mutazioni L858R e L861Q)
• aver sperimentato beneficio clinico dal trattamento con EGFR-TKI, secondo i criteri di Jackman (Jackman et al 2010) e successivamente una evidente progressione sistemica (RECIST o WHO) durante la terapia con EGFR-TKI.
7. I pazienti devono esprimere la mutazione T790M su un campione tumorale prelevato tramite re-biopsia dopo la conferma radiologica di progressione di malattia, prima dell’inclusione nello studio clinico. Tutti i pazienti devono aver effettuato in precedenza un trattamento con EGFR-TKI. I campioni bioptici verranno analizzati localmente.
8. Performance status secondo i criteri ECOG 0-2, in assenza di deterioramento delle condizioni cliniche generali nelle ultime due settimane precedenti l'arruolamento e un’aspettativa minima di vita di 12 settimane.
9. Almeno una lesione (misurabile e/o non misurabile) che possa essere accuratamente valutata tramite TC o RMN alla valutazione basale e alle successive rivalutazioni radiologiche.
10. I pazienti devono possedere adeguate capacità di comprensione verbale per rispondere ai questionari somministrati dall’investigatore durante lo studio.
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| E.4 | Principal exclusion criteria |
1. Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site).
2. Concrete possibility to be enrolled in any of the other ongoing clinical studies with AZD9291 (http://www.cancer.gov). The study will enroll patients recorded as screening failure in AURA-3 and CAURAL or not fulfilling inclusion/exclusion criteria ab initio or with a poor tumor sample not suitable for central analysis.
3. Treatment with any of the following:
• Treatment with an EGFR-TKI (e.g., erlotinib, gefitinib, or afatinib) within 8 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment. (If sufficient washout time has not occurred due to schedule or PK properties, an alternative appropriate washout time based on known duration and time to reversibility of drug related adverse events could be agreed upon by the Sponsor and the Investigator).
• Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment
• Previous treatment with AZD9291, or a 3rd generation EGFR TKIs (e.g., CO-1686)
• Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study treatment
4. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inhibitors of CYP2C8 and potent inhibitors or inducers of CYP3A4
5. Treatment with an investigational drug within five half-lives of the compound
6. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
7. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
8. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9291.
9. Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3 electrocardiograms (ECGs).
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250msec.
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
10. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
11. History of hypersensitivity to active or inactive excipients of AZD9291 or drugs with a similar chemical structure or class to AZD9291.
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1. Coinvolgimento diretto nella progettazione e/o realizzazione dello studio (criterio valido sia per il personale dello Sponsor della sperimentazione clinica che per quello del centro sperimentatore).
2. Possibilità concreta di essere arruolato in un qualsiasi altro studio clinico in corso con AZD9291 (http://www.cancer.gov).
3. Una delle seguenti condizioni:
¿ Trattamento con EGFR-TKI (e.g., Erlotinib, Gefitinib, o Afatinib) entro 8 giorni dalla prima dose di AZD9291, o entro circa 5 emivite del farmaco in uso
¿ Qualsiasi chemioterapia citotossica, farmaco sperimentale o altro agente antineoplastico relativo al precedente trattamento oncologico o studio clinico, entro 14 giorni dalla prima dose di AZD9291
¿ Precedente trattamento con AZD9291, o un EGFR-TKI di terza generazione (es. CO-1686)
¿ Un intervento di chirurgia maggiore (escluso il posizionamento di accessi vascolari) entro 4 settimane dall’inizio del trattamento con AZD9291
¿ Radioterapia estesa a più del 30% del midollo osseo o con ampio campo di irradiazione entro 4 settimane dalla prima dose di AZD9291.
4. Pazienti che stanno assumendo farmaci o sostanze naturali inibitori di CYP2C8 e/o inibitori o induttori del CYP3A4 (o impossibilitati a interrompere l’uso almeno una settimana prima dell'inizio del trattamento con AZD9291).
5. Trattamento con un farmaco sperimentale entro 5 emivite del composto.
6. Qualsiasi tossicità, non ancora risolta, relativa ad una pregressa terapia di grado maggiore a 1 secondo i Common Terminology Criteria for Adverse Events (CTCAE) all'inizio del trattamento con AZD9291, fatta eccezione per alopecia di grado 2, neuropatia legata ad una precedente chemioterapia con derivato del platino.
7. Compressione del midollo spinale o metastasi cerebrali, a meno che non siano asintomatiche, stabili e che non richiedano l’utilizzo di steroidi per almeno 4 settimane prima dell’inizio del trattamento con AZD9291.
8. Nausea e vomito refrattari, malattie infiammatorie gastrointestinali croniche, incapacità a deglutire capsule e compresse o pregressa resezione intestinale tale da precludere un adeguato assorbimento di AZD9291.
9. Una delle seguenti condizioni cardiache:
¿ Intervallo QT corretto (QTc) > 470 msec, misurato su 3 referti elettrocardiografici (ECGs).
¿ Qualsiasi anomalia clinicamente significativa del ritmo cardiaco, conduzione o morfologia degli ECG registrati in condizioni di riposo, blocco di branca destra completo, blocco di conduzione di 3° e 2° grado, intervallo PR > 250 msec.
¿ Qualsiasi fattore a rischio di allungamento del QTc o di eventi aritmici, scompenso cardiaco, ipocaliemia, sindrome congenita del QT lungo, familiarità per sindrome del QT lungo o morte improvvisa al di sotto di 40 anni nei familiari di primo grado o l'impiego di qualsiasi farmaco responsabile dell'allungamento l’intevallo QTc.
10. Pregressa storia di malattie interstiziali polmonari, malattie interstiziali polmonari farmaco-indotte, polmoniti attiniche che abbiano richiesto l’uso di steroidi, o qualsiasi evidenza clinica di interstiziopatie polmonari in fase attiva.
11. Storia di ipersensibilità ad eccipienti attivi o inattivi di AZD9291 o a farmaci con simile struttura chimica o classe di AZD9291.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To investigate the tolerability of AZD9291 when given orally to a real life population of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), who have progressed after prior therapy with an Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) agent. |
| Valutare la tollerabilità di AZD9291 quando somministrato per via orale a pazienti affetti da NSCLC localmente avanzato o metastatico, a seguito di progressione dopo precedente terapia con EGFR-TKI. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| To evaluate patients' perception of symptomatic Adverse Events (AEs) when under continuous treatment with AZD9291, and to compare it to physicians evaluation, being the medical evaluation performed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. |
| Valutare la percezione da parte dei pazienti degli eventi avversi (AEs) in corso di trattamento con AZD9291 e confrontarla con la medesima valutazione effettuata da parte del personale medico di riferimento, attraverso l¿utilizzo dei "Common Terminology Criteria for Adverse Events" (CTCAE), versione 4.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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
|
| All patients will continue to be followed up for an updated analysis that will occur between 12-24 months after the last patient has been enrolled |
| follow up a 12-24 mesi dopo ultimo paziente arruolato |
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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 | 4 |
| 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 | 4 |
| 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 |
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