| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with histologically or cytologically documented EGFRm (Ex19del and/or L858R) NSCLC with resectable (stage II to select IIIB) disease |
| Pazienti con NSCLC con EGFRm documentato istologicamente o citologicamente (Ex19del e/o L858R) con malattia resecabile (stadio clinico da II a IIIB) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with EGFR mutation positive, resectable Non-small Cell Lung Cancer |
| Pazienti con tumore polmonare non a piccole cellule resecabile con recettore del fattore di crescita epidermico positivo alle mutazioni |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029520 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIA |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029518 |
| E.1.2 | Term | Non-small cell lung cancer stage II |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| 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 determine the efficacy of osimertinib as monotherapy or in combination with chemotherapy compared to chemotherapy alone, as neoadjuvant treatment |
| Determinare l'efficacia di osimertinib come monoterapia o in combinazione con chemioterapia rispetto alla chemioterapia da sola, come trattamento neoadiuvante |
|
| E.2.2 | Secondary objectives of the trial |
- To further assess the efficacy of osimertinib as monotherapy or in combination with chemotherapy compared to chemotherapy alone as neoadjuvant treatment, by assessment of pathological complete response (pCR), EFS, DFS, downstaging and OS.
- To assess impact of treatment on patients' disease-related symptoms and health-related quality of life in patients
- To further assess the efficacy of osimertinib as monotherapy or in combination with chemotherapy as compared to chemotherapy alone as neoadjuvant treatment, in patients with or without EGFRm detectable at screening in plasma-derived ctDNA
- To compare the baseline tumour EGFR mutation status in screened patients with evaluable results from baseline plasma samples.
- To compare the local cobas EGFR Mutation Test v2 and FoundationOne CDx results used for patient selection with the retrospective central cobas EGFR Mutation Test v2 results from baseline tumour samples.
- To characterise the PK of osimertinib and its metabolites |
- Valut ulteriorm l’efficacia di osimertinib come monoterap o in combinaz con chemiot rispetto alla chemiot da sola come trattam neoadiuvante, tramite valutaz di risp patolog completa (pCR), EFS, DFS, sottostadiazione e OS.
- Valut l'impatto del trattam sui sintomi dei paz relativi alla malattia e sulla QoL correlata alla salute nei paz
- Valut ulteriorm l'efficacia di osimertinib come monoterap o in combinaz con chemiot risp alla chemiot da sola come trattam neoadiuvante, in paz con o senza EGFRm rilevab allo screening nel ctDNA derivato dal plasma
- Confrontare lo stato della mutaz tumorale EGFR al bas nei paz sottoposti a screening con risultati valutab da campioni di plasma al bas.
- Confrontare i risultati dei test cobas® EGFR Mutation Test v2 e FoundationOne® CDx eseguiti a liv locale e usati per la selez dei paz con i risultati retrospettivi del test cobas® EGFR Mutation Test v2 eseg a liv centrale sui camp tum al bas.
- Caratterizzare la PK di osimertinib e dei suoi metaboliti |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female, at least 18 years of age. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative
- Histologically or cytologically documented NSCLC with completely resectable (Stage II - IIIB N2) disease (according to Version 8 of the IASLC Cancer Staging Manual [IASLC Staging Manual in Thoracic Oncology 2016]).
- Complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a MDT evaluation (which should include a thoracic surgeon, specialised in oncologic procedures).
- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day
of first dosing
- A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q). |
- Soggetti di sesso maschile o femminile, di almeno 18 anni d’età. Per i pazienti di età <20 anni e arruolati in Giappone, deve essere ottenuto un consenso informato scritto dal paziente e dal suo rappresentante legale
- NSCLC documentato istologicamente o citologicamente con malattia completamente resecabile (Stadio II - IIIB N2) (secondo la versione 8 del Manuale di stadiazione del cancro IASLC [Manuale di stadiazione IASLC in Thoracic Oncology 2016]).
- La resezione chirurgica completa del NSCLC primario deve essere considerata realizzabile, secondo valutazione MDT (che dovrebbe includere un chirurgo toracico, specializzato in procedure oncologiche).
- Eastern Cooperative Oncology Group (ECOG) PS di 0 o 1 al momento dell'arruolamento, senza alcun deterioramento rispetto alle 2 settimane precedenti al basale o il giorno della prima somministrazione
- Un tumore che ospita una delle 2 mutazioni comuni di EGFR note per essere associate alla sensibilità EGFR-TKI (Ex19del, L858R), da sole o in combinazione con altre mutazioni EGFR (cioè T790M, G719X, inserzioni Exon20, S7681 e L861Q). |
|
| E.4 | Principal exclusion criteria |
- Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
- History of another primary malignancy, except for the following: Malignancy treated with curative intent and with no known active disease =2 years before the first dose of investigational product (IP) and of low potential risk for recurrence; Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease; Adequately treated carcinoma in situ without evidence of disease
- Patients who have pre-operative radiotherapy treatment as part of their care plan
- Mixed small cell and NSCLC histology
- Stages I, IIIB N3, IIIC, IVA, and IVB NSCLC
- T4 tumours infiltrating the aorta, the oesophagus and/or the heart; and/or any bulky N2 disease
- Patients who are candidates to undergo only segmentectomies or wedge resections
- Prior treatment with any systemic anti-cancer therapy for NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug
- Prior treatment with EGFR-TKI therapy
- Current use of (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4 (at least 3 weeks prior) |
- Anamnesi medica pregressa di ILD, ILD indotta da farmaci, polmonite da radiazioni che ha richiesto il trattamento con steroidi o qualsiasi evidenza di ILD clinicamente attiva.
- Storia di un'altra neoplasia primaria, ad eccezione di quanto segue: Malignità trattata con intento curativo e senza malattia attiva nota =2 anni prima della prima dose di prodotto sperimentale (PI) e con basso rischio potenziale di recidiva;Tumore della pelle diverso dal melanoma adeguatamente trattato o lentigo maligna senza evidenza di malattia. Carcinoma in situ adeguatamente trattato senza evidenza di malattia.
- Pazienti sottoposti a trattamento di radioterapia preoperatoria nell'ambito del loro piano di assistenza
- Istologia mista a piccole cellule e NSCLC
- Stadi I, IIIB N3, IIIC, IVA e IVB NSCLC
- Tumori T4 che si infiltrano nell'aorta, nell'esofago e / o nel cuore; e / o qualsiasi malattia “bulky” N2
- Pazienti candidati a sottoporsi solo a segmentectomie o resezioni a cuneo
- Trattamento precedente con qualsiasi terapia anticancro sistemica per NSCLC inclusi chemioterapia, terapia biologica, immunoterapia o qualsiasi farmaco sperimentale
- Trattamento precedente con terapia EGFR-TKI
- Uso corrente di (o non in grado di interromperne l'uso prima di ricevere la prima dose del trattamento in studio) farmaci o integratori a base di erbe noti per essere forti induttori del citocromo P450 (CYP) 3A4 (almeno 3 settimane prima) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Major Pathological Response(MPR) (<=10% residual cancer cells in the surgical specimen post-surgery, as assessed per central pathology laboratory) |
| Risposta patologica maggiore (Major Pathological Response, MPR) ( definita come <=10% delle cellule tumorali residue nel campione chirurgico post-intervento, secondo la valutazione del laboratorio di patologia centrale) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From randomization until time of surgery |
| Dalla randomizzazione fino al momento dell'intervento |
|
| E.5.2 | Secondary end point(s) |
Complete pathological Response(pCR) (absence of any residual cancer cell in the surgical specimen assessed post-surgery); EFS; DFS;
Downstaging; Overall Survival (OS)
- Change from baseline in Patient reported outcomes (ePRO)
- Concordance of EGFRm status between tumour tissue DNA and patientmatched plasma-derived ctDNA
- Corcordance of EGFR mutation status between the local and central cobas EGFR mutation test results from baseline tumour samples.
- PK plasma concentrations of osimertinib |
Risposta patologica completa (pCR) (assenza di eventuali cellule tumorali residue nel campione chirurgico valutato dopo l’intervento chirurgico); EFS; DFS; sottostadiazione; Sopravvivenza globale (OS)
- Variazione rispetto al basale degli esiti riportati dal paziente (ePRO)
- Corrispondenza dello stato di mutazione di EGFR tra il DNA del tessuto tumorale e ctDNA derivato dal plasma.
- Corrispondenza dello stato di mutazione di EGFR tra i risultati del test cobas di mutazione EGFR eseguiti a livello locale e centrale provenienti dai campioni tumorali basali.
- Concentrazioni plasmatiche di PK di osimertinib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Approximately 5.5 years after patients are randomized |
| Circa 5,5 anni dopo che i pazienti sono stati randomizzati |
|
| 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 | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Due bracci con chemioterapia standard saranno in doppio cieco e il braccio in monoterapia sarà in ap |
| Two arms with SoC chemotherapy will be double-blinded and the monotherapy arm will be open-label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 | Information not present in EudraCT |
| 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 |
| Brazil |
| Chile |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Russian Federation |
| Taiwan |
| Thailand |
| Turkey |
| United States |
| Vietnam |
| Austria |
| Bulgaria |
| Germany |
| Italy |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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