E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with histologically or cytologically documented non-squamous NSCLC with completely resectable (Stage II - IIIB N2) disease |
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E.1.1.1 | Medical condition in easily understood language |
Patients with EGFR mutation positive, resectable Non-small Cell Lung Cancer |
Patienten mit resektablem nicht-kleinzelligem Bronchialkarzinom mit Mutation des epidermalen Wachstumsfaktor-Rezeptors |
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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 | 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) |
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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) |
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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) |
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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 determine the efficacy of osimertinib as monotherapy or in combination with chemotherapy compared to chemotherapy alone, as neoadjuvant treatment |
Bestimmung der Wirksamkeit von Osimertinib als Monotherapie oder in Kombination mit einer Chemotherapie im Vergleich zur Chemotherapie allein, als neoadjuvante Behandlung |
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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 |
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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 non-squamous 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 Mulit-disciplinary Team (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). |
- Männlich oder weiblich, mindestens 18 Jahre alt. Bei Patienten im Alter < 20 Jahren, die in Japan in die Studie eingeschlossen werden, muss eine schriftliche Einwilligungserklärung vom Patienten und seinem gesetzlichen Vertreter eingeholt werden. 5 - Histologisch oder zytologisch dokumentiertes non-squamous NSCLC mit vollständig resezierbarer (Stadium II-IIIB N2) Erkrankung (gemäß Version 8 des IASLC-Handbuchs zur Bestimmung von Krebsstadien [IASLC Staging Manual in Thoracic Oncology 2016]). - Eine vollständige chirurgische Resektion des primären NSCLC muss gemäß Beurteilung durch MDT-Evaluierung (die einen auf onkologische Verfahren spezialisierten Thoraxchirurgen einschließen sollte) als erreichbar erachtet werden. - Eastern Cooperative Oncology Group (ECOG) Leistungsstatus von 0 oder 1 bei Studieneinschluss, ohne Verschlechterung in den letzten zwei Wochen vor der Baseline oder dem Tag der ersten Verabreichung. - Ein Tumor, der eine der beiden häufigen EGFR-Mutationen aufweist, von denen bekannt ist, dass sie mit der EGFR-TKI-Sensitivität (Ex19del, L858R) assoziiert sind, entweder allein oder in Kombination mit anderen EGFR-Mutationen (d. h. T790M, G719X, Exon20-Insertionen, S7681 und L861Q).
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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) |
- Frühere medizinische Vorgeschichte von ILD, medikamenteninduzierter ILD, Strahlungspneumonitis, die eine Steroidbehandlung erforderte, oder Hinweise auf eine klinisch aktive ILD. - Vorgeschichte einer anderen primären malignen Erkrankung mit Ausnahme von Folgendem: • Kurativ behandelte maligne Erkrankung ohne bekannte Krankheitsaktivität ≥ 2 Jahre vor der ersten Dosis des Prüfpräparats (IP) und mit geringem potenziellem Risiko eines Rezidivs • Adäquat behandelter weißer Hautkrebs oder Lentigo maligna ohne Krankheitsanzeichen • Angemessen behandeltes Carcinoma in situ ohne gegenwärtige Krankheitsanzeichen - Patienten, die eine präoperative Strahlentherapie als Teil ihres Behandlungsplans haben. - Gemischte Histologie von kleinzelligem Lungenkarzinom und NSCLC. - NSCLC in den Stadien I, IIIB N3, IIIC, IVA und IVB. - T4-Tumore, die die Aorta, die Speiseröhre und/oder das Herz infiltrieren; und/oder jede sperrige N2-Krankheit. - Patienten, die Kandidaten für eine reine Segmentektomie oder Keilresektion sind. - Vorherige Behandlung mit einer systemischen Krebstherapie bei NSCLC, einschließlich Chemotherapie, biologischer Therapie, Immuntherapie oder eines Prüfpräparats. - Vorherige Behandlung mit EGFR-TKI-Therapie - 16 Gegenwärtige Verwendung von Medikamenten oder pflanzlichen Nahrungsergänzungsmitteln, die bekanntermaßen starke Verursacher von Cytochrom P450 (CYP) 3A4 sind (mindestens 3 Wochen vorher) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Major Pathological Response (MPR) (≤10% residual cancer cells in the main tumour, as assessed per central pathology laboratory post-surgery) |
• Gutes pathologisches Ansprechen (Major Pathological Response, MPR) (definiert als ≤ 10 % Restkrebszellen in der chirurgischen Probe nach dem operativen Eingriff, nach Beurteilung durch das zentrale pathologische Labor) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From date of randomization to an average of 12 weeks after the first dose |
Beginnend zum Datum der Randomisierung bis 12 Wochen nach der ersten Dosis (gemittelt) |
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E.5.2 | Secondary end point(s) |
- Complete pathological Response (pCR) (absence of any residual cancer cells in the dissected tumour samples, including the main tumour and lymph nodes, 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 patient-matched 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 |
• pCR (definiert als das Fehlen jeglicher Restkrebszellen in der chirurgischen Probe, die nach dem operativen Eingriff beurteilt wurde) • Differenz zwischen den Behandlungsarmen der bereinigten mittleren Veränderung gegenüber Baseline der EORTC QLQ-C30- und EORTC QLQ-LC13-Scores • Übereinstimmung des EGFR-Mutationsstatus zwischen der Desoxyribonukleinsäure (DNA) des Tumors und der aus dem Plasma stammenden ctDNA gegenüber Baseline • Übereinstimmung des EGFR-Mutationsstatus zwischen den Ergebnissen des lokalen EGFR-Mutationstests und des zentralen cobas® EGFR-Mutationstests v2 aus Tumorproben • PK-Plasmakonzentrationen von Osimertinib und dem Metaboliten AZ5104; und das Verhältnis von Metabolit zu Osimertinib für jede PK-Probe (in CSR enthalten) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Approximately 5.5 years after patients are randomized |
Näherungsweise 5.5 Jahre nach der Randomisierung der Patienten |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Samples collected for the Genomics Initiative are considered primary use and will be whole exome or whole genome sequenced. Analysis will be performed for both known and novel health related genes and this broad genetic research will not restrict to disease or drug. Sequencing data generated is for research purposes only and cannot be used for clinical decision making and there will not be any clinical endpoints delivered to the study, as a result of testing performed. |
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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 | No |
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 |
Two arms with SoC chemotherapy will be double-blinded and the monotherapy arm will be open-label |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Brazil |
Canada |
Chile |
China |
India |
Israel |
Japan |
Korea, Republic of |
Mexico |
Peru |
Singapore |
Taiwan |
Thailand |
United States |
Viet Nam |
Switzerland |
Russian Federation |
Turkey |
Austria |
Bulgaria |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
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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
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 |