| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with unresectable Stage III non-small cell lung cancer (NSCLC), who have not progressed following platinum-based sequential chemoradiation therapy (sCRT) |
| patients présentant un cancer bronchique non à petites cellules (CBNPC) de stade III non résécable n'ayant pas progressé après une chimioradiothérapie séquentielle (CRTs) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A specific type of lung cancer |
| type spécifique de cancer du poumon |
|
| 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 | 10029519 |
| E.1.2 | Term | Non-small cell lung cancer stage III |
| 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 assess the safety and tolerability profile of durvalumab (MEDI4736) as defined by Grade 3 and Grade 4 TRAEs within 6 months from the initiation of durvalumab (MEDI4736) treatment. |
| Évaluer le profil de sécurité d’utilisation et de tolérance du durvalumab (MEDI4736) tel qu’il est défini par les EILT (événements indésirables liés au traitement) de Grade 3 et de Grade 4 dans les 6 mois suivant l'initiation du traitement par durvalumab (MEDI4736) |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of durvalumab (MEDI4736) treatment in terms of PFS and OS.
- To further assess the efficacy of durvalumab (MEDI4736) treatment in terms of ORR and DoR.
- To assess the efficacy of durvalumab (MEDI4736) treatment in terms of lung cancer mortality.
- To further assess the safety and tolerability profile of durvalumab (MEDI4736) treatment, including all AEs. |
- Évaluer l’efficacité du traitement par durvalumab (MEDI4736) en termes de PFS et d’OS
-Évaluer de manière plus approfondie l’efficacité du traitement par durvalumab (MEDI4736) en termes d’ORR et de DoR
-Évaluer l’efficacité du traitement par durvalumab (MEDI4736) en termes de mortalité due au cancer bronchique
- Évaluer le profil de sécurité d’utilisation et de tolérance du traitement par durvalumab (MEDI4736), y compris tous les EI |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Genetic research (Appendix D of study protocol, dated 16 Jul 2018)
Rationale and Objectives
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity and PD. Variable response to therapy may be due to genetic determinants that impact drug absorption, distribution, metabolism, and excretion; MOA of the drug; disease aetiology; and/or molecular subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis from consenting patients.
AstraZeneca intends to collect, analyse, and store DNA for genetic research to explore how genetic variations may affect clinical parameters, risk and prognosis of diseases, and the response to medications. Genetic research may lead to better understanding of diseases, better diagnosis of diseases or other improvements in health care and to the discovery of new diagnostics, treatments or medications.
In addition, collection of DNA samples from populations with well described clinical characteristics may lead to improvements in the design and interpretation of clinical studies and, possibly, to genetically guided treatment strategies.
All patients will be asked to participate in this genetic research. Participation is voluntary and if a patient declines to participate there will be no penalty or loss of benefit. The patient will not be excluded from any aspect of the main study. |
|
| E.3 | Principal inclusion criteria |
- Informed consent as detailed in the protocol.
- 18 years or older at the time of signing the ICF.
- Histologically-or cytologically-documented NSCLC with locally-advanced, unresectable Stage III disease (according to the IASLC Staging Manual Version 8 [IASLC 2016]). Positron emission tomography (PET)/CT, MRI of the brain, and endobronchial ultrasound with biopsy are highly encouraged at diagnosis.
- Receipt of sCRT which must have been completed within 28 days prior to first IP dose administration in the study as defined in the protocol.
- Patients must not have progressed following platinum-based sCRT, as per Investigator-assessed RECIST 1.1 criteria as defined in the protocol.
- Must have a life expectancy of at least 12 weeks at enrolment.
- WHO/ECOG PS ≤2.
- Adequate organ and marrow function at enrolment as defined in the protocol.
- Body weight >30 kg at enrolment and first IP dose administration.
- Male or female.
- Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. Age-specific requirements are detailed in the protocol. |
- consentement éclairé signé décrit dans le protocole
-18 ans ou plus au moment de la signature de l’ICF
-CBNPC documenté histologiquement ou cytologiquement avec une maladie de stade III localement avancée non résécable (selon le manuel de stadification de l’IASLC, Version 8 [IASLC 2016]). Des examens par tomographie par émission de positons (TEP)/TDM, IRM cérébral et échographie endobronchique avec biopsie sont fortement encouragés lors du diagnostic
-Administration d’une CRTs, devant être terminée dans les 28 jours précédant l’administration de la première dose de PE dans l'étude
-Les patients ne doivent pas avoir progressé après une CRTs à base de sels de platine, conformément aux critères RECIST 1.1 évalués par l’investigateur
-Espérance de vie d'au moins 12 semaines lors du recrutement
-IP OMS/ECOG ≤ 2
-Fonction médullaire et organique adéquate lors du recrutement
-Poids corporel >30 kg lors du recrutement et de l'administration de la première dose de PE
-Homme ou femme
-Femmes ménopausées ou, si elles ne sont pas ménopausées, test de grossesse sérique ou urinaire négatif. Les femmes seront considérées comme ménopausées en cas d’aménorrhée depuis 12 mois sans autre cause médicale. Les exigences spécifiques de l’âge sont décrits dans le protocole
|
|
| E.4 | Principal exclusion criteria |
- Patients with locally-advanced NSCLC whose disease has progressed following platinum-based sCRT.
- Patients who have disease considered for surgical treatment as part of their care plan, such as Pancoast or superior sulcus tumours.
- Mixed small-cell lung cancer and NSCLC histology.
- History of allogeneic organ transplantation.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Exceptions to this criterion are defined in the protocol.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
- History of another primary malignancy except for:
-- Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence.
-- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
-- Adequately treated carcinoma in situ without evidence of disease.
- History of leptomeningeal carcinomatosis.
- History of active primary immunodeficiency.
- Active infection including tuberculosis, hepatitis B, hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Patients with a past or resolved hepatitis B virus (HBV) infection are eligible. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
- Any unresolved toxicity of NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. More details to be found in the protocol.
- Known allergy or hypersensitivity to durvalumab (MEDI4736) or any of the IP excipients.
- Patients who have received cCRT for locally-advanced NSCLC, or who received sCRT with at least 2 concomitant CRT cycles. Prior surgical resection (ie, Stage I or II) is permitted.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
- Prior exposure to immune-mediated therapy, including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. Exceptions to this criterion are detailed in the protocol.
- Previous IP assignment in the present study.
- Concurrent enrolment in another clinical study, unless it is an observational clinical study or the follow-up period of an interventional study.
- Participation in another clinical study with an IP during the 4 weeks prior to the first IP dose administration.
- Prior randomisation or treatment in a previous durvalumab (MEDI4736) ± tremelimumab clinical study regardless of treatment arm assignment.
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of IP.
- Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements.
- Genetic research study (optional): Exclusion criteria for participation in the optional (DNA) genetic research component of the study include:
-- Previous allogeneic bone marrow transplant.
-- Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection. |
-Patients présentant un CBNPC localement avancé dont la maladie a progressé après une CRTs à base de sels de platine.
-Patients présentant une maladie pour laquelle un traitement chirurgical est envisagé dans le cadre de leur plan de soins, comme une tumeur de Pancoast ou de l'apex pulmonaire.
-Histologie mixte cancer bronchique à petites cellules et CBNPC.
-Antécédents d’allogreffe d'organe.
-Affection autoimmune ou inflammatoire documentée, active ou antérieure (y compris maladie inflammatoire de l'intestin [par exemple, colite ou maladie de Crohn], diverticulite [à l’exception d’une diverticulose], lupus érythémateux disséminé, sarcoïdose ou syndrome de Wegener [granulomatose avec polyangéite, maladie de Graves, polyarthrite rhumatoïde, hypophysite, uvéite, etc.])
-Maladie intercurrente non contrôlée incluant, sans s’y limiter : infection en cours ou active, insuffisance cardiaque congestive symptomatique, hypertension artérielle non contrôlée, angor instable, arythmie cardiaque, pneumopathie interstitielle, affections GI chroniques graves associées à une diarrhée, ou maladie psychiatrique/situation sociale qui limiterait le respect des exigences de l’étude, augmenterait sensiblement le risque d’EI ou compromettrait la capacité du patient à fournir son consentement éclairé écrit
-Antécédents d'autre cancer primitif, sauf :
-- Cancer traité dans un but curatif, sans maladie active connue ≥5 ans avant la première dose de PE et avec un faible risque potentiel de récidive.
-- Cancer de la peau de type non mélanome ou lentigo malin correctement traité, sans signe de la maladie.
-- Carcinome in situ correctement traité sans signe de la maladie.
-Antécédents de carcinomatose leptoméningée.
-Antécédents de déficit immunitaire primitif actif.
- Infection active, incluant la tuberculose
- Les patients avec une infection à virus de l’hépatite B (VHB) passée ou résolue sont éligibles. Les patients positifs pour les anticorps dirigés contre le virus de l’hépatite C sont éligibles uniquement si la réaction en chaîne par polymérase (PCR) est négative pour l'acide ribonucléique (ARN) du VHC
-Toute toxicité de Grade NCI CTCAE ≥ 2 non résolue après un précédent traitement anticancéreux, à l’exception d’une alopécie, d’un vitiligo et valeurs biologiques définies dans les critères d’inclusion.
-Allergie ou hypersensibilité connues au durvalumab (MEDI4736) ou à l’un des excipients du PE.
-Patients ayant reçu une CRTc pour un CBNPC localement avancé ou une CRTs avec au moins deux cycles de CRT concomitants. Une précédente résection chirurgicale (c’est-à-dire, Stade I ou II) est autorisée.
- Administration d’un vaccin atténué vivant dans les 30 jours précédant la première dose de PE.
-Précédente exposition à des traitements à médiation immunitaire, y compris, sans s’y limiter, d'autres anticorps anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2, à l’exception des vaccins anticancéreux thérapeutiques.
- Utilisation actuelle ou passée de médicaments immunosuppresseurs dans les 14 jours précédant la première dose de PE.
-Précédente affectation du PE dans la présente étude.
-Recrutement concurrent dans une autre étude clinique, sauf s'il s'agit d’une étude clinique observationnelle (non interventionnelle) ou la période de suivi d’une étude interventionnelle.
-Participation à une autre étude clinique avec un PE au cours des 4 semaines précédant l'administration de la première dose de PE.
-Randomisation ou traitement dans une précédente étude clinique sur le durvalumab (MEDI4736) ± tremelimumab, quel que doit l'affectation
-Femmes enceintes ou qui allaitent, ou hommes ou femmes aptes à procréer qui refusent d’utiliser une méthode efficace de contraception durant la période allant de la sélection à 90 jours après la dernière dose de PE.
- Avis de l’investigateur selon lequel la participation du patient à l’étude est inappropriée et la probabilité est faible que le patient respecte les procédures, restrictions et exigences de l'étude.
-Étude de recherche génétique (facultative) :
Les critères de non-inclusion pour la participation à la composante recherche génétique (ADN) facultative de l'étude incluent :
(a) Précédente greffe allogénique de moelle osseuse
(b) Transfusion de sang entier non déplété en leucocytes dans les 120 jours précédant le recueil de l'échantillon génétique. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Grade 3 or Grade 4 TRAEs |
| Les EI de Grade 3 ou 4 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients will receive IMP every 4 weeks (q4w) for a maximum of 24 months.
Efficacy for all patients will be assessed every 8 weeks (q8w) for the first 12 months and every 12 weeks (q12w) thereafter, until disease progression; plus an additional follow-up scan is performed if clinically feasible. Additional scans can be completed per standard practice post disease progression.
Patients who have discontinued treatment will be followed up for 90 days after IP discontinuation, and thereafter followed up with tumour assessments until RECIST 1.1-defined radiological PD plus an additional follow-up scan or until death (whichever comes first). |
|
| E.5.2 | Secondary end point(s) |
- Median PFS according to RECIST 1.1 as assessed by the Investigator.
- PFS12 and PFS24 according to RECIST 1.1 as assessed by the Investigator.
- Median OS, OS12, OS24, and OS36.
- ORR according to RECIST 1.1 as assessed by the Investigator.
- DoR according to RECIST 1.1 as assessed by the Investigator.
- Lung cancer mortality.
- AEs, SAEs, AESIs, imAEs, physical examinations, vital signs including BP, pulse, ECGs, and laboratory findings including clinical chemistry, haematology and urinalysis. |
- PFS médiane selon les critères RECIST 1.1 telle qu’elle est évaluée par l’investigateur
-PFS12 et PFS24 médianes selon les critères RECIST 1.1 telles qu’elles sont évaluées par l’investigateur
-OS, OS12, OS24 et OS36 médianes
-ORR selon les critères RECIST 1.1 tel qu’il est évalué par l’investigateur
-DoR selon les critères RECIST 1.1 telle qu’elle est évaluée par l’investigateur
-Mortalité due au cancer bronchique
-EI, EIG, EIIP, EIim, examens physiques, signes vitaux incluant PA, pouls, paramètres ECG et paramètres de laboratoire incluant biologie, hématologie et analyse d'urine |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will receive IMP every 4 weeks (q4w) for a maximum of 24 months.
Efficacy for all patients will be assessed every 8 weeks (q8w) for the first 12 months and every 12 weeks (q12w) thereafter, until disease progression; plus an additional follow-up scan is performed if clinically feasible. Additional scans can be completed per standard practice post disease progression.
Patients who have discontinued treatment will be followed up for 90 days after IP discontinuation, and thereafter followed up with tumour assessments until RECIST 1.1-defined radiological PD plus an additional follow-up scan or until death (whichever comes first).
All patients in the study should be followed up for survival every 12 weeks until death, withdrawal of consent, or the end of the study. |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarker; Quality of life |
|
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study is defined as the last visit of the last patient undergoing the study, i.e. LPLV. |
| Dernière visite du dernier patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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