| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with non-small cell lung carcinoma (NSCLC). |
| Patienten met niet-kleincellig longcarcinoom (NSCLC). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung carcinoma. |
| Longkanker. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| The overall aim of this study is to demonstrate increase of tumor-infiltrating CD8+ T cells in non-small cell lung cancer during neo-adjuvant treatment with durvalumab (MEDI4736). |
| Het primaire doel van deze studie is het demonstreren van een toename aan tumor-infiltrerende CD8+ T-cellen in niet-kleincellig longcarcinoom tijdens neo-adjuvante behandeling met durvalumab (MEDI4736). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study will be:
1. correlative studies across different imaging modalities
2. validation of in vivo imaging findings with other potential biomarkers derived from quantitative immune histochemistry and peripheral blood immune profiling
3. assessment of neo-adjuvant durvalumab (MEDI4736) on outcome measures related to clinical care |
Secundaire doelen van deze studie zijn:
1. uitvoeren van correlerend onderzoek tussen verschillende beeldvormende modaliteiten
2. validatie van bevindingen tijdens in-vivo beeldvorming met andere potentiele biomarkers afgeleid van kwantitatieve immuun-histochemie en perifere bloed immuun profilering
3. beoordelen van neo-adjuvante behandeling met durvalumab (MEDI4736) op uitkomstmaten gerelateerd aan reguliere klinische zorg
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients must meet all of the following criteria:
1. Male or female subjects aged >50 years at time of study entry
2. Histopathological proven primary non-small cell lung cancer, with fully evaluable histological biopsies available
3. ECOG performance status of 0 or 1
4. AJCC stage I, II or IIIa as determined by contrast-enhanced CT chest-abdomen and F-18-FDG PET/CT: cT1cN0-1M0, cT2aN0-1M0 en cT3N0-1M0 (T3 separate nodule)
5. Solid appearance of the tumor on contrast-enhanced CT
6. Scheduled for resection with curative intent
7. Patients should be medically operable defined by:
8. Sufficient cardiopulmonary function
9. Major contra-indications for surgery.
10. No underlying immune disease (neutro- or lymphopenia, coagulation disorders) that could interfere with T-cell isolation
11. Life expectancy at least 6 months
12. Written informed consent and comply with study protocol for the duration of the study and follow-up
13. Adequate laboratory values (refer to study protocol) |
Alle patiënten moeten aan onderstaande criteria voldoen:
1. Man of vrouw, leeftijd >50 jaar bij start studiedeelname
2. Histopathologisch bewezen primair niet-kleincellig longcarcinoom, met evalueerbare histologische biopsies beschikbaar
3. ECOG performance status 0 of 1
4. AJCC stadium I, II of IIIa
5. Solide ogende tumor op basis van CE-CT
6. Gepland voor resectie met curatieve opzet
7. Geschikt voor operatieve ingreep, gebaseerd op:
8. Voldoende cardiopulmonaire functie.
9. Geen belangrijke contra-indicaties voor chirurgie.
10. Geen onderliggen de immuunziekte (neutro- of lymfopenie, stollingsaandoeningen) die kunnen interfereren met T-cel isolatie
11. Levensverwachting minimaal 6 maanden
12. Getekend informed consent en mogelijkheid tot het volgen van het studieprotocol gedurende het onderzoek en follow-up
13. Adequate laboratoriumwaarden (zie studieprotocol) |
|
| E.4 | Principal exclusion criteria |
A patient will be excluded from participation in the trial if one or more of the following criteria are met:
1. Inability to lie supine for more than 30 minutes
2. Documented previous severe allergic reaction to iodine-based contrast media, despite adequate pre-medication.
3. Indication for cervical mediastinoscopy
4. Participation in another clinical study with an investigational product during the past 6 months
5. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
6. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) <6 months prior to the first dose of study drug
7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
8. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
9. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab (MEDI4736) may be included only after consultation with the Study Physician.
10. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
11. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 6 months of the first dose of study drug
12. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
13. History of allogenic organ transplantation.
14. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., 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]).
15. 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
16. History of active primary immunodeficiency
17. Active infection including: tuberculosis, hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, human immunodeficiency virus (positive HIV 1/2 antibodies), Epstein Barr Virus (EBV, positive IgM antibodies), cytomegalo virus (CMV, positive IgM antibodies)
18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab (MEDI4736); exceptions apply.
19. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab (MEDI4736). Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab (MEDI4736) and up to 30 days after the last dose of durvalumab (MEDI4736).
20. 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 durvalumab (MEDI4736) monotherapy.
21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
22. Prior randomisation or treatment in a previous durvalumab (MEDI4736) and/or tremelimumab clinical study regardless of treatment arm assignment.
23. Patients who have received prior anti–PD-1, anti PD-L1 or anti CTLA-4.
24. 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. |
Een patiënt zal worden geexcludeerd van deelname aan de studie als ze voldoen aan een of meerdere van onderstaande criteria:
1. Niet in staat om 30 minuten aaneengesloten op de rug te liggen.
2. Voorgeschiedenis met ernstige allergische reactie voor jodiumhoudend contrastmiddel, ondanks adequate pre-medicatie.
3. Indicatie voor cervicale mediastinoscopie.
4. Deelname aan een andere studie met IMP in de afgelopen 6 maanden.
5. Gelijktijdige deelname in een andere studie [uitzondering van toepassing].
6. Laatste dosis anti-kanker therapie < 6 maanden voor de eerste gift studiemedicatie.
7. Niet-opgeloste toxiciteit NCI CTCAE graad ≥2 van eerdere anti-kanker behandelingen [uitzonderingen van toepassing].
8. Patiënten met graad ≥2 neuropathie worden op individuele basis geëvalueerd door de studiearts.
9. Patiënten met irreversibele toxiciteit waarvan niet verwacht wordt dat deze verergerd door behandeling met durvalumab (MEDI4736) worden op individuele basis geëvalueerd door de studiearts.
10. Gelijktijdige behandeling met chemotherapie, IP, biologische of hormonale therapie [uitzondering van toepassing].
11. Radiotherapie op meer dan 30% van het beenmerg of groot-veld bestraling in de 6 maanden voorafgaand aan de eerste dosering studiemedicatie.
12. Aanzienlijke chirurgische ingreep in de 28 dagen voorafgaand aan de eerste dosering studiemedicatie.
13. Voorgeschiedenis met allogene orgaantransplantatie.
14. Actieve of voorgeschiedenis met auto-immuunziekte of ontsteking
15. Voorgeschiedenis met een tweede primaire tumor [uitzonderingen van toepassing].
16. Voorgeschiedenis met actieve primaire immunodeficiëntie.
17. Actieve infectie [specificatie van toepassing]
18. Actueel of eerder gebruik van immuunsuppressieve medicatie in de 14 dagen voorafgaand aan de eerste dosering durvalumab [uitzonderingen van toepassing]
19. Toediening van vaccinaties met levende, verzwakte organismen in de 30 dagen voorafgaand aan de eerste dosering durvalumab.
20. Vrouwelijke patiënten die zwanger zijn, borstvoeding geven of een effectieve vorm van anticonceptie weigeren.
21. Bekende allergie of overgevoeligheid voor een van de gebruikte studiemedicaties of hulpstoffen.
22. Randomisatie of behandeling in een eerdere klinische studie met durvalumab of tremelimumab, ongeacht behandelarm.
23. Patiënten met een eerdere toediening anti-PD-1, anti-PD-L1 of anti-CTLA-4 [extra criteria van toepassing].
24. Ongeschikt om deel te nemen op basis van het oordeel van de onderzoeker. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study will be to demonstrate 1) feasibility and 2) safety of two courses durvalumab (MEDI4736) 750 mg Q2W in neo-adjuvant setting in resectable NSCLC.
Study parameter 1): no delayed surgical procedures, all surgery should be performed within 42 days after the first therapeutic dose of durvalumab (MEDI4736).
Study parameter 2): number of grade 3 or higher adverse events related to durvalumab (MEDI4736).
|
Het primaire eindpunt van deze studie is om aan te tonen: 1) haalbaarheid en 2) veiligheid van 2 behandelcycli durvalumab (MEDI4736) 750 mg Q2W in een neo-adjuvante setting bij reseceerbare NSCLC.
Studieparameter 1): geen vertraging voor chirurgische procedures, alle chirurgie dient binnen 42 dagen na de eerste therapeutische dosering durvalumab (MEDI4736) te zijn verricht.
Studieparameter 2): aantal adverse events met graad 3 of hoger in relatie tot durvalumab (MEDI4736). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
LSLV.
|
| Na de laatste visite van de laatste deelnemer. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
1. Correlative studies across different imaging modalities
2. Validation of in vivo imaging findings with other potential biomarkers derived from quantitative immune histochemistry and peripheral blood immune profiling
3. Assessment of neo-adjuvant durvalumab (MEDI4736) on outcome measures related to clinical care |
Secundaire eindpunten:
1. Correlatie van onderzoeken over verschillende beeldvormingsmodaliteiten.
2. Validatie van bevindingen van in vivo beeldvorming met andere potentiele biomarkers, afgeleid van kwantitatieve immuun-histochemie en perifere immuun profiling van bloed.
3. Beoordelen van neo-adjuvante behandeling met durvalumab (MEDI4736) op resultaten, gerelateerd aan reguliere zorg. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| LSLV. |
| Na de laatste visite van de laatste deelnemer. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | 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.8.3 |
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.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
| LSLV |
| Laatste visite van de laatste deelnemer. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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