E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced, metastatic high grade neuroendocrine carcinomas NEC G3 (WHO 2010) |
fortgeschrittenes, metastasiertes, gering differenziertes Neuroendokrines Karzinom NEC G3 (WHO) |
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E.1.1.1 | Medical condition in easily understood language |
neuroendocrine cancer |
neuroendokriner Krebs |
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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 |
To assess the clinical activity of avelumab as determined by the disease control rate (DCR) according to RECIST1.1 from start of study drug until documented disease progression (PD), assessed every 8 weeks for the first 6 month and every 12 weeks thereafter. |
Beurteilung der klinischen Aktivität von Avelumab anhand der Krankheitskontrollrate (DCR) nach RECIST1.1 von der ersten Gabe der Studienmediaktion bis zur dokumentierten Tumorprogression (PD), beurteilt alle 8 Wochen innerhalb der ersten 6 Monate und alle 12 Wochen danach |
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E.2.2 | Secondary objectives of the trial |
To assess disease control rate (DCR) on other assessments To assess the objective response rate (ORR) To assess the best overall response (BOR) To assess the duration of disease control. To assess the progression-free survival time (PFS). To assess the overall survival (OS). To assess the time to response (TTR) To assess the quality of life (QoL). To evaluate the safety and tolerability. Exploratory objectives include assessment of subclassification of the NEC according to histomorphological differentiation and proliferation rate Ki67 (20-55 % vs. > 55%), changes from baseline in Chromogranin A (CgA) and Neuron specific enolase (NSE) levels, and evaluation of PD-L1 expression and the potential association of these factors with response rate, evaluation of tumor growth rate (TGR), and evaluation of Tumor response according to irRECIST. |
Bestimmung der Krankheitskontrollrate (DCR) zu anderen Einschätzungen Bestimmung der Gesamtansprechrate (ORR) Bestimmung des besten Ansprechens (BOR) Bestimmung der Dauer des Ansprechens Bestimmung des Progressionsfreien Überlebens (PFS) Bestimmung des Gesamtüberlebens (OS) Bestimmung der Zeit bis zum Ansprechen (TTR) Bestimmung der Lebensqualität (QoL) Bewertung der Sicherheit und Verträglichkeit Explorative Ziele beinhalten die Subklassifizierung der NEC anhand der immunhistochemischen Differenzierung und Proliferationsrate von Ki67 (20-55 % vs. > 55%), Änderungen des Gehaltes von Chromogranin A (CgA) und der Neuronenspezifischen Enolayse (NSE), Bestimmung der PD-L1-Expression und Bewertung möglicher Zusammenhänge dieser Faktoren mit der Ansprechrate, Bestimmung der Tumorwachstumsrate (TGR) und Bestimmung des Tumoransprechens nach irRECIST
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female patient ≥ 18 years - Histologically proven neuroendocrine neoplasia NEC G3 (WHO 2010) - One block or 20 slides (4 microns) of archival tumor tissue to perform central pathological review and biomarker assessment - No curative option available - Progressive disease within 9 months before study initiation and after prior at least one chemotherapy (platinum based chemotherapy or STZ/TEM/DTIC based chemotherapy in NET G3) - Presence of measurable disease as per RECIST1.1 criteria - ECOG Performance Status 0 – 2 - Written informed consent |
- Männliche oder weibliche Patienten ≥ 18 Jahre - Histologisch gesicherte neuroendokrine Neoplasie NEC G3 (WHO 2010) - Ein Block oder 20 Schnitte (4 Mikrometer) von Archiv-Tumorgewebe, um Biomarker-Untersuchungen durchzuführen - Keine Therapieoption mit Heilungsaussichten verfügbar - Progression innerhalb von 9 Monaten vor Studienbeginn und nach vorhergehender Chemotherapie (Platin-basierte Chemotherapie oder STZ/TEM/DTIC-basierte Chemotherapie bei NET (G3) - Vorliegen einer messbaren Erkrankung nach RECIST1.1-Kriterien - ECOG Performance Status 0 – 2 - Unterschriebene Einwilligungserklärung
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E.4 | Principal exclusion criteria |
- Merkel Cell carcinoma (MCC) or small cell lung cancer (SCLC) - Typical or Atypical Carcinoid of the lung with a Ki67 < 20% - Prior therapy with any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) - Neuroendocrine tumors that are potentially curable by surgery - Major surgery within 4 weeks of first dose of study medication. - TACE, TAE, SIRT or PRRT within 3 months of starting study treatment - Patients pretreated with Interferon as last treatment line prior to study entry - Concurrent anticancer treatment - active infection requiring systemic therapy including, HIV/AIDS, HBV or HCV - Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent - Pregnancy or lactation - Vaccination within 4 weeks of the first dose of avelumab and while on trial |
- Merkelzellkarzinom (MCC) oder kleinzelliges Lungenkarzinom (SCLC) - Typisches oder Atypisches Karzinoid der Lunge mit Ki67 < 20% - Frühere Therapie mit einem Antikörper/Medikament welches gezielt T-Zell Ko-regulatorische Proteine beeinflußt (Immun-Checkpoint Inhibitoren) - Neuroendokrine Tumoren, welche durch eine Operation potentiell heilbar sind - Große Operation innerhalb von 4 Wochen vor der ersten Studienmedikationsgabe - TACE, TAE, SIRT oder PRRT innerhalb von 3 Monaten vor Start der Studienbehandlung - Patienten, welche mit Interferon als letzter Behandlungslinie vor Studienstart vorbehandelt worden sind - Andere Tumortherapie - Klinisch relevante akute oder chronische Infektionen, inklusive HIV, HBV oder HCV - Aktive Autoimmunerkrankung, welche sich verschlechtern könnte, wenn ein immunstimulierendes Agens gegeben wird - Schwangerschaft oder Stillen - Impfungen innerhalb von 4 Wochen vor der ersten Dosis von Avelumab und während der Studie
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the disease control rate (CR, PR, SD according to RECIST1.1) after 16 weeks of study treatment |
Das primäre Zielkriterium ist die Krankheitskontrollrate (CR, PR, SD nach RECIST) nach 16 Wochen Studienbehandlung |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 16 weeks of study treatment |
nach 16 Wochen Studienbehandlung |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are: - Disease control rate (DCR) on other assessments - Objective response rate (ORR) on every assessment according to RECIST1.1 - Best overall response (BOR) according to RECIST1.1 - Duration of disease control and time to response (TTR) according to RECIST1.1 - Median Progression-free survival time (PFS) - Overall survival (OS) and survival rate after 1 and 2 years - Quality of life (QoL) assessed by EORTC QLQ-C30 on every assessment - Number, severity, and duration of treatment-related AEs according to NCICTCAE v4.0 The exploratory efficacy endpoints are: - histomorphological subclassification into NET G3 (differentiated morphology, ki67 20-55%) versus NEC G3 (small cell or large cell undifferentiated morphology and/or Ki67 > 55%) - Chromogranin A (CgA) and Neuron specific enolase (NSE) serum levels - PD-L1 expression measured by IHC or other established techniques - Tumor growth rate (TGR) - Disease control rate (DCR) according irRECIST
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Die sekundären Zielkriterien sind: - Krankheitskontrollrate (DCR) zu anderen Einschätzungen - Gesamtansprechrate (ORR) zu jeder Einschätzung nach RECIST1.1 - Bestes Ansprechen (BOR) nach RECIST1.1 - Dauer des Ansprechens und Zeit bis zum Ansprechen (TTR) nach RECIST1.1 - Progressionsfreies Überleben (PFS) - Gesamtüberlebens (OS) und Überlebensrate nach 1 und 2 Jahren - Lebensqualität (QoL) ermittelt anhand EORTC-QLQ-C30 zu jeder Visite - Anzahl, Schwere und Dauer von behandlungsbedingten unerwünschten Ereignissen nach NCI-CTCAE v4.0 Explorative Ziele sind: - Histomorphologische Unterteilung zwischen NET G3 (differenzierte Morphologie, Ki67 (20-55 %) und NEC G3 (kleinzellige oder großzellige undifferenzierte Morphologie und/oder Ki67 > 55%) - Chromogranin A (CgA) und Neuronenspezifischer Enolayse (NSE) Serumlevel - PD-L1-Expression gemessen anhand Immunhistochemie oder anderer etablierter Techniken - Tumorwachstumsrate TGR) - Krankheitskontrollrate (DCR) nach irRECIST
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
DCR, ORR: on every assessment BOR: after 16, 24 weeks and 1 year TTR: after 1 year PFS: after 1 year OS and survival rate: after 1 and 2 year QoL: assessed on every assessment |
DCR, ORR: zum jeden Zeitpunkt des Tumorassessments BOR: nach 16 Wochen, nach 24 Wochen und 1 Jahr TTR: nach 1 Jahr PFS: nach 1 Jahr OS und Überlebensrate: nach 1 und 2 Jahren QoL: zu jeder Visite |
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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 | 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.8.3 |
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 | 5 |
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
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LVLS |
Letzter Besuch des Letzten Patienten |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |