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Cancer Immunology, Immunotherapy

, Volume 68, Issue 9, pp 1547–1559 | Cite as

A phase II study of the L19IL2 immunocytokine in combination with dacarbazine in advanced metastatic melanoma patients

  • Benjamin Weide
  • Thomas Eigentler
  • Chiara Catania
  • Paolo Antonio Ascierto
  • Stefano Cascinu
  • Jürgen C. Becker
  • Axel Hauschild
  • Antonella Romanini
  • Riccardo Danielli
  • Reinhard Dummer
  • Uwe Trefzer
  • Giuliano EliaEmail author
  • Dario NeriEmail author
  • Claus GarbeEmail author
Clinical Trial Report

Abstract

Engineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000 mg/m2 of body surface on day 1 of 21-day cycles) as single agent, while in two other arms L19IL2 (22.5 million international units of IL2 equivalents) was added, based on two different schedules of administration. In total, 69 patients with stage IV melanoma were enrolled (24 in the dacarbazine arm, 23 and 22 in the other combination arms, respectively) and 67 received treatment. Analyses of efficacy results show a statistically significant benefit in terms of overall response rate and median progression-free survival for patients receiving L19IL2 in combination with DTIC, compared to DTIC as single agent. In light of these results, further clinical investigations with L19IL2 (alone or in combination with other agents) are warranted.

Keywords

Stage IV melanoma Immunocytokine L19IL2 Dacarbazine Phase II study 

Abbreviations

ALT

Alanine amino transferase

CTCAE

Common Terminology Criteria for Adverse Events

CR

Complete response

CT

Computed tomography

DTIC

Dacarbazine

ECOG

Eastern Cooperative Oncology Group

EDB

Extra-domain B

GGT

Gamma glutamyl transpeptidase

HD IL2

High-dose interleukin 2

MUGA

Multigated radionuclide angiography

NCI

National Cancer Institute

ORR

Objective response rate

PR

Partial response

PD

Progressive disease

RD

Recommended dose

SAE

Serious adverse event

SD

Stable disease

ULN

Upper limit of normal

Notes

Acknowledgements

We thank all patients, families, staff, and investigators of the participating hospitals. We are very grateful to Dr. Jacopo Piazzi, Philogen S.p.A., for his support with data management and statistical analysis.

Author contributions

Study conception and design: BW, TE, CC, PAA, SC, JCB, AH, AR, RD, RD, UT, DN, CG. Patient recruitment and management: BW, TE, CC, PAA, SC, JCB, AH, AR, RD, RD, UT, CG. Data acquisition, management, analysis, and interpretation: BW, AH, GE, DN, CG. Manuscript preparation: BW, AH, GE, DN, CG.

Funding

This study was funded by Philogen S.p.A. The sponsor was involved in study design, data collection, analysis, and interpretation, writing of the article, and in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

Benjamin Weide has received speaker or advisory board honoraria from Amgen, CureVac, Philogen, Novartis as well as research funding from Bristol-Myers Squibb (BMS), Merck, Sharp & Dohme (MSD) and Philogen. Paolo Ascierto reports grants and personal fees from BMS, grants and personal fees from Roche-Genentech, personal fees from MSD, grants and personal fees from Array, personal fees from Novartis, personal fees from Merck Serono, personal fees from Pierre Fabre, personal fees from Incyte, personal fees from Genmab, personal fees from NewLink Genetics, personal fees from Medimmune, personal fees from AstraZeneca, personal fees from Syndax, personal fees from Sun Pharma, personal fees from Sanofi, personal fees from Idera, personal fees from Ultimovacs, personal fees from Sandoz, personal fees from Immunocore, personal fees from 4SC, outside the submitted work; Jürgen C. Becker has received speaker honoraria from Amgen, Merck Serono, and Pfizer, advisory board honoraria from Amgen, CureVac, eTheRNA, Lytix, Merck Serono, Novartis, Rigontec, and Takeda as well as research funding from Alcedis, Boehringer Ingelheim, BMS and Merck Serono; he also received travel support from 4SC and Incyte; Axel Hauschild received clinical trial support, speaker´s honoraria, or consultancy fees from the following companies: Amgen, BMS, Merck Serono, MSD, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec, Sanofi-Genzyme, and Sun Pharma; Reinhard Dummer reports intermittent, project focused consulting and/or advisory relationships with Novartis, MSD, BMS, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome outside the submitted work; Giuliano Elia is an employee of Philochem AG, a company of the Philogen group; Dario Neri is shareholder and Board Member of Philogen S.p.A.; Claus Garbe reports personal fees from Philogen, during the conduct of the study; personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, personal fees from NeraCare, grants and personal fees from BMS, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. All other authors declare no conflict of interest.

Ethical approval and ethical standards

The protocol was approved by the regulatory authorities Paul-Ehrlich-Institut in Germany (authorization no. 593/01 of 01/07/2008), ISS in Italy (authorization of 21/02/2008), Swissmedic in Switzerland (authorization no. 2011DR2225 of 30/12/2011) and BASG in Austria (authorizations nos. 717349/0001 and 717350/0001 of 06/04/2011). The study was also approved by the ethics committee of the coordinating center for the 3 participating centers in Germany (Ethikkommission an der Medizinischen Fakultät der Eberhard-Karls-Universitäts und am Universitätsklinikum Tübingen, Tübingen, Germany—approval number: 33/2008AMG1 of 01/09/2010 for Tübingen; and of 25/01/2011 for Kiel and Berlin); by the central ethic committee at IEO in Milan, Italy (authorization no. R363-IEO S387/607 of 21/02/2008) and four local ethics committees for the other four participating centers in Italy (Ancona, approval number 210520 of 02/12/2010; Naples, approval number CEI/538/10 of 25/11/2010; Pisa, approval number 2497/2008 of 01/12/2010; and Siena, approval number 82/2009 of 21/10/2010); by the local ethics committee for the participating center in Switzerland (Kantonale Ethikkommission Zürich (KEK), Zürich, Switzerland—approval number: KEK-ZH-Nr. 2011-0362 of 15/11/2011); and by the local ethics committee for the participating center in Austria (Ethikkommission Medizinischer Universitäts Graz, Graz, Austria—approval number 23-176 ex 10/11 of 06/04/2011). The study was conducted in accordance with Good Clinical Practice guidelines (EudraCT No.: 2007-005737-11; ClinicalTrials.gov Identifier: NCT01055522). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent on being treated as well as on the use of generated data for research purposes and publication was obtained from all individual participants included in the study.

Supplementary material

262_2019_2383_MOESM1_ESM.pdf (312 kb)
Supplementary material 1 (PDF 311 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of DermatologyUniversity Medical CenterTübingenGermany
  2. 2.Division of Thoracic OncologyIEO, European Institute of Oncology IRCCSMilanItaly
  3. 3.Istituto Nazionale Tumori, IRCCS Fondazione PascaleNaplesItaly
  4. 4.Ospedali Riuniti AnconaAnconaItaly
  5. 5.Medical University of GrazGrazAustria
  6. 6.University Hospital Schleswig-Holstein (UKSK)KielGermany
  7. 7.Azienda Ospedaliero-Universitaria PisanaPisaItaly
  8. 8.Azienda Ospedaliero-Universitaria SeneseSienaItaly
  9. 9.University Hospital Zurich and University ZurichZurichSwitzerland
  10. 10.CharitéBerlinGermany
  11. 11.Philochem AGOtelfingenSwitzerland
  12. 12.Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical SciencesETH ZurichZurichSwitzerland
  13. 13.Sektion Dermatologische OnkologieUniversität Tübingen HautklinikTübingenGermany
  14. 14.Università di Modena e Reggio EmiliaModenaItaly
  15. 15.Translational Skin Cancer ResearchDeutsches Konsortium für Translationale Krebsforschung (DKTK) Partner Site EssenEssenGermany
  16. 16.Deutsches Krebsforschungszentrum (DKFZ)HeidelbergGermany
  17. 17.Dermatologikum BerlinBerlinGermany

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