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Nimotuzumab and radiotherapy for treatment of newly diagnosed diffuse intrinsic pontine glioma (DIPG): a phase III clinical study

  • G. FleischhackEmail author
  • M. Massimino
  • M. Warmuth-Metz
  • E. Khuhlaeva
  • G. Janssen
  • N. Graf
  • S. Rutkowski
  • A. Beilken
  • I. Schmid
  • V. Biassoni
  • S. K. Gorelishev
  • C. Kramm
  • H. Reinhard
  • P. G. Schlegel
  • R.-D. Kortmann
  • D. Reuter
  • F. Bach
  • N. E. Iznaga-Escobar
  • U. Bode
Clinical Study

Abstract

Background

Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence.

Methods

The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3).

Results

All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression.

Conclusions

Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

Keywords

Children DIPG EGFR Nimotuzumab Radiotherapy Diffuse midline glioma 

Notes

Acknowledgements

Authors are thankful to all patients and their families who were a part of the study. We would also like to thank all pediatricians, medical doctors, neurologists, medical oncologists and nurses who participated and without whose contribution this study would not have been possible.

Funding

This study was funded by Oncoscience GmbH, Schenefeld, Germany (Study No.: OSAG 101-BSC-05). Oncoscience GmbH has also provided the investigational drug nimotuzumab.

Compliance with ethical standards

Conflicts of interest

GF, MM, MWM, EK, GJ, NG, SR, AB, IS, VB, SKG, CK, HR, PGS, RDK and UB have received research funding and expense allowance for study conduct from Oncoscience GmbH. GF and UB have received support from Oncoscience GmbH for meeting travel to present study results. NEIE is an employee of the Center of Molecular Immunology, the research institution that patented and manufactures nimotuzumab. DR is an employee of Oncoscience GmbH. FB was an employee and has had stock options of Oncoscience GmbH that funded this study and has provided the investigational drug.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national committees. The trial was conducted in accordance with 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The institutional review boards or ethics committees of all participating centers reviewed and approved the protocol. All parents/guardians and patients, where appropriate, gave their written informed consent.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • G. Fleischhack
    • 1
    • 2
    Email author
  • M. Massimino
    • 3
  • M. Warmuth-Metz
    • 4
  • E. Khuhlaeva
    • 5
  • G. Janssen
    • 6
  • N. Graf
    • 7
  • S. Rutkowski
    • 8
    • 9
  • A. Beilken
    • 10
  • I. Schmid
    • 11
  • V. Biassoni
    • 3
  • S. K. Gorelishev
    • 5
  • C. Kramm
    • 6
    • 12
  • H. Reinhard
    • 7
    • 13
  • P. G. Schlegel
    • 8
  • R.-D. Kortmann
    • 14
  • D. Reuter
    • 15
  • F. Bach
    • 15
  • N. E. Iznaga-Escobar
    • 16
  • U. Bode
    • 2
  1. 1.Paediatric Haematology and Oncology, Paediatrics IIIUniversity Hospital of EssenEssenGermany
  2. 2.Department of Paediatric Haematology/Oncology, Children Medical HospitalUniversity of BonnBonnGermany
  3. 3.Paediatric UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanoItaly
  4. 4.Department of NeuroradiologyUniversity of WuerzburgWürzburgGermany
  5. 5.Paediatric Neurosurgical DepartmentBurdenko Neurosurgical InstituteMoscowRussia
  6. 6.Department of Paediatric Haematology/Oncology, Children’s Medical HospitalUniversity of DuesseldorfDüsseldorfGermany
  7. 7.Department of Paediatric Haematology/OncologySaarland UniversityHomburg/SaarGermany
  8. 8.Department of Paediatric Hematology/OncologyUniversity of Wuerzburg, University Children’s HospitalWuerzburgGermany
  9. 9.Department of Paediatric Haematology and OncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  10. 10.Department of Paediatric Haematology/OncologyMedical School, Children’s Medical HospitalHannoverGermany
  11. 11.Department of Paediatric Haematology/Oncology, Children’s Medical HospitalUniversity of MunichMunichGermany
  12. 12.Division of Paediatric Haematology and Oncology, Department of Child and Adolescent HealthUniversity Medical Center GöttingenGöttingenGermany
  13. 13.Paediatric Haematology and OncologyAsklepios HospitalSankt AugustinGermany
  14. 14.Department of RT and RadiooncologyUniversity of LeipzigLeipzigGermany
  15. 15.Oncoscience GmbHSchenefeldGermany
  16. 16.Center of Molecular ImmunologyHavanaCuba

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