Elsevier

European Journal of Cancer

Volume 83, September 2017, Pages 177-184
European Journal of Cancer

Original Research
Open-label, multicentre, randomised, phase II study of the EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study)

https://doi.org/10.1016/j.ejca.2017.06.015Get rights and content

Highlights

  • BERNIE evaluated the role of bevacizumab in childhood/adolescent metastatic soft tissue sarcoma.

  • The addition of bevacizumab to the chemotherapy backbone appeared tolerable.

  • The primary end-point of event-free survival did not show statistically significant improvement.

  • These data do not support the use of bevacizumab in metastatic RMS.

Abstract

Purpose

We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

Patients and methods

Eligible patients aged ≥6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, ±bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, ±bevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee.

Results

One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8–35.9) with chemotherapy and 20.6 months (95% CI: 15.2–24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] = 0.93; 95% CI: 0.61–1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73–2.09) versus 0.64 (95% CI: 0.32–1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2–47.9) with chemotherapy and 54.0% (95% CI: 40.9–66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6–35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab.

Conclusion

The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement.

Trial registration: ClinicalTrials.gov, NCT00643565.

Introduction

Soft tissue sarcomas (STSs) are a heterogeneous group of malignant tumours, in paediatrics conventionally divided into rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma STS (NRSTS), with NRSTS subdivided into multiple histological subtypes [1]. RMS is the most common form of STS in children [2]. Multi-modality treatment, including surgery, radiotherapy and chemotherapy, allows 3-year overall survival (OS) in 80–85% of the patients presenting with localised RMS [3], [4]. However, the prognosis for patients with metastatic RMS is poor [5], [6], [7]. In a pooled analysis of studies in children with metastatic RMS, the 3-year event-free survival (EFS) was only 27% [5]. Furthermore, lack of improvement with conventional chemotherapy has highlighted the need for new and effective treatments [8]. NRSTS are poorly sensitive to chemotherapy; however, multi-modality treatments that include chemotherapy have increasingly been attempted [9], [10].

Significant overexpression of the angiogenic factor, vascular endothelial growth factor (VEGF), has been reported in adult STS [11], [12]. Anti-VEGF monoclonal antibodies inhibit tumour angiogenesis in preclinical paediatric tumour models, including RMS [13], [14]. Bevacizumab, an anti-VEGF monoclonal antibody, is approved for use in a range of adult tumours in combination with chemotherapy, and was well tolerated in a phase I study in children with refractory solid tumours [15]. The present study evaluated the efficacy of the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic STS.

Section snippets

Study design

This open-label, multicentre, randomised phase II study evaluated the addition of bevacizumab to standard chemotherapy in children and adolescents aged ≥6 months to <18 years with untreated metastatic RMS or NRSTS (BO20924/ITCC-006; ClinicalTrials.gov: NCT00643565).

Full eligibility criteria are described in Supplementary Table S1. Any wounds, tumour-related bleeding or clotting diathesis were to be healed/resolved within the 3 weeks of randomisation. Key exclusion criteria included: prior

Patients

Between July 2008 and October 2013, 154 patients were randomised to receive chemotherapy (n = 80) or bevacizumab plus chemotherapy (n = 74; intent-to-treat [ITT] population). The ITT population comprised 103 patients with RMS (high-risk, n = 78) and 49 with NRSTS. Two patients were enrolled where subsequent pathology yielded other diagnoses (one Wilm's tumour, one Ewing's sarcoma). Four randomised patients did not receive study treatment (Supplementary Fig. S1). Baseline characteristics were

Discussion

This randomised study did not meet its primary end-point of improved EFS with bevacizumab plus chemotherapy in children and adolescents with metastatic RMS and NRSTS. Bevacizumab in combination with chemotherapy in relapsed RMS did not improve EFS compared with historical controls in a North American study [19]. The observed 1-year EFS (57% control arm, 75% experimental arm) and 2-year EFS (41% in both arms) rates are comparable with published data [5], [8], despite the fact that 51% of the

Funding

This work was supported by F. Hoffmann-La Roche Ltd. The sponsor was involved in data analysis in collaboration with the authors. All authors had full access to the data and the corresponding authors took full responsibility for the final decision to submit the manuscript for publication. Dr Julia C. Chisholm was supported by the National Institute for Health Research Biomedical Research Centre of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. EpSSG is supported by

Conflict of interest statement

JCC has acted in a consulting/advisory role for F. Hoffmann-La Roche Ltd and Merck and received travel, accommodation or expenses from Roche; JHMM has acted in a consulting/advisory role for F. Hoffmann-La Roche Ltd and received travel, accommodation or expenses from Roche; MC has acted in a consulting/advisory role for F. Hoffmann-La Roche Ltd; GB has acted in a consulting/advisory role for Loxo Oncology and received research funding from IndenaSpA, and travel, accommodation or expenses from

Acknowledgements

The authors thank the patients, caregivers and medical staff involved in this study from the recruiting countries (Belgium, Brazil, Chile, Czech Republic, France, Germany, Israel, Italy, Poland, Spain, The Netherlands and the UK). They also thank Gilles Vassal, Raphael Rousseau, Christophe Dhalluin, Emily Roberts-Thomson, Alice Palmer, Yannick Kerloeguen, Chenglin Ye and Gudrun Zahlmann for their contributions to the study. Third-party medical writing support, under the direction of the

References (23)

  • B.J. Weigel et al.

    Intensive multiagent therapy, including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation, in patients with high-risk rhabdomyosarcoma: a report from the children's oncology group

    J Clin Oncol

    (2016)
  • Cited by (0)

    1

    These authors contributed equally.

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