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A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors

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Abstract

Purpose

Children with relapsed/refractory central nervous system (CNS) tumors require novel combinations of therapies. Irinotecan and temozolomide (IT) is a frequently used therapy with an established toxicity profile. Bevacizumab is an anti-VEGF monoclonal antibody with demonstrated activity in CNS tumors. Therefore, the combination of these agents has therapeutic potential in CNS tumors. The objective of this study was to determine the maximum tolerated dose (MTD) of escalating dose IT combined with a fixed dose of bevacizumab (BIT) in children with relapsed/refractory CNS tumors.

Methods

A phase I trial was performed in a 3 + 3 design. Therapy toxicities and radiologic responses to treatment were described.

Results

One hundred eighty cycles of therapy were administered to 26 patients. The MTD of BIT was dose level 1, (bevacizumab 10 mg/kg on days 1 and 15, irinotecan 125 mg/m2 on days 1 and 15, and temozolomide 125 mg/m2 on days 1–5 of 28-day cycles). The regimen was well tolerated with primarily hematologic toxicity, which was not dose limiting. Among 22 response-evaluable patients, there was 1 complete response (CR), 6 partial responses (PR), and 10 stable diseases (SD) with an overall response rate (ORR: CR + PR) of 31.8%.

Conclusion

At the MTD, BIT therapy was well tolerated, and prolonged treatment courses of up to 24 cycles were feasible, with radiographic responses observed. Further evaluation is needed for efficacy in a phase II trial (NCT00876993, registered April 7, 2009, www.clinicaltrials.gov).

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Availability of data and material

Data and material will be made available upon request to the corresponding author.

Abbreviations

CNS:

Central nervous system

VEGF:

Vascular endothelial growth factor

IT:

Irinotecan and temozolomide

BIT:

Bevacizumab, irinotecan, and temozolomide

MTD:

Maximum tolerated dose

ANC:

Absolute neutrophil count

ULN:

Upper limit of normal

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

JHACH:

Johns Hopkins All Children’s Hospital

DLT:

Dose-limiting toxicity

MRI:

Magnetic resonance imaging

CR:

Complete response

PR:

Partial response

SD:

Stable disease

CTCAE:

Common Terminology Criteria for Adverse Events

PK:

Pharmacokinetic

IV:

Intravenous

PO:

Oral administration

FDA:

Food and drug administration

GI:

Gastrointestinal

LGG:

Low-grade glioma

HGG:

High-grade glioma

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Acknowledgements

This study was generously supported by the V Foundation (www.v.org) and the Brain Tumor Alliance/Miles for Hope. We thank the patients, families, and staff at our institutions that help with all aspects of trial conduct. This work has been supported in part by the Clinical and Translational Research Organization (CTRO) at Johns Hopkins All Children’s Hospital.

Funding

This study was funded by The V Foundation and Miles for Hope/Brain Tumor Alliance.

Author information

Authors and Affiliations

  1. Cancer and Blood Disorders Institute, Johns Hopkins All Children’s Hospital, 501 6th Avenue South, St Petersburg, FL, 33701, USA

    Jonathan Metts & Stacie Stapleton

  2. Hospital Medicine, MyMichigan Health, Alma, MI, USA

    Brittany Harrington

  3. Golisano Children’s Hospital of Southwest Florida, Fort Myers, FL, USA

    Emad Salman

  4. Division of Pediatric Hematology/Oncology, Nemours Children’s Health, Jacksonville, FL, USA

    Scott M. Bradfield

  5. Data Coordinating Center for Pediatric Multicenter Studies, Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital, St Petersburg, FL, USA

    Jennifer Flanary, Maua Mosha & Ernest Amankwah

  6. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ernest Amankwah

Authors
  1. Jonathan Metts
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  2. Brittany Harrington
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  3. Emad Salman
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  8. Stacie Stapleton
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Contributions

Stacie Stapleton created the study concept and design. Subject recruitment and treatment were performed by Stacie Stapleton, Scott Bradfield, and Emad Salman. Material preparation, data collection, and analysis were performed by Brittany Harrington, Jennifer Flanary, Maua Mosha, and Ernest Amankwah. The first draft of the manuscript was written by Jonathan Metts and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jonathan Metts.

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Ethics approval

This study was approved by the Institutional review board (IRB) of the coordinating center (Johns Hopkins All Children’s Hospital, # IRB00054010). The study was also approved by the IRBs of each participating institution.

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Informed consent was obtained prior to study enrollment for each patient or parent, as appropriate. Assent was obtained when appropriate.

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No conflicts of interest or competing interests to disclose.

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Metts, J., Harrington, B., Salman, E. et al. A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors. Childs Nerv Syst 38, 919–928 (2022). https://doi.org/10.1007/s00381-022-05479-7

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