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Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas

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Abstract

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m2 po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2–67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.

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Abbreviations

HGG:

High grade glioma

GBM:

Glioblastoma

TMZ:

Temozolomide

BEV:

Bevacizumab

VOR:

Vorinostat

MRI:

Magnetic resonance imaging

RANO:

Response Assessment in Neuro-Oncology

CI:

Confidence interval

PFS:

Progression-free survival

PFS6:

6-Month progression-free survival

OS:

Overall survival

PR:

Partial response

CR:

Complete response

DVT:

Deep venous thrombosis

PE:

Pulmonary embolus

MGMT:

Methyl guanine methyl transferase

KPS:

Karnofsky performance status

MTD:

Maximum tolerated dose

DLT:

Dose-limiting toxicity

HDAC:

Histone deacetylases

CBC:

Complete blood count

CMP:

Comprehensive metabolic panel

ULN:

Upper limit of normal

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Acknowledgements

We would like to thank Mrs. Kelly Seagroves for assisting with preparation of this manuscript. This work was supported by Merck Sharp & Dohme Corp and Genentech, Inc.

Funding

VOR was provided by Merck Sharp & Dohme Corp. BEV was provided by Genentech, Inc.

Author information

Author notes

  1. Katherine B. Peters

    Present address: Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, DUMC 3624, Durham, NC, 27710, USA

Authors and Affiliations

  1. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA

    Katherine B. Peters, Annick Desjardins & Henry S. Friedman

  2. Department of Neurology, Duke University Medical Center, Durham, NC, USA

    Katherine B. Peters & Annick Desjardins

  3. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    Henry S. Friedman

  4. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    James E. Herndon II

  5. Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

    Katherine B. Peters, Eric S. Lipp, Elizabeth Miller, James E. Herndon II, Frances McSherry, Annick Desjardins & Henry S. Friedman

  6. Division of Hematology/Oncology, Department of Medicine, Dana Farber Cancer Institute, Boston, MA, USA

    David A. Reardon

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Correspondence to Katherine B. Peters.

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Conflict of interest

AD received financial compensation from Genentech/Roche for Advisory Board participation. HSF received financial compensation from Genentech/Roche for Speakers Bureau participation and consultation. DAR received financial compensation from Genentech/Roche and Merck Advisory Board participation. The rest of the authors declare that they have no conflict of interest.

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Peters, K.B., Lipp, E.S., Miller, E. et al. Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas. J Neurooncol 137, 349–356 (2018). https://doi.org/10.1007/s11060-017-2724-1

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  • DOI: https://doi.org/10.1007/s11060-017-2724-1

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