Journal of Neuro-Oncology

, Volume 137, Issue 2, pp 349–356 | Cite as

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

  • Katherine B. Peters
  • Eric S. Lipp
  • Elizabeth Miller
  • James E. HerndonII
  • Frances McSherry
  • Annick Desjardins
  • David A. Reardon
  • Henry S. Friedman
Clinical Study
  • 179 Downloads

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.

Keywords

Recurrent Malignant gliomas Vorinostat Bevacizumab Temozolomide 

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

Notes

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.

Compliance with ethical standards

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Katherine B. Peters
    • 1
    • 2
    • 3
    • 6
  • Eric S. Lipp
    • 6
  • Elizabeth Miller
    • 6
  • James E. HerndonII
    • 5
    • 6
  • Frances McSherry
    • 6
  • Annick Desjardins
    • 2
    • 3
    • 6
  • David A. Reardon
    • 7
  • Henry S. Friedman
    • 2
    • 4
    • 6
  1. 1.Preston Robert Tisch Brain Tumor CenterDuke University School of MedicineDurhamUSA
  2. 2.Department of NeurosurgeryDuke University Medical CenterDurhamUSA
  3. 3.Department of NeurologyDuke University Medical CenterDurhamUSA
  4. 4.Department of PediatricsDuke University Medical CenterDurhamUSA
  5. 5.Department of Biostatistics and BioinformaticsDuke University Medical CenterDurhamUSA
  6. 6.Duke Cancer InstituteDuke University Medical CenterDurhamUSA
  7. 7.Division of Hematology/Oncology, Department of MedicineDana Farber Cancer InstituteBostonUSA

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