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01-03-2014 | Original Article

Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers

Authors: Jennifer J. Wheler, Filip Janku, Gerald S. Falchook, Tiffiny L. Jackson, Siqing Fu, Aung Naing, Apostalia M. Tsimberidou, Stacy L. Moulder, David S. Hong, Hui Yang, Sarina A. Piha-Paul, Johnique T. Atkins, Guillermo Garcia-Manero, Razelle Kurzrock

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2014

Abstract

Purpose

Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers.

Methods

Bevacizumab was administered at escalating dosages of 2.5–11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3–10 mg/kg on days 1–28 every 28 days to determine the maximum tolerated dose. Pharmacodynamic parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels).

Results

Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease (SD) ≥6 months was reported in 4/57 (7 %) of patients, including two patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with SD ≥6 months showed histone acetylation, while 8 of 36 (22 %) without SD ≥6 months demonstrated histone acetylation (p = 0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 vs. 5.8 months; p = 0.012).

Conclusions

The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction, and prostate cancer. Patients with hypertension had improved overall survival.

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Title: Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers
Authors: Jennifer J. Wheler
Filip Janku
Gerald S. Falchook
Tiffiny L. Jackson
Siqing Fu
Aung Naing
Apostalia M. Tsimberidou
Stacy L. Moulder
David S. Hong
Hui Yang
Sarina A. Piha-Paul
Johnique T. Atkins
Guillermo Garcia-Manero
Razelle Kurzrock
Publication date: 01-03-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2384-1

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