Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.
BACKGROUND
Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.


METHODS
This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.


RESULTS
In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.


CONCLUSIONS
These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.
Munster
P N
PN
Division of Hematology and Oncology, University of California, San Francisco, CA 94143, USA. pmunster@medicine.ucsf.edu
Marchion
D
D
Thomas
S
S
Egorin
M
M
Minton
S
S
Springett
G
G
Lee
J-H
JH
Simon
G
G
Chiappori
A
A
Sullivan
D
D
Daud
A
A
D000107:Acetylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006321:Heart / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000032:analysis; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000077337:Vorinostat; D004317:Doxorubicin; D006655:Histone Deacetylases