A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

Abstract

BACKGROUND:

Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib.

METHODS:

Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11.

RESULTS:

29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST.

CONCLUSIONS:

The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

• Authors: Dustin A Deming, Jacob Ninan, Howard H Bailey, Jill M Kolesar, Jens Eickhoff, Joel M Reid, Matthew M Ames, Renee M McGovern, Dona Alberti, Rebecca Marnocha, Igor Espinoza-Delgado, John Wright, George Wilding, William R Schelman
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 2 Pg. 323-9 (Apr 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24114123 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Pyrazines
• Vorinostat
• Bortezomib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Boronic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Bortezomib
• Female
• Histone Deacetylase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics)
• Vorinostat