A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies.

Abstract

BACKGROUND:

A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors.

METHODS:

Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1.

RESULTS:

Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1.

CONCLUSIONS:

This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.

• Authors: William R Schelman, Anne M Traynor, Kyle D Holen, Jill M Kolesar, Steven Attia, Tien Hoang, Jens Eickhoff, Zhisheng Jiang, Dona Alberti, Rebecca Marnocha, Joel M Reid, Matthew M Ames, Renee M McGovern, Igor Espinoza-Delgado, John J Wright, George Wilding, Howard H Bailey
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 6 Pg. 1539-46 (Dec 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 24114121 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

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)
• Bortezomib
• Female
• Histone Deacetylase Inhibitors (administration & dosage, blood, pharmacokinetics)
• Humans
• Hydroxamic Acids (administration & dosage, blood, pharmacokinetics)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (blood, drug therapy)
• Pyrazines (administration & dosage)
• Vorinostat
• Young Adult