Translational phase I trial of vorinostat (suberoylanilide hydroxamic acid) combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia.

Abstract

PURPOSE:

To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts.

EXPERIMENTAL DESIGN:

In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m(2)) and cytarabine (1 or 2 g/m(2) twice a day if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design.

RESULTS:

Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment.

CONCLUSIONS:

Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings.

• Authors: Ivana Gojo, Ming Tan, Hong-Bin Fang, Mariola Sadowska, Rena Lapidus, Maria R Baer, France Carrier, Jan H Beumer, Bean N Anyang, Rakesh K Srivastava, Igor Espinoza-Delgado, Douglas D Ross
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 7 Pg. 1838-51 (Apr 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23403629 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2013 AACR.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Hydroxamic Acids
• Neoplasm Proteins
• Tumor Necrosis Factor Decoy Receptors
• Cytarabine
• Vorinostat
• Etoposide

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cytarabine (administration & dosage)
• Etoposide (administration & dosage)
• Female
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Hydroxamic Acids (administration & dosage)
• Karyotype
• Leukemia, Myeloid, Acute (drug therapy, genetics, mortality)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Proteins (genetics, metabolism)
• Recurrence
• Translational Research, Biomedical
• Treatment Outcome
• Tumor Necrosis Factor Decoy Receptors (genetics, metabolism)
• Vorinostat
• Young Adult