title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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: University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC), Baltimore, MD 21201, USA.
authors: Ivana
authors: I
authors: Gojo
authors: Ming
authors: M
authors: Tan
authors: Hong-Bin
authors: HB
authors: Fang
authors: Mariola
authors: M
authors: Sadowska
authors: Rena
authors: R
authors: Lapidus
authors: Maria R
authors: MR
authors: Baer
authors: France
authors: F
authors: Carrier
authors: Jan H
authors: JH
authors: Beumer
authors: Bean N
authors: BN
authors: Anyang
authors: Rakesh K
authors: RK
authors: Srivastava
authors: Igor
authors: I
authors: Espinoza-Delgado
authors: Douglas D
authors: DD
authors: Ross
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat; D055815:Young Adult
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D003561:Cytarabine; D000077337:Vorinostat; D005047:Etoposide
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