title: Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.
abstract: PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat.  PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied.  RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients.  CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.
authors.affiliation: Princess Margaret Hospital Phase I Consortium, Toronto, ON, Canada.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stathis
authors.forename: Sebastien J
authors.initials: SJ
authors.lastname: Hotte
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Holger W
authors.initials: HW
authors.lastname: Hirte
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.forename: Patricia
authors.initials: P
authors.lastname: Moretto
authors.forename: Sheila
authors.initials: S
authors.lastname: Webster
authors.forename: Anne
authors.initials: A
authors.lastname: Laughlin
authors.forename: Lee-Anne
authors.initials: LA
authors.lastname: Stayner
authors.forename: Shauna
authors.initials: S
authors.lastname: McGill
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Wen-Jiang
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Julianne L
authors.initials: JL
authors.lastname: Holleran
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu