Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. Academic Article uri icon

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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

  • Stathis, Anastasios
  • Hotte, Sebastien
  • Chen, Eric X
  • Hirte, Holger
  • Oza, Amit M
  • Moretto, Patricia
  • Webster, Sheila
  • Laughlin, Anne
  • Stayner, Lee-Anne
  • McGill, Shauna
  • Wang, Lisa
  • Zhang, Wen-Jiang
  • Espinoza-Delgado, Igor
  • Holleran, Julianne L
  • Egorin, Merrill J
  • Siu, Lillian L

publication date

  • May 20, 2009