PURPOSE: To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. PATIENTS AND METHODS: Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. RESULTS: Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. CONCLUSION: The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.
PURPOSE: To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. PATIENTS AND METHODS: Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. RESULTS: Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patientspatients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. CONCLUSION: The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.
Authors: Susan E Bates; Zhirong Zhan; Kenneth Steadman; Tomasz Obrzut; Victoria Luchenko; Robin Frye; Robert W Robey; Maria Turner; Erin R Gardner; William D Figg; Seth M Steinberg; Alex Ling; Tito Fojo; Kin Wah To; Richard L Piekarz Journal: Br J Haematol Date: 2009-10-28 Impact factor: 6.998
Authors: S Thomas; R Aggarwal; T Jahan; C Ryan; T Troung; A M Cripps; P Raha; K T Thurn; S Chen; J A Grabowsky; J Park; J Hwang; A Daud; P N Munster Journal: Ann Oncol Date: 2016-02-21 Impact factor: 32.976
Authors: U Lassen; L R Molife; M Sorensen; S-A Engelholm; L Vidal; R Sinha; R T Penson; P Buhl-Jensen; E Crowley; J Tjornelund; P Knoblauch; J S de Bono Journal: Br J Cancer Date: 2010-06-15 Impact factor: 7.640
Authors: A Rocca; S Minucci; G Tosti; D Croci; F Contegno; M Ballarini; F Nolè; E Munzone; A Salmaggi; A Goldhirsch; P G Pelicci; A Testori Journal: Br J Cancer Date: 2009-01-13 Impact factor: 7.640
Authors: P N Munster; D Marchion; S Thomas; M Egorin; S Minton; G Springett; J-H Lee; G Simon; A Chiappori; D Sullivan; A Daud Journal: Br J Cancer Date: 2009-09-08 Impact factor: 7.640