2077 Background: Vorinostat (SAHA) induces differentiation & growth arrest in a variety of human carcinoma cell lines by inhibiting HDAC. It also enhances the efficacy of chemotherapy. We are conducting a phase I study to evaluate the combination of vorinostat, Cb & P for patients with advanced solid malignancies. Methods: Patients with advanced solid malignancies who were candidates for combination therapy with Cb & P were eligible. Vorinostat was given orally on d 1–14 of each 21-d-cycle, except in cycle 1 when begun on d -4 to facilitate PK studies. Cb & P were given on d 1 of each cycle. Plasma concentrations of vorinostat, & its 2 major metabolites were quantitated with a novel LC-MS/MS assay. Results: Dose level 4 has been determined as the recommended phase II dose (RP2D) for the combination, since the RP2D of single agent vorinostat is 400 mg on this schedule. Observed toxicities included nausea, vomiting, neutropenia & thrombocytopenia, none of which were dose-limiting. Of 9 patients evaluable for response, 4 had PR (1 head & neck cancer, 3 non-small cell lung cancer), & 2 had stable disease. Vorinostat was rapidly absorbed & AUC increased with dose. Vorinostat PK parameters included Tmax 0.5–2 h, t1/2 1.6 ± 0.5 h, & CL/F 5.8 ± 1.7 l/min. Cb & P did not alter vorinostat PK. 4-Anilino-4-oxobutanoic acid was the major, & long-lived, vorinostat metabolite, with Cmax 1.5–7 fold > vorinostat Cmax & t ½ ∼6h. Vorinostat glucuronide Cmax was 1–5 fold > vorinostat Cmax & glucuronide t ½ ∼2h. The RP2D cohort is being expanded to 12 patients to obtain additional clinical & PK data. Conclusions: Vorinostat can be safely administered in combination with Cb & P at their recommended doses. Vorinostat PK are not altered by Cb & P. Promising anti-cancer activity has been noted in patients with advanced NSCLC. Support: U01CA099168–01, U01CA62505, NIH/NCCR/GCRC grant 5M01RR 00056. [Table: see text] No significant financial relationships to disclose.
A phase I study of docetaxel and 5-fluorouraciI in patients with advanced solid malignancies