Abstract A185: Phase I clinical, pharmacokinetic, and pharmacodynamic study of SB939, an oral histone deacetylase inhibitor (HDACi), in patients with advanced solid tumors

Abstract Background: SB939 is an orally available, potent, competitive HDACi selective for Class I, II and IV histone deacetylases. Preclinical evaluation of SB939 in a broad spectrum of xenograft mouse models revealed dose-dependent tumor growth inhibition. In the HCT116 colorectal cancer model, SB939 showed superior activity compared to other HDACi and prolonged histone H3 acetylation (acH3) in tumor tissues lasting ≥ 24 hours. Methods: Patients (pts) with advanced solid malignancies were enrolled into 7 dose levels (DL). At DL1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other DLs. Detailed PK sampling was performed on cycle 1 days 1 and 5 (for DL1 on days 1 and 3). Peripheral blood mononuclear cells (PBMC) were collected on cycle 1 at various time points for determination of acH3 levels using a validated Western blot assay. MTD was defined as dose with ≥ 2/3–6 pt with DLT. Results: To date, 28 pts have received a total of 72 cycles: median age 62 (range 48–88); F:M = 10:18; ECOG 0:1:2 = 7;17:4; tumor types = colorectal (15), neuroendocrine (3), gastric (2), lung (2) and others (6); prior chemotherapy regimens 0:1:2:3+ = 5:1:6:16. The most frequent non-hematologic adverse events (AE) of at least possible attribution to SB939 were (% of pts with all grade/gr 3+): fatigue (46%/7%), nausea (29%/0%), anorexia (21%/4%), vomiting (18%/4%) and diarrhea (11%/0%). Hematologic AE were all mild to moderate. DLT occurrence is described below, with the 90 mg DL declared MTD. PK analysis showed dose-proportional increases in AUC and Cmax. Elimination half-life is 6–9 hours. PBMC analysis for acH3 (lysine9/14) showed highest levels at 3 hours post-dose with return to baseline by 24 hours. The average relative acH3 levels at 70 mg dose level in this study are comparable to those obtained at 60 mg dose level in another phase I study of SB939, which evaluates a different schedule of thrice weekly (every other day) for 3 out of 4 weeks. Four pts (14%) received 4 or more 4-week cycles of SB939 (range 6–10). Conclusions: SB939 is well tolerated at up to 70 mg on this schedule of 5 consecutive days every 2 weeks. The 70 mg DL is being expanded and will likely be the RP2D. Phase II trials in prostate cancer and sarcoma are planned. Dose level Schedule Total no of cycles No of pts with DLT/Total no of pts DLT Other significant toxicity 10 3 days 6 0/3 - - Q2W 10 5 days 16 1/6^ - - Q2W 20 5 days 18 1/6 Gr 3 - Q2W myositis 30 5 days 19 0/4 - - Q2W 50 5 days 6 0/4 - - Q2W 70 5 days 5 0/3 - - Q2W 90 5 days 2 1/2* Gr 3 2 gr 2 N/V Q2W fatigue 1 gr 2 QTc ^ gr 3 bilirubin rise subsequently declared not drug related * neither pt completed a full cycle Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A185.