Final results of a first-in-human phase I trial of PBI-05204, an inhibitor of AKT, FGF-2, NF-Kb, and p70S6K in advanced cancer patients

3023 Background: PBI-05204 (Oleandrin), a cardiac glycoside, inhibits the α-3 subunit Na-K ATPase pump. Relative expression of the α-3 subunit in tumor cells correlates with proliferation. Oleandrin inhibits FGF-2 export, activation of NF-Kβ, phosphorylation of Akt, p70S6K, decreasing mTOR activity. In this first-in-human study, we sought to determine the MTD/recommended phase II dose and to define the pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in advanced cancer patients (pts). Methods: Trial was a 3+3 phase I design. PBI-05240 was given for 21 of 28 days. Dose was increased by 100% if no related grade 2 adverse event (AE) emerged and increased by 50% if a grade 2 AE occurred. Blood samples were drawn for PK and drug-mediated changes in pAkt, p70S6K, and S6 (mTOR effectors) expression in peripheral blood mononuclear cells (PBMCs) for PD analysis. Results: 46 pts were dosed at 8 dose levels (DL) of PBI-05204 (0.6 to 10.2 mg/day). 2 dose-limiting toxicities occurred at DL 8 (grade 3 prote...