A first-in-human phase I trial of PBI-05204 (oleandrin), an inhibitor of Akt, FGF-2, NF-Kb, and p70S6K in advanced solid tumor patients

3537 Background: PBI-05204 contains oleandrin, a cardiac glycoside, which inhibits the α-3 subunit Na-K ATPase pump. Over-expression of the α-3 subunit in malignant cells correlates with the tumor proliferation. Oleandrin inhibits FGF- 2 export and activation of NF-Kβ and inhibits phosphorylation of Akt. PBI-05204 also inhibits p70S6K, decreasing mTOR activity. In this ongoing study of PBI-05204, we sought to determine the DLTs, MTD and recommended phase II dose in advanced solid tumors patients (pts) and to characterize its’ pharmacokinetics (PK) and pharmacodynamics (PD). Methods: This was a standard 3+3 phase I design. PBI-05240 was given orally for 21 days of 28 days. Dose was increased by 100% if no related grade 2 adverse event (AE) was observed and increased by 50% if a grade 2 AE occurred. If no other grade 2 AE were observed then subsequent dose escalation was resumed at 100%. In order to determine drug-mediated changes in pAkt, p70S6K, and S6 (mTOR effectors) expression as a surrogate marker of target effect, peripheral blood mononuclear cells (PBMCs) were obtained in addition to PKs. Results: To date 15 pts have received PBI-05204 at 5 dose levels (0.6 mg to 10.2 mg/day), 2 pts are currently active at dose level 5. No DLT has been observed thus far. 10 out of 15 pts (67%) experienced only grade 1 AEs, most common: fatigue and constipation (20%). No significant cardiac toxicities have been observed, only first degree AV block and grade 2 PVC's. Of the 15 evaluable pts, 3 had stable disease for > 4 months, with bladder, colorectal, and fallopian tube cancer pts having an 11, 16, and 10% reduction by RECIST respectively. PKs initially show dose-dependent peak plasma oleandrin concentrations are reached at 2–4 hr following administration with > 50% cleared in 6 hrs. Western blots of PBMCs showed PBI-05204 markedly reduced phosphorylation of Akt, p70S6K, and S6 in a time dependent manner in 4 pts (1 at dose level 2, and 3 and 2 at dose level 5). Reduction of these effectors was observed concomitantly with relatively higher levels of Na, K-ATPase α-3 subunit expression. Conclusions: PBI-05204 is tolerated up to 10.2/mg/day with very little AE's or cardiotoxicity. Initial response evaluation shows activity in diverse tumors with PD analysis suggesting target effect. [Table: see text]