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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 proteinuria,fatigue) thus the MTD was DL7. Most common AEs were fatigue (56.1%), abdominal pain (41.5%), constipation (41.5%), nausea (41.5%), and diarrhea (39.0%). Cardiac disorders were reported in 10 pts (24.4%), all grade 1, except for 1 pt with grade 2 SVT. Of the 45 evaluable pts, 7 had stable disease for > 4 months, with bladder, colorectal, fallopian tube, breast, appendecal and pancreatic carcinoma (2 pts). Dose dependent mean peak concentrations as high as 2 ng/mL were achieved. Mean AUC: 5 - 36 μg/L*hr across DLs with a half-life range of 6-14 hrs. Western blot analysis of PBMCs showed markedly reduced phosphorylation of Akt, p70S6K, and S6 in a time dependent manner in 7 pts (1 at DL 2, 3, 1 at DL 5 and 2 at DL 6). Reduction of these effectors was concomitant with higher levels of Na, K-ATPase aƒ{3 subunit expression. In these pts, results of proteomic array analysis showed other oncogenic pathways-NFkB, VEGF and STAT5 were down regulated after 21 days on study.


CONCLUSIONS
PBI-05204 is well tolerated up to 10.2/mg/day with very little AEs or cardiotoxicity. Initial PD analysis suggesting target effect.