3003 Background: GSK795 is a potent pan-isoform inhibitor of AKT. The objectives were to define the maximum tolerated dose (MTD), and to evaluate the PK, PD and clinical activity of GSK795 in patients (pts) with advanced solid tumors.
METHODS
GSK795 was given orally, once daily (QD) in this two-part study of dose-escalation (Part 1) with expansion (Part 2) at the MTD in selected tumor types to evaluate the clinical activity. Alternative dosing schedules were also investigated.
RESULTS
Preliminary data are available for 66 pts that received ≥ 1 dose of GSK795, including pts with endometrial (12) and prostate cancer (9) as well as other tumor types selected for either PTEN loss or PIK3CA mutation (7). Doses explored were 10, 20, 40, 75, 100 and 150mg QD. The MTD was 75 mg QD. Dose-limiting toxicities were G3 hyperglycemia (n=2), G4 hypoglycemia (n=1), G3 hypoglycemia (n=1), and G2 stomatitis (n=1); all were reversible. The most common (>10%) drug-related adverse events were diarrhea (47%; G3/4 0%), nausea (33%; G3/4 0%), fatigue (26%; G3/4 0%), vomiting (18%; G3/4 0%), decreased appetite (15%; G3/4 0%), dyspepsia (15%; G3/4 0%), hyperglycemia (15%; G3/4 11%), and rash (15%; G3/4 3%). AUC (0-24) and Cmax generally increased in a dose-proportional manner. Median Tmax was 2 to 3 hr and the effective t½ ranged from 2.0 to 5.5 days. 6/7 pts dosed at ≥75mg QD given a carbohydrate challenge at baseline and steady state exhibited either increased post-prandial glucose values, or a delay in the return to baseline of post-prandial values, suggesting a PD effect of GSK795 on glucose. One pt with anal cancer (PIK3CA and PTEN status unknown) had a partial response. 5/ 12 evaluable endometrial pts are still on trial; 2 of these pts with PIK3CA mutation and/or PTEN loss have had stable disease (↓25% and 0%) for ≥ 6 months. 6/ 9 evaluable prostate pts are still on trial; 2 of these pts with partial or complete PTEN loss have had SD (bone only disease) ≥ 6 months.
CONCLUSIONS
The AKT inhibitor GSK795 has been well tolerated with reversible, predictable toxicities and PD evidence of target inhibition. Tumor decreases and SD ≥ 6 months has been observed in pts with an activated PI3K/AKT pathway.