Abstract B137: Pharmacokinetics and pharmacodynamic biomarkers for the dual PI3K/mTOR inhibitor GDC‐0980: Initial phase I evaluation

Background: The PI3K‐AKT‐mTOR signaling pathway is deregulated in a wide variety of cancers. GDC‐0980 is a potent, selective, dual inhibitor of class I PI3K and mTOR kinase with in vitro IC 50 of 4.8 nM for p110α/p85 and apparent Ki of 17.3 nM for human mTOR. GDC‐0980 potently inhibits tumor growth of xenografts and has demonstrated activity in preclinical models bearing PI3K mutant, PTEN‐null, K‐ras mutant, as well as PI3K pathway wild‐type tumors in vitro and in vivo . Methods: Two Phase I dose escalation studies were initiated using a 3+3 design in patients (pts) with solid tumors or non‐Hodgkin9s lymphoma who had progressed on, or were intolerant of, standard therapy. In study PIM4604g, GDC‐0980 is administered as a single oral dose followed by a 1‐week PK sampling period, and then administered daily (QD) on a 3‐week on/1‐week off schedule. Steady‐state PK is evaluated after 1 week of continuous dosing. A second trial, PIM4605g, evaluating a once weekly (QW) dosing of GDC‐0980 with a 4‐week cycle was also initiated with a focus on PD evaluation using mandatory tumor biopsies and imaging. Immunohistochemical assays for pS6 PD marker evaluation were developed for clinical evaluation of pre‐ and post‐dose tumor biopsies. Surrogate PD assays include an assessment of pAKT levels in platelet‐rich plasma (PRP) coinciding with PK evaluation in both studies and an evaluation of tumor biopsies for marker modulation in PIM4605g. Results: As of September 2009, a total of 15 patients have been treated in the two Phase I studies. Nine pts were treated in three successive cohorts of 2 mg, 4 mg, and 8 mg GDC‐0980 QD in PIM4604g, and 6 pts were treated in the first cohort with 6 mg GDC‐0980 QW in PIM4605g. GDC‐0980 has been generally well tolerated. There have been no dose‐limiting toxicities and no drug‐related Grade ≥ 3 events reported in either study. Preliminary PK data suggests that GDC‐0980 is rapidly absorbed with dose‐appropriate increases in Cmax and AUC under fasting conditions. Preliminary surrogate PD data show decreases in pAKT levels in PRP reflective of drug levels in plasma. Preliminary data from comparison of tumor biopsies obtained at baseline and following administration of GDC‐0980 demonstrate a > 50% decrease in pS6 staining by immunostaining consistent with downstream modulation of the PI3K pathway. Conclusions: GDC‐0980 is a potent, oral, dual PI3K/mTOR inhibitor with promising preclinical activity. No significant toxicities have been observed to date in these ongoing Phase I studies at exposures producing PD modulation in surrogate tissue and tumor. Favorable preliminary PK profiles have been observed at initial dose levels. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B137.