Abstract

3021 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent inhibitor of class I PI3K and demonstrates broad activity in preclinical xenograft models. Methods: A 2-stage phase I study of GDC-0941 was initiated (GDC4254g). Stage 1 utilized a 3+3 escalation design in patients (pts) with advanced solid tumors. Stage 2 is an expansion phase including pts with multiple myeloma, PIK3CA mutant (mt) tumors, and tumors evaluable by magnetic resonance imaging (MRI) methods. A single dose of GDC-0941 was administered followed by a 1-week washout and then QD dosing on a 21/28- or 28/28-day dose schedule. Objectives include: safety, pharmacokinetics, pharmacodynamic (PD) endpoints in tumor and platelet rich plasma (PRP); evaluating the use of imaging modalities (FDG-PET and functional MRI studies); and examining any relationship of PIK3CA mt status and PTEN expression and clinical activity. Results: Stage 1 has been completed with 42 pts enrolled in 11 cohorts (15-450 mg QD, 21/28-day schedule). Drug-related adverse events (AEs) reported in ≥ 10% of pts were nausea, diarrhea, fatigue, vomiting, dysgeusia, and decreased appetite. The MTD was exceeded at 450 mg with DLT of Grade (Gr) 3 maculopapular rash in 2 pts. Other drug-related AEs ≥ Gr 3 have been Gr 3 fatigue at 450 mg, Gr 3 neutropenia at 330 mg, and Gr 4 hyperglycemia at 130 mg. GDC-0941 displays dose-proportional PK. Decreased levels of pAKT in PRP correlated with GDC-0941 plasma concentrations. Signs of clinical activity include a partial response by RECIST in a pt with melanoma (V600E RAF mt) treated at 330 mg on-study for > 9 mo; a small bowel GIST (cKIT exon 9 mt) pt treated at 450 mg with 49% decrease by FDG-PET on-study for >7 mo; and an ovarian cancer (PTEN negative) pt treated at 100 mg with 30% decrease by FDG-PET, 56% decrease in pS6 staining in paired biopsies, and 80% decrease in CA-125 who was on study for ~5 months. Conclusions: GDC-0941 is generally well tolerated below 450 mg QD with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. The potential phase II dose is under evaluation.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.