2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.
Phase IB Dose-Escalation Study of BEZ235 or BKM120 in Combination with Paclitaxel (PTX) in Patients With Advanced Solid Tumors
