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Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: The RAS/RAF/MEK and PI3K/AKT signaling pathways are both 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 alone when these agents are dosed either 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 combination dosing of GDC-0973 and GDC-0941. Pts received once daily (QD) GDC-0973 + GDC-0941 on a 21 day on/7 day off (21/7) schedule or intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 QD on a 21/7 schedule. Initial doses were 20 mg GDC-0973 + 80 mg GDC-0941 on 21/7 schedule; 100 mg GDC-0973 + 130 mg GDC-0941 on intermittent schedule. Serial plasma PK samples, FDG-PET and CT scans were obtained. Results: 30 pts have enrolled - 27 pts in 6 cohorts on 21/7 schedule; 3 pts on intermittent schedule. DLTs were grade 3 lipase (n=1) and grade 4 CPK elevation (n=1). Adverse events related to study drug combination were diarrhea (90%; all G1/2), fatigue (61%; 50% G1/2, 11% G3), nausea (61%; all G1/2), rash (50%; 45% G1/2, 5% G3), vomiting (33%; all G1/2), decreased appetite (17%; all G1/2), and dysgeusia (17%; all G1/2). Preliminary analysis indicates PK of GDC-0973 or GDC-0941 are not altered when dosed in combination. 6 of 15 pts had an FDG-PET partial metabolic response at one or more timepoints. Decreases in RECIST measurable target lesions were seen in 5 pts: 2 with melanoma (-75%; -27%), 1 prostate cancer (-21%), and 2 NSCLC (-18%; -13%). 3 pts had prolonged stable disease > 6 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 I trials. There are early signs of anti-tumor activity. Dose escalation on both schedules continues and updated data will be presented.
Abstracts by G. Shapiro:
A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.Meeting: 2013 ASCO Annual Meeting | Abstract No: 2500
A phase I, dose-escalation, safety, pharmacokinetic, pharmacodynamic study of thioureidobutyronitrile, a novel p53 targeted therapy, in patients with advanced solid tumors.Meeting: 2013 ASCO Annual Meeting | Abstract No: TPS2627
A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: Updated report.Meeting: 2011 ASCO Annual Meeting | Abstract No: 3051