3099 Background: OSI-906 is an oral inhibitor of IGF-1R and IR. Increased IGF-1R and IR activity is observed in human cancers and implicated in resistance to chemotherapy. In preclinical studies, OSI-906 blocked IGF-1R/IR-AKT pathway activity evoked by PAC treatment. This is the first study that combines OSI-906 with a cytotoxic agent.
METHODS
Patients (pts) with advanced solid tumors received weekly (qw) IV PAC (80 mg/m2) with intermittent OSI-906 (Arm A, d1-3q7d) or continuous OSI-906 (Arm B, BID d1-21). The primary objective was to determine the maximum tolerated dose (MTD) of OSI-906 + PAC using a standard 3x3 phase I design.
RESULTS
55 pts were treated (46F:9M, median age 57 yrs). OSI-906 doses of 300 mg to 600 mg QD d1-3q7d in Arm A and 75mg to 150 mg BID in Arm B were explored. Dose-limiting toxicities in Arm A (450mg QD, n=9) were grade G3 neutropenia, G2 neuropathy and G3 deep vein thrombosis (DVT), and in Arm B (150mg BID, n=11) were G3 hyperglycemia, G3 fatigue and G4 pulmonary embolism (PE). DVT and PE were reported as unrelated to OSI-906. Complete adverse event data are available on 46 pts. Most common drug-related toxicities were (any grade; grade 3): fatigue (54%; 15%), nausea (48%; 0%), alopecia (41%; 0%), diarrhea (35%; 7%), rash (30%; 2%), neuropathy (26%; 2%) and dysgeusia (24%; 0%). Median treatment duration was 11 weeks (range 1-68 wks); 11 pts (21%) were on study for ≥24 wks, and 11 pts are ongoing. In pts with ovarian cancer (n=29), 5 had partial response and 11 had stable disease. Preliminary PK results suggest no relevant PK interaction when OSI-906 administered 2 hours prior to PAC.
CONCLUSIONS
OSI-906 + PAC was well tolerated at doses up to the single agent MTDs. A phase II study of OSI-906 + PAC in pts with ovarian cancer is planned.