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3098^ Background: OSI-906 is an oral inhibitor of IGF-1R and IR tyrosine kinases. IGF-1R:EGFR cross-talk contributes to resistance to agents targeting either pathway, supporting trials of dual receptor inhibition. METHODS: Sequential cohorts received escalating doses of OSI-906 + E (100 or 150 mg/d). Objectives included MTD determination, safety, response and PK/PD. Three dosing schedules (S) were investigated; S1: intermittent OSI-906 QD 1-3 q7 d at 50-600 mg + E; S2: continuous OSI-906 QD at 50-400 mg + E; and S3: continuous BID OSI-906 at 100 and 150 mg + E. RESULTS: To date, 94 pts have been enrolled (47 M/47 F, median age 61 yrs) and 90 treated, with toxicity data in 79. In S1 (n=40) DLTs were G4 ALT/AST and G3 hyperglycemia in 2 pts at OSI-906 600 mg + E 100 mg; G3 ALT/AST in 1 pt at 450+100 mg; and G3 hyperglycemia, and G3 QTc prolongation in 2 pts at 450+150 mg. Evaluation at 400+150 mg is ongoing. DLTs in S2 (n=24) were asymptomatic G3 QTc prolongation in 2 pts at 400+100 mg. DLT in S3 (n=12) was G3 anorexia at 150+150 mg. Transient G1-2 hyperglycemia (53 pts, 67%) and hyperinsulinemia (15 pts, 19%) were consistent with IR inhibition. QTc prolongation related to OSI-906 was reported in 6 pts (8%). E-related skin changes occurred in 51 (65%) pts, with rash in 62% pts, pruritus and dry skin in 23% each. Other therapy-related AEs were diarrhea (56%), fatigue (49%), nausea (44%), anorexia (22%), and vomiting (20%). PK data show no substantial drug-drug interaction. PD effects of OSI-906 were observed after co-administration with E. Four pts had partial response: 1 pt at S2 50+100 mg (spinal chordoma), 2 at S1 450+150 mg (NSCLC, anal cancer) and 1 pt at S3 150+150 mg (NSCLC). Stable disease (SD) 12+ weeks was seen in 17/71 pts (24%), of whom 4/33 (12%) were on intermittent (S1) and 13/38 (34%) on continuous (S2 and S3) OSI-906. CONCLUSIONS: OSI-906 and E are well-tolerated and associated with prolonged SD and tumor regression. MTD and recommended phase II dose/schedule was determined as S3 OSI-906 150 mg BID + E 150 mg QD. A NSCLC expansion cohort (14 pts) is evaluating exploratory biomarkers, and additional NSCLC studies are ongoing with this combination.

Type

Journal article

Journal

J Clin Oncol

Publication Date

20/05/2011

Volume

29