Phase I study of OSI-906, dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) in combination with erlotinib (E) in patients with advanced solid tumors.
Macaulay VM., Middleton MR., Eckhardt SG., Juergens RA., Rudin CM., Manukyants A., Gogov S., Poondru S., Gedrich R., Gadgeel SM.
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.