Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors

Abstract

3544 Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5 hr; AUC0-∞ 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses > 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for > 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues. [Table: see text]