Phase I study of intermittent dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF- 1R) and insulin receptor (IR) in patients with advanced solid tumors.

Abstract

2530 Background: OSI-906 is a potent inhibitor of IGF-1R and IR tyrosine kinase activity. Increased IGF-1R activity is observed in human malignancies and implicated in resistance to chemotherapy. Methods: Patients (pt) with advanced solid tumors received escalating doses of OSI-906 in 3 intermittent dose schedules: (S1) days (d) 1-3 q14 d, (S2 - bridging cohort) d1-5 q14 d and (S3) d1-7 q14 d to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity for S1 and S3. Results: 61 pt have been treated (29M: 32F, median age 60 yrs). Cohorts dosed: S1:10-750 mg; S2: 450 mg; and S3: 450 and 600 mg. Seven dose-limiting toxicities (DLTs) were observed: 4 pt with fasting grade 3 hyperglycemia (2 pt at 600 mg S1, 750 mg S1, and 600 mg S3), grade 4 fatigue (600 mg S3), grade 3 QTc interval prolongation and grade 3 vomiting (both at 750 mg S1). Most common drug related toxicities (any grade; grade 3) were; nausea (21%; 8%), vomiting (17%; 7%) and diarrhea (11%; 0%). PK results indicate linear exposure of OSI-906 with median Tmax and t3/4 of 1-8 and 2-5 hours, respectively. Plasma OSI-906 concentrations above the predicted efficacious concentration (1μ M) were achieved at MTD. PD effects related to growth hormone and IGF-1R/IR axes were observed and were associated with higher plasma OSI-906 concentrations. Twenty-four pt (39%) had stable disease for ≥ 12 weeks (w) including heavily pretreated NSCLC (43 w duration) and extraskeletal myxoid chondrosarcoma (84+ w duration). Of 11 adrenocortical carcinoma (ACC) pt treated, 1 pt with metastatic disease had a durable partial response (73% reduction by RECIST) of 64+ w duration, and 4 pt have stable disease at 12 w. Five ACC pts continue on study. Conclusions: MTD has been established in S1 and S3 at 600 mg QD. OSI 906 was well tolerated at doses up to MTD, and demonstrated dose proportional PK. PK and PD data indicate that OSI-906 concentrations sufficient for modulation of GH-IGF1 signaling axis were achieved. Preliminary antitumor activity was seen, particularly in ACC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI OSI Genentech, OSI Genentech, OSI