Final results of a phase I study evaluating the combination of linsitinib, a dual inhibitor of insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor (IR) with weekly paclitaxel (PAC) in patients (Pts) with advanced solid tumors.
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e13502 Background: Linsitinib (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, linsitinib blocked IGF-1R/IR-AKT pathway activity evoked by PAC treatment. This study combines linsitinib + a cytotoxic agent. Methods: Pts with advanced solid tumors received weekly IV PAC (80mg/m2) in 21-day cycles with intermittent linsitinib (Arm A, d1-3q7d) or continuous linsitinib (Arm B, B2 and B3, twice daily (BID) d1-21). The primary objective was to determine the maximum tolerated dose (MTD) of linsitinib + PAC using a standard 3+3 phase I design. Results: 58 pts were treated (49F:9M, median age 58 yrs). Linsitinib doses of 300mg to 600mg daily (QD) d1-3q7d in Arm A and 75mg to 150 mg BID in Arm B were evaluated. Dose limiting toxicities in Arm A (n=27) were grade G3 neutropenia, G2 neuropathy and G3 deep vein thrombosis (DVT), and in Arm B (n=31) were G3 hyperglycemia, G3 fatigue (n=2) and G4 pulmonary embolism (PE). DVT and PE were reported as unrelated to linsitinib. MTD: Arm A = 600mg QD d1-3q7d Arm B = 150mg BID. Most common drug-related toxicities in ≥20%were (any grade; G3): fatigue (60%; 15.5%), nausea (48%; 0%), alopecia (48%; 0%), diarrhea (36%; 5%), drug eruption (21%; 2%), neuropathy (26%; 2%) and dysgeusia (24%; 0%). The median duration of exposure (days) for Arm A was 64.5, 91.0, 132.0 and 159.5 for the 300mg, 400mg, 450mg and 600mg doses, respectively. In Arm B, median duration of exposure (days) was 232.0 and 87.5 for the 75mg and 150mg doses, respectively. Partial response was achieved in 6 pts (10%)-3 ovarian, 1 primary peritoneal, 1 endometrial, and 1 esophageal. Stable disease was achieved in 25 pts (43%) - 10 ovarian, 2 primary peritoneal, 1 endometrial, and 12 pts in other tumor types. Pharmacokinetic (PK) results suggested no substantial PK interaction when linsitinib was administered 2 hours prior to PAC. Conclusions: Linsitinib + PAC did not show any unexpected safety concerns given the known mechanism of action, at doses up to the single agent MTDs. Clinical trial information: NCT00889382.
