A novel targeted oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor and its implications for patients with non-small cell lung cancer (NSCLC): A phase I clinical trial.

Abstract

7539 Background: The small-molecule IGF-1R inhibitor picropodophyllin (PPP) is the active compound in the oral suspension AXL1717. PPP has shown extensive preclinical antitumor effects against a wide range of cancers supporting its use as a single agent treatment. Methods: The clinical phase Ia/b study on advanced progressive cancer patients with various solid tumors and without remaining treatment options aimed at establishing the recommended phase II dose (RPTD) and the maximum tolerated dose (MTD) of AXL1717. Phase Ia consisted of single day dosing and phase Ib multiday dosing (to an accumulated total of 28 days of treatment; 2*28 days following amendment) with 3 weeks intermission between treatments. Non-progressing patients could continue treatment in the extension study without time limitation (treated 119 weeks). PK samples were obtained at 10 different time-points after the morning dose when appropriate. Results: Phase Ia included 16 patients treated with 78 BID doses ranging from 5-2900 mg AXL1717 BID without any dose-limiting toxicity. Phase Ib included 39 patients treated with doses between 290-930 mg BID in periods between 7-28 days, totally for 147 weeks. Phase Ib showed that AXL1717 was well tolerated and neutropenia was the only detected dose-related, reversible, dose-limiting toxicity (DLT). RPTD dose was set at 390 mg BID to minimize neutropenia. Although the study was not designed for efficacy assessment, some patients, mainly with NSCLC, showed signs of clinical benefit, including 3 partial responses and 12 patients with stable disease. The 15 patients with NSCLC and treatment duration of more than 2 weeks with single agent AXL1717 in 3rd or 4th line showed a median time to progression of 31 weeks and a survival time of 60 weeks with 4 patients being alive at cut-off. Down-regulation of IGF-1R on granulocytes and increases of serum IGF-1 were seen. The systemic exposure of AXL1717 was dose-dependent and sufficient for antitumor effects. Conclusions: AXL1717 has a good safety profile and demonstrated promising clinical benefits in this severely ill and heavily pretreated patient cohort, especially in patients with NSCLC.