A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. Material and methods. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. results and conclusion. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.
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.
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