Abstract 1372: Cediranib alone and in combination with mechanistically distinct antitumor therapies in vivo
Authors: Juliane M. Jürgensmeier, Jane Kendrew, Rajesh Odedra, Armelle Logie, Philippa Wood, Paula Valentine, Sharon Barnett, Robert W. Wilkinson, Donald J. Ogilvie, Paul Elvin, Paul Smith, Anderson Ryan, Stephen R. Wedge
Journal: Cancer Research (2010)

Abstract Cediranib (RECENTIN™) is a highly potent vascular endothelial growth factor (VEGF) signaling inhibitor of all three VEGF receptors that is suitable for once-daily oral dosing. Cediranib is currently in Phase III development in first-line colorectal cancer and recurrent glioblastoma. Work is ongoing to determine its potential utility in a range of other tumors including lung cancer. The aim of these preclinical studies was to examine the effect of combining cediranib with the following mechanistically distinct antitumor therapies: saracatinib (AZD0530; Src inhibitor), AZD6244 (MEK 1/2 inhibitor), 5-fluorouracil (5-FU), docetaxel, cisplatin, oxaliplatin, gemcitabine, pemetrexed and irinotecan. Details of the combination dosing schedules and xenograft models are provided in Table 1. Tumor cells grown in vitro were injected subcutaneously into the dorsal flank of female athymic mice (Swiss nu/nu genotype, ≥6 weeks of age). Mice were randomized into treatment groups (9-15 per group) once the mean tumor volume reached ∼200 mm3. When cediranib was dosed with parenterally administered agents, cediranib administration preceded that of the parenteral therapy by 2 hours. Antitumor effects were assessed by comparing mean tumor size at the end of the dosing period (12-28 days, depending on the model; Table 1) and significance was determined using the t-test (P&amp;lt;0.05). An overview of the results is presented in the Table. Combination therapy was well tolerated; the mean body weight loss at the end of each study was ≤10% of the pre-treatment weight. These data suggest cediranib can be combined with certain chemotherapeutic and targeted agents in preclinical models. The effects of the combination treatments were greater than those of the monotherapy treatments.Table 1.Cediranib alone and in combination with other antitumor therapies in vivoTreatmentXenograft modelScheduleDayInhibition vs vehicle control (%)P valueCediranib + targeted agentsCediranib + saracatinibCalu-6 (lung)Cediranib 3 mg/kg/day po2861&amp;lt;0.001*Saracatinib 50 mg/kg/day po2850&amp;lt;0.001*Concurrent2876&amp;lt;0.001†‡Cediranib + AZD6244Calu-6 (lung)Cediranib 1.5 mg/kg/day po2450&amp;lt;0.0005*AZD6244 3 mg/kg twice daily po (starting on day 10)2450&amp;lt;0.0005*Concurrent2477&amp;lt;0.0005*; &amp;lt;0.005†‡Cediranib + cytotoxic agentsCediranib + 5-FULS174T (colorectal)Cediranib 3 mg/kg/day po1579&amp;lt;0.001*5-FU 50 mg/kg iv weekly1520NS*Concurrent1592&amp;lt;0.05†; &amp;lt;0.001*‡Cediranib + docetaxelMX-1 (breast)Cediranib 3 mg/kg/day po2168&amp;lt;0.001*Docetaxel 10 mg/kg iv weekly21&amp;gt;100&amp;lt;0.001*Concurrent21&amp;gt;100&amp;lt;0.001*†‡Cediranib + cisplatinCalu-6 (lung)Cediranib 1.5 mg/kg/day po2243&amp;lt;0.001*Cisplatin 3 mg/kg iv weekly2253&amp;lt;0.001*Concurrent22620.0012†; 0.053‡Cediranib + oxaliplatinLS174T (colorectal)Cediranib 1.5 mg/kg/day po1257&amp;lt;0.001*Oxaliplatin 7.5 mg/kg iv weekly128NS*Concurrent1272&amp;lt;0.05†; &amp;lt;0.001‡Cediranib + gemcitabineCalu-6 (lung)Cediranib 3 mg/kg/day po2471&amp;lt;0.001*Gemcitabine 75 mg/kg ip twice weekly2480&amp;lt;0.001*Concurrent2498&amp;lt;0.001†; &amp;lt;0.001‡Cediranib + pemetrexedMX-1 (breast)Cediranib 1.5 mg/kg/day po2251&amp;lt;0.05*Pemetrexed 75 mg/kg/day po (5 days on, 2 days off, 5 days on, 8 days off)2249&amp;lt;0.05*Concurrent2281&amp;lt;0.005*; &amp;lt;0.05†‡Cediranib + irinotecanLS174T (colorectal)Cediranib 3 mg/kg/day po1577&amp;lt;0.001*Irinotecan 25 mg/kg/day weekly1535&amp;lt;0.01*Concurrent1598&amp;lt;0.001*†‡NS, not significant*compared with vehicle control; †compared with cediranib alone; ‡compared with antitumor therapy alone Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1372.