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<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 vivo

TreatmentXenograft modelScheduleDayInhibition vs vehicle control (%)P value
Cediranib + targeted agents 
Cediranib + saracatinib Calu-6 (lung) Cediranib 3 mg/kg/day po 28 61 <0.001* 
Saracatinib 50 mg/kg/day po 28 50 <0.001* 
Concurrent 28 76 <0.001†‡ 
Cediranib + AZD6244 Calu-6 (lung) Cediranib 1.5 mg/kg/day po 24 50 <0.0005* 
AZD6244 3 mg/kg twice daily po (starting on day 10) 24 50 <0.0005* 
Concurrent 24 77 <0.0005*; <0.005†‡ 
Cediranib + cytotoxic agents 
Cediranib + 5-FU LS174T (colorectal) Cediranib 3 mg/kg/day po 15 79 <0.001* 
5-FU 50 mg/kg iv weekly 15 20 NS* 
Concurrent 15 92 <0.05†; <0.001*‡ 
Cediranib + docetaxel MX-1 (breast) Cediranib 3 mg/kg/day po 21 68 <0.001* 
Docetaxel 10 mg/kg iv weekly 21 >100 <0.001* 
Concurrent 21 >100 <0.001*†‡ 
Cediranib + cisplatin Calu-6 (lung) Cediranib 1.5 mg/kg/day po 22 43 <0.001* 
Cisplatin 3 mg/kg iv weekly 22 53 <0.001* 
Concurrent 22 62 0.0012†; 0.053‡ 
Cediranib + oxaliplatin LS174T (colorectal) Cediranib 1.5 mg/kg/day po 12 57 <0.001* 
Oxaliplatin 7.5 mg/kg iv weekly 12 8 NS* 
Concurrent 12 72 <0.05†; <0.001‡ 
Cediranib + gemcitabine Calu-6 (lung) Cediranib 3 mg/kg/day po 24 71 <0.001* 
Gemcitabine 75 mg/kg ip twice weekly 24 80 <0.001* 
Concurrent 24 98 <0.001†; <0.001‡ 
Cediranib + pemetrexed MX-1 (breast) Cediranib 1.5 mg/kg/day po 22 51 <0.05* 
Pemetrexed 75 mg/kg/day po (5 days on, 2 days off, 5 days on, 8 days off) 22 49 <0.05* 
Concurrent 22 81 <0.005*; <0.05†‡ 
Cediranib + irinotecan LS174T (colorectal) Cediranib 3 mg/kg/day po 15 77 <0.001* 
Irinotecan 25 mg/kg/day weekly 15 35 <0.01* 
Concurrent 15 98 <0.001*†‡ 
TreatmentXenograft modelScheduleDayInhibition vs vehicle control (%)P value
Cediranib + targeted agents 
Cediranib + saracatinib Calu-6 (lung) Cediranib 3 mg/kg/day po 28 61 <0.001* 
Saracatinib 50 mg/kg/day po 28 50 <0.001* 
Concurrent 28 76 <0.001†‡ 
Cediranib + AZD6244 Calu-6 (lung) Cediranib 1.5 mg/kg/day po 24 50 <0.0005* 
AZD6244 3 mg/kg twice daily po (starting on day 10) 24 50 <0.0005* 
Concurrent 24 77 <0.0005*; <0.005†‡ 
Cediranib + cytotoxic agents 
Cediranib + 5-FU LS174T (colorectal) Cediranib 3 mg/kg/day po 15 79 <0.001* 
5-FU 50 mg/kg iv weekly 15 20 NS* 
Concurrent 15 92 <0.05†; <0.001*‡ 
Cediranib + docetaxel MX-1 (breast) Cediranib 3 mg/kg/day po 21 68 <0.001* 
Docetaxel 10 mg/kg iv weekly 21 >100 <0.001* 
Concurrent 21 >100 <0.001*†‡ 
Cediranib + cisplatin Calu-6 (lung) Cediranib 1.5 mg/kg/day po 22 43 <0.001* 
Cisplatin 3 mg/kg iv weekly 22 53 <0.001* 
Concurrent 22 62 0.0012†; 0.053‡ 
Cediranib + oxaliplatin LS174T (colorectal) Cediranib 1.5 mg/kg/day po 12 57 <0.001* 
Oxaliplatin 7.5 mg/kg iv weekly 12 8 NS* 
Concurrent 12 72 <0.05†; <0.001‡ 
Cediranib + gemcitabine Calu-6 (lung) Cediranib 3 mg/kg/day po 24 71 <0.001* 
Gemcitabine 75 mg/kg ip twice weekly 24 80 <0.001* 
Concurrent 24 98 <0.001†; <0.001‡ 
Cediranib + pemetrexed MX-1 (breast) Cediranib 1.5 mg/kg/day po 22 51 <0.05* 
Pemetrexed 75 mg/kg/day po (5 days on, 2 days off, 5 days on, 8 days off) 22 49 <0.05* 
Concurrent 22 81 <0.005*; <0.05†‡ 
Cediranib + irinotecan LS174T (colorectal) Cediranib 3 mg/kg/day po 15 77 <0.001* 
Irinotecan 25 mg/kg/day weekly 15 35 <0.01* 
Concurrent 15 98 <0.001*†‡ 

NS, not significant

*compared with vehicle control; †compared with cediranib alone; ‡compared with antitumor therapy alone

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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.

©2010 American Association for Cancer Research
2010