The topoisomerase I inhibitor gimatecan exhibits synergistic antitumor activity in combination with imatinib mesylate and everolimus against malignant glioma xenografts.

2073 Background: The novel oral lipophilic camptotecan gimatecan (ST1481; NVP-LBQ707) has shown antitumor activity against malignant glioma xenografts and synergistic effects with temozolomide (Vassal et al. Proceedings ASCO 2007). The present work evaluated gimatecan with tyrosine kinase inhibitor imatinib mesylate and mTOR inhibitor everolimus in glioma.,In vivo antitumor activity was evaluated against subcutaneous advanced stage IGRG121 and IGRG93 xenografts derived from primary malignant gliomas. Gimatecan 0.19 or 0.05 mg/kg/d was administered orally q5d/w x 4 weeks, imatinib 150 mg/kg/d q5d/w x 4 weeks, everolimus 5 mg/kg/d q3d/w.,In IGRG121, gimatecan 0.19 mg/kg resulted in 2 PR and 2 CR of 8 tumors, significant tumor growth delay (TGD) in median time to reach 5 times initial tumor volume of 46.6 days compared to controls (p<0.01; Kruskal-Wallis test) and a tumor log cell kill (LCK) of 5.8. Imatinib and everolimus were inactive with 1.4 and 3.3 days TGDs (p=ns). Imatinib and gimatecan achieved 100% tumor regressions (6 PR and 2 CR of 8 tumors), a TGD of 49.6 days (p<0.001) and a LCK of 6.2. The observed/estimated TGD ratio of 1.30 suggests the combination being synergistic. In contrast, gimatecan and everolimus resulted in 1 PR out of 6 tumors, TGD of 42.6 days (p<0.001), and LCK of 5.2, which was not superior to gimatecan alone. IGRG93 had been proven highly sensitive to gimatecan which at 0.05 mg/kg resulted in 5 PR and 2 CR out of 10 tumors, TGD of 32.5 days compared to controls (p<0.001) and LCK of 2.5. Although imatinib activity was limited in this PDGFRA gene amplified glioma (TGD 9.2 days (p=ns); LCK 0.1), its combination with gimatecan resulted in 8 CR of 8 tumors, TGD of >66.0 days (p<0.001), and LCK 5.4. The observed/estimated TGD ratio of 1.75 suggested the combination being highly synergistic. Similarly everolimus was inactive (TGD 6.6 days (p=ns); LCK 0.2), but administration with gimatecan resulted in 7 CR and 2 PR of 9 tumors, TGD of 57.8 days (p<0.001), LCK of 4.9 and an observed/estimated TGD ratio of 1.31.,Imatinib and everolimus potentiated antitumor activity of gimatecan against glioma xenografts suggesting their combination for the treatment of malignant glioma. [Table: see text].