In vivo efficacy of gimatecan, a Novartis new topoisomerase 1 inhibitor alone or combined with RAD001, bevacizumab or erlotinib in breast, lung and ovary human cancer xenografts.

783 Gimatecan, a novel oral lipophilic camptothecin with a favorable pharmacology profile, is a promising anticancer agent currently in clinical development. Current studies focused on evaluating the antitumor activities of gimatecan as a single agent and in combination with bevacizumab, erlotinib and the mTOR inhibitor RAD001 in seven breast cancer, three NSCLC and one ovarian cancer murine xenograft models. We used a new xenograft model where primary tumors from cancer patients were directly transplanted into female Swiss nude mice. Drug effects were measured based on complete tumor regression with or without recurrence and in case of partial response, tumor growth inhibition (% TGI) and growth delay (TGD) leading to survival prolongation were measured. Gimatecan was orally administered via gavages at 0.32, 0.24, 0.16 and 0.12 mg/kg/day daily for 5 days per week for 4 weeks. In breast BC146 tumor bearing-nude mice, single agent gimatecan was well tolerated showing no deaths or weight loss at gimatecan doses below 0.48 mg/kg. Complete tumor regressions were observed at a low 0.03 mg/kg (10% of the highest dosage), without recurrence 90 days after the start of treatment. Anti-tumor activity was not observed with single agent bevacizumab and RAD001, but anti-tumor activity was restored when either agent was combined with gimatecan in BC146 line. In six other BC lines also showed high sensitivities to gimatecan, one being resistant to anthracycline and docetaxel based treatments. The squamous NSCLC IC1, resistant to platinum based therapy, and moderately sensitive to docetaxel, responded to gimatecan modestly and only at the highest dosage (72% of optimal TGI and TGD of 2-fold). The lung adenocarcinoma IC14, poorly sensitive to platinum based therapy and sensitive to docetaxel, responded to the 0.12 mg dosage, with a TGD of 4-fold and tumor regressions at the higher dosages. Gimatecan efficacy was not increased by combination with erlotinib, which did not reduced tumor growth as a single agent. Combination with RAD001 and bevacizumab are in course of test. The lung adenocarcinoma IC8 regressed significantly under gimatecan treatment. The ovarian model OVA2 displayed a high sensitivity to gimatecan, with complete regressions at the highest dosages and late recurrences at the two lowest dosages. Bevacizumab showed a modest efficacy and significantly reinforced the gimatecan antitumor effect with RAD001 giving similar results. Our first series of studies confirmed the high efficacy of gimatecan in 7/7 HBC, 2/3 NSCLC, ovary, retinoblastoma, pancreas tumor models, irrespective of their sensitivity or resistance to standard treatment and was well tolerated with the dosages and the protocol used.