14061 Background: Oblimersen (OBL; Genasense®) is a phosphorothioate-modified antisense oligodeoxynucleotide (ODN) that down-regulates Bcl-2 and may enhance the response to chemotherapy in patients with melanoma and chronic lymphocytic leukemia (CLL). Extensive safety data for Genasense and other systemically administered ODNs have been obtained using low-dose continuous intravenous infusions (CIVI). However, this method is inconvenient and unsuitable for drug combinations that employ frequent or discontinuous dosing. We have now established that OBL can be effectively administered by high-dose, short IV infusions. Methods: We tested multiple treatment schedules of OBL, alone and in combination with paclitaxel, paclitaxel albumin nanoparticles, imatinib, sorafenib, sunitinib, and erlotinib against human tumor xenografts (melanoma A375, NSCLC A549 and H460, colon HT29 and SW620) grown in C.B-17/SCID mice. Results: Periodic OBL monotherapy (high dose IV Q2–3d) yielded consistently superior antitumor efficacy when compared with low- dose daily IV injections. These results have been obtained against all tumor models evaluated to date. This increased efficacy was also observed when OBL was combined with any other therapeutic agent. For combination treatments that included taxanes, efficacy was shown to be schedule dependent. Conclusions: These results, and recent clinical observations, suggest that brief high-dose IV infusions of OBL may significantly increase antitumor activity, and may obviate the need for CIVI. Brief high-dose IV infusions are being incorporated into ongoing clinical trials to evaluate the safety and efficacy of OBL in combination with other agents. No significant financial relationships to disclose.
Development of a Fully Human Anti-PDGFRβ Antibody That Suppresses Growth of Human Tumor Xenografts and Enhances Antitumor Activity of an Anti-VEGFR2 Antibody
