Preclinical Efficacy of Campthothecin-Polymer Conjugate (IT-101) in Human Burkitt Lymphoma Bearing Mice.

First line combination chemotherapy can result in long-term disease-free survival (DFS) in 65–90% of patients with Burkitt lymphoma (BL) depending on prognostic factors at presentation. However, only a small number of patients with relapsed/refractory diseases can achieve long-term DFS after the high-dose therapy and hematopoietic stem cell rescue. Irinotecan (CPT-11) and topotecan, two analogues of campthothecin (CPT), have been successfully used alone or in combination with other cytotoxic agents as salvage treatments for patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) other than BL. A disadvantage of CPT-11 and topotecan observed in early clinical trials was a high incidence of treatment-related toxicity (TRT). IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclodextrin-based polymer, has recently been developed to minimize TRT and increase anti-tumor activity. To evaluate preclinical efficacy and toxicity of IT-101, we conducted an in vivo study in nude mice bearing subcutaneous xenografts from human BL-derived Daudi cell line stably transfected with plasmid DNA containing firefly luciferase (ffluc) reporter gene. The tumor-derived ffluc activity was evaluated in vivo using an IVIS 100 imaging system (Xenogen); background ffluc luminescence was defined as ≤10⁶ p/sec/cm²/sr. Ten days after subcutaneous tumor injection, 42 nude mice with tumor-derived ffluc activity of >10⁸ p/sec/cm²/sr were allocated into six different treatment groups as followings: Group 1 (no therapy); Group 2 (CPT-11 100mg/kg, ip, qwk × 3); Group 3 (IT-101 5mg/kg, iv, qwk × 3); Group 4 (IT-101 10mg/kg, iv, qwk × 3); Group 5 (IT-101 15mg/kg, iv, qwk × 2); and Group 6 (IT-101 single dose of 15mg/kg, iv). The average tumor-derived ffluc activity among all of the treatment groups was equally distributed. Tumor burden was monitored weekly by tumor-derived ffluc activity and physical tumor measurements. After completion of the treatment, there were two treatment-related deaths (TRDs; body weight loss >20%) and one non-TRD in group 5 and 6, respectively. At the 3^rd week after starting therapy, all treatment groups that received two or three weekly doses of IT-101 (Groups 3, 4, and 5) had 100% complete tumor regression (CTR), determined by ffluc activity (<10⁶ p/sec/cm²/sr) and remained tumor free at 90 days post-therapy. In contrast, 57% (4/7) of mice in Group 2 and 83% (5/6) of mice in Group 6 had initial CTR but all had tumor re-growth by day 69. These results demonstrate that a single dose of IT-101 at 15mg/kg is not sufficiently efficacious while two weekly doses of IT-101 at 15mg/kg are associated with unacceptable toxicity. However, we are able to demonstrate that the three weekly doses of IT-101 at 5 or 10mg/kg are well tolerated and can produce superior anti-tumor activity against Daudi cell line as compared with CPT-11.