Phase 1 study of XL119, a rebeccamycin analog, in patients with refractory hematologic malignancies

Rebeccamycin is an antitumor antibiotic produced by the actinomycete Saccharotrix aerocolonigenes. Rebeccamycin has activity against topoisomerase I by stabilizing the topoisomerase-DNA covalent complex.1–4 Rebeccamycin is also capable of intercalating DNA in absence of topoisomerase I. Because of the insolubility of rebeccamycin, semisynthetic and water-soluble derivatives of rebeccamycin have been created. XL119 (NSC 655,649) is such a compound that is different from rebeccamycin in its mechanism of action. In contrast to rebeccamycin, XL119 has no activity against topoisomerase I but strongly inhibits topoisomerase II.5 In contrast to topoisomerase II inhibition by both etoposide and teniposide, which stabilize cleaved DNA by inhibiting religation of the cleaved DNA strands, XL119 inhibits the catalytic step necessary for the passage of the intact DNA strand through the single-strand DNA break. This action leads to the formation of single, rather than double, DNA strand breaks. XL119 has antitumor activity against P388 leukemia, melanoma, reticulum cell sarcoma, lung and colon carcinoma cell lines, and solid tumor specimens obtained from children.6,7 Against etoposide resistant cell lines A 549 and HCT 116, the IC50 of XL119 has been 0.03 and 0.19 μM, respectively.8 Keeping in line with its better solubility, XL119 is more active than rebeccamycin in intraperitoneally implanted P388 murine leukemia model, confirming its distal site activity. Plasma concentrations achieved in prior phase 1 studies using an intravenous schedule have been consistently higher than the concentrations (range, 0.03–0.21 μg/mL) required for in vitro inhibition of topoisomerase II levels.9 Two phase 1 trials of XL119 in nonhematologic malignancies have explored different dosing schedules. In one, XL119 was given as a single dose every 3 weeks10 and the other study9 explored a dose schedule of 5 consecutive days every 3 weeks. Dose-dependent myelosuppression has been the dose-limiting toxicity (DLT) in both studies with minimal grade 3/4 nonhematologic toxicity. A third 2-step phase 1 study examined both the single-dose and multiple-dose format and has reported similar toxicities.11 Because XL119 has shown preclinical antileukemia activity in an intraperitoneally implanted leukemia model, topoisomerase II inhibitors have activity in hematologic malignancies and the putative mechanism of action differs from epipodophyllotoxins, a phase 1 study of XL119 in relapsed/refractory hematologic malignancies was initiated. Increased angiogenesis as evidenced by increased microvessel density in the bone marrow is seen in acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS).12 Levels of plasma vascular endothelial growth factor (VEGF), a surrogate marker for angiogenesis, have prognostic implications in AML.13,14 Thus, monitoring of VEGF levels during therapy of leukemias may have a potential for pharmacodynamic evaluation of activity of investigational agents. Most chemotherapeutic agents induce cell death by activating the mitochondrial pathway of apoptosis.15 Activation of terminal caspases like caspase-3 is the convergence point for different pathways of apoptosis. Thus, plasma caspase-3 activity can potentially provide pharmacodynamic information regarding induction of apoptosis by therapeutic agents. Herein we report the first phase 1 study of XL119 in hematologic malignancies. Because preclinical modeling suggested schedule dependency for this agent and no significant nonhematologic toxicity was noted with a 5-day schedule as compared with a 1-day schedule, daily times 5 days every 21 days was the schedule selected for this study. The results of correlative studies are also reported.