A phase I study of rebeccamycin analog in combination with oxaliplatin in patients with refractory solid tumors

Abstract

Summary Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1–5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m2/d for five days along with oxaliplatin 130 mg/m2 on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.

Chemistry and Properties of Indolocarbazoles

“…148 In a phase I study in patients with refractory solid tumors, becatecarin in combination with oxaliplatin displayed some activity but not as a single agent. 149 Induction of single strand DNA-cleavage mediated by topoisomerase I has been observed for J-107088 (edotecarin, 138) a long time ago, accounting for its efficacy in an in vivo nude mouse model xenografted with various human cancer cell lines. 150 Further examples of the antitumor activity of 138 were demonstrated in a study involving pediatric and adult CNS tumor xenografts in athymic nude mice.…”

Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development

“…UCN-01 strongly inhibits CHK-1 ( ki = 5.6 nM), PDK-1 (IC 50 = 5.0 nM), and PKC β 37 (IC 50 = 10 nM) [ 142 – 144 ]. It also inhibits CDKs CDK-1 ( ki = 95 nM), CDK-2 ( ki = 30 nM), and CDK-4 ( ki = 3.6 µM), and isoforms of PKCs, with an IC 50 of less than 1 µM [ 289 – 291 ].…”

An Unusual Role for a Mobile Flavin in StaC-like Indolocarbazole Biosynthetic Enzymes

“…Isolated from Streptomyces and other soil- and marine-dwelling actinomycete bacteria (Jensen et al, 2007; Sánchez et al, 2006), staurosporine (Figure 1A) has no assigned native function but has proven to be a potent protein kinase inhibitor (Ruegg and Burgess, 1989) with an analog (7-hydroxy-staurosporine, also known as UCN-01) in clinical trials as an anti-cancer agent (Edelman et al, 2007; Jimeno et al, 2008; Welch et al, 2007). Rebeccamycin (Figure 1A), isolated from Lechevalieria aerocolonigenes , shares a very similar aglycone scaffold with staurosporine and an analog of this compound, becatecarin, is also in clinical trails afforded by its antitumor activity (Dowlati et al, 2009; Nock et al, 2011). However, unlike staurosporine, rebeccamycin analogs inhibit DNA replication by stabilizing DNA-topoisomerase I complexes (Bailly et al, 1997), showing the therapeutic diversity of indolocarbazole compounds.…”