Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial
Michael D. Hogarty, David S. Ziegler, Andrea Franson, Yueh‐Yun Chi, Denice Tsao‐Wei, Kangning Liu, Rohan Vemu, Eugene W. Gerner, Elizabeth Bruckheimer, Anasheh Shamirian, Beth Hasenauer, Frank M. Balis, Susan Groshen, Murray D. Norris, Michelle Haber, Julie R. Park, Katherine K. Matthay, Araz Marachelian
Abstract
Abstract Background MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan. Methods Patients 2–30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m 2 /day, with celecoxib (500 mg/m 2 daily), cyclophosphamide (250 mg/m 2 /day) and topotecan (0.75 mg/m 2 /day) IV for 5 days, for up to one year with G-CSF support. Results Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m 2 /day. Conclusion High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].