Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

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/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/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/m2/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].

• Authors: 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
• Journal: British journal of cancer (Br J Cancer) Vol. 130 Issue 5 Pg. 788-797 (Mar 2024) ISSN: 1532-1827 [Electronic] England
• PMID: 38200233 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2024. The Author(s).

Chemical References

• Celecoxib
• Cyclophosphamide
• Topotecan

Topics

• Child
• Humans
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Celecoxib (therapeutic use)
• Cyclophosphamide (therapeutic use)
• Neoplasm Recurrence, Local (drug therapy)
• Neuroblastoma (drug therapy, genetics)
• Topotecan (therapeutic use)
• Child, Preschool
• Adolescent
• Young Adult
• Adult