Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors.

Abstract

BACKGROUND:

EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors.

PROCEDURE:

EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2) ). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination.

RESULTS:

Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2) . At dose levels above 16 mg/m(2) , Grade ≥3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2) . Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for ≥8 cycles.

CONCLUSIONS:

EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma.

• Authors: Robin E Norris, Suzanne Shusterman, Lia Gore, Jodi A Muscal, Margaret E Macy, Elizabeth Fox, Noah Berkowitz, Aby Buchbinder, Rochelle Bagatell
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 61 Issue 10 Pg. 1792-7 (Oct 2014) ISSN: 1545-5017 [Electronic] United States
• PMID: 24962521 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• EZN-2208
• Polyethylene Glycols
• Camptothecin

Topics

• Adolescent
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Neoplasm Recurrence, Local (drug therapy)
• Neoplasms (drug therapy)
• Polyethylene Glycols (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Young Adult