Phase I dose-escalation study of EZN-2208 (PEG-SN38), a novel conjugate of poly(ethylene) glycol and SN38, administered weekly in patients with advanced cancer.

Abstract

PURPOSE:

This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38.

METHODS:

Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m(2).

RESULTS:

Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1-11). Twenty patients (49 %) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m(2) cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m(2) cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51 %), diarrhea (46 %), fatigue (41 %), alopecia (29 %), neutropenia (24 %), and vomiting (22 %). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged, was observed as best response.

CONCLUSIONS:

EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m(2).

• Authors: Amita Patnaik, Kyriakos P Papadopoulos, Anthony W Tolcher, Muralidhar Beeram, Saïk Urien, Larry J Schaaf, Sanaa Tahiri, Tanios Bekaii-Saab, François M Lokiec, Keyvan Rezaï, Aby Buchbinder
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 6 Pg. 1499-506 (Jun 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23543270 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

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

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Data Interpretation, Statistical
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Infusions, Intravenous
• Irinotecan
• Male
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Polyethylene Glycols (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Prodrugs (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome