Investigational New Drugs

, Volume 29, Issue 2, pp 340–346

A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer

  • Qing Zhou
  • Daniel Gustafson
  • Sujatha Nallapareddy
  • Sami Diab
  • Stephen Leong
  • Karl Lewis
  • Lia Gore
  • Wells A. Messersmith
  • Anthony M. Treston
  • S. Gail Eckhardt
  • Carolyn Sidor
  • D. Ross Camidge
PHASE I STUDIES

DOI: 10.1007/s10637-009-9383-9

Cite this article as:
Zhou, Q., Gustafson, D., Nallapareddy, S. et al. Invest New Drugs (2011) 29: 340. doi:10.1007/s10637-009-9383-9

Summary

Background 2-methoxyestradiol (2ME2) is an estradiol-17β metabolite with antiproliferative and antiangiogenic activities. ENMD-1198 is an analog of 2ME2 which was developed to decrease the metabolism and increase both the bioavailability and antitumor activities of the parent molecule. This first-in-human phase I study evaluated the tolerability, pharmacokinetics and preliminary evidence of activity of ENMD-1198 in advanced cancer patients. Methods Eligible patients received ENMD-1198 orally once daily in Part A (standard 3 + 3 dose escalation design), or in Part B (accelerated dose escalation design). Cycle 1 consisted of 28 days daily dosing followed by a 14-(Part A) or 7-(Part B) day observation period, then continuously in 28 day cycles thereafter. Results A total of 29 patients were enrolled in 12 dose cohorts (5 to 550 mg/m2/d). The most common drug-related toxicities were Grade 1/2 fatigue (55%), nausea and vomiting (37%), and constipation (34%). Two DLTs (Grade 4 neutropenia) occurred at 550 mg/m2/day, and 425 mg/m2/d was declared the maximum tolerated dose. ENMD-1198 was absorbed rapidly with a Tmax of 1–2 h. Exposure to ENMD-1198 (Cmax and AUC0–24hr) increased linearly with dose. The mean terminal half-life was 15 h. A 3-fold accumulation was found after multiple doses. Five patients achieved stabilization of disease for at least 2 cycles, three of whom (with neuroendocrine carcinoma of pancreas, prostate cancer and ovarian cancer) demonstrated prolonged stabilization ranging from 8–24.5 cycles. Conclusion ENMD-1198 is well-tolerated with a pharmacokinetic exposure profile compatible with once daily dosing. The recommended phase II dose of ENMD-1198 is 425 mg/m2/d. Early evidence of prolonged disease stabilization in pre-treated patients suggests ENMD-1198 is worthy of additional investigation.

Keywords

ENMD-1198 Phase I Pharmacokinetics 

Abbreviations

2ME2

2-methoxyestradiol

NCD

NanoCrystal® Dispersion

VEGF

Vascular endothelial growth factor

PK

Pharmacokinetic

DLT

Dose limiting toxicity

MTD

Maximum tolerated dose

LC/MS/MS

Liquid chromatography-tandem mass spectrometry

ECOG

Eastern Cooperative Oncology Group

CTCAE v3

Common Terminology Criteria for Adverse Events, Version 3.0

RECIST

Response Evaluation Criteria In Solid Tumors

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Qing Zhou
    • 1
    • 2
  • Daniel Gustafson
    • 3
  • Sujatha Nallapareddy
    • 1
  • Sami Diab
    • 1
  • Stephen Leong
    • 1
  • Karl Lewis
    • 1
  • Lia Gore
    • 1
  • Wells A. Messersmith
    • 1
  • Anthony M. Treston
    • 4
  • S. Gail Eckhardt
    • 1
  • Carolyn Sidor
    • 4
  • D. Ross Camidge
    • 1
    • 5
  1. 1.Developmental Therapeutics Program, Division of Medical OncologyUniversity of ColoradoAuroraUSA
  2. 2.Division of Pulmonary Oncology, Cancer CenterGuangdong General Hospital & Guangdong Academy of Medical SciencesGuangzhouChina
  3. 3.University of Colorado Comprehensive Cancer Center Pharmacology CoreColorado State UniversityFort CollinsUSA
  4. 4.EntreMed, Inc.DurhamUSA
  5. 5.University of Colorado Comprehensive Cancer CenterAuroraUSA