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Investigational New Drugs

, Volume 29, Issue 2, pp 340–346 | Cite as

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

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

Notes

Acknowledgments

Mark Morrow (Clinical Study Co-ordination), University of Colorado Cancer Center.

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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

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