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

Abstract

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 T(max) of 1-2 h. Exposure to ENMD-1198 (C(max) and AUC₀₋₂₄ hr 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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 29 Issue 2 Pg. 340-6 (Apr 2011) ISSN: 1573-0646 [Electronic] United States
• PMID: 20084425 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• 2-methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide
• Antineoplastic Agents
• Estrenes
• Estradiol
• 2-Methoxyestradiol

Topics

• 2-Methoxyestradiol
• Administration, Oral
• Adult
• Aged
• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Demography
• Dogs
• Dose-Response Relationship, Drug
• Estradiol (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Estrenes (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (blood, drug therapy)
• Rats
• Species Specificity