Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors.


METHODS
Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry.


RESULTS
Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n = 3), 800 mg bid (n = 3), 1600 mg bid (n = 6), 2200 mg bid (n = 5) and 3000 mg bid (n = 3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over three years.


CONCLUSIONS
MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.
Dahut
William L
WL
Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Lakhani
Nehal J
NJ
Gulley
James L
JL
Arlen
Philip M
PM
Kohn
Elise C
EC
Kotz
Herbert
H
McNally
Debbie
D
Parr
Allyson
A
Nguyen
Diana
D
Yang
Sherry X
SX
Steinberg
Seth M
SM
Venitz
Jürgen
J
Sparreboom
Alex
A
Figg
William D
WD
D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002196:Capillaries / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D014057:Tomography, X-Ray Computed
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004958:Estradiol; D000077584:2-Methoxyestradiol