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Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors.
- Source :
-
Gynecologic oncology [Gynecol Oncol] 2010 Dec; Vol. 119 (3), pp. 457-61. Date of Electronic Publication: 2010 Sep 09. - Publication Year :
- 2010
-
Abstract
- Objectives: Receptors for luteinizing hormone-releasing hormone (LHRH) can be utilized for targeted chemotherapy of cytotoxic LHRH analogs. The compound AEZS-108 (previously AN-152) consists of [D-Lys⁶]LHRH linked to doxorubicin. The objectives of this first study in humans with AESZ-108 were to determine the maximum tolerated dose and to characterize the dose-limiting toxicity, pharmacokinetics, preliminary efficacy, and hormonal effects.<br />Methods: The study included 17 women with histologically confirmed epithelial cancer of the ovary, endometrium, or breast that was metastatic or unresectable and for which standard curative or palliative measures could not be used or were no longer effective or tolerated. In each patient, immunohistochemistry of primary tumor or metastatic lesion confirmed that the tumors expressed LHRH receptors.<br />Results: One patient each received intravenous doses of 10, 20, 40, or 80 mg/m² of AEZS-108, six received 160 mg/m² and seven 267 mg/m² at 3 week intervals. Dose-limiting leukopenia and neutropenia were observed at the highest dose. A total of 6 patients, 3 patients each in both upper dose groups, showed responses to AEZS-108. The half-life of AESZ-108 was estimated to be about 2h.<br />Conclusions: The maximum tolerated dose of AESZ-108 in the absence of supportive medication is 267 mg/m² and this dose is recommended as starting dose for therapeutic Phase II studies.<br /> (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Subjects :
- Antibiotics, Antineoplastic administration & dosage
Antibiotics, Antineoplastic adverse effects
Antibiotics, Antineoplastic blood
Antibiotics, Antineoplastic pharmacokinetics
Breast Neoplasms blood
Breast Neoplasms metabolism
Dose-Response Relationship, Drug
Doxorubicin administration & dosage
Doxorubicin adverse effects
Doxorubicin blood
Doxorubicin pharmacokinetics
Endometrial Neoplasms blood
Endometrial Neoplasms metabolism
Female
Gonadotropin-Releasing Hormone administration & dosage
Gonadotropin-Releasing Hormone adverse effects
Gonadotropin-Releasing Hormone blood
Gonadotropin-Releasing Hormone pharmacokinetics
Humans
Hydrocortisone metabolism
Maximum Tolerated Dose
Middle Aged
Ovarian Neoplasms blood
Ovarian Neoplasms metabolism
Pituitary Gland drug effects
Breast Neoplasms drug therapy
Doxorubicin analogs & derivatives
Endometrial Neoplasms drug therapy
Gonadotropin-Releasing Hormone agonists
Gonadotropin-Releasing Hormone analogs & derivatives
Ovarian Neoplasms drug therapy
Receptors, LHRH biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1095-6859
- Volume :
- 119
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gynecologic oncology
- Publication Type :
- Academic Journal
- Accession number :
- 20828803
- Full Text :
- https://doi.org/10.1016/j.ygyno.2010.08.003