Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors

Günter Emons, Manfred Kaufmann, Grigor Gorchev, Valentina Tsekova, Carsten Gründker, Andreas R. Günthert, Lars C. Hanker, Maya Velikova, Herbert Sindermann, Jürgen Engel, Andrew V Schally

Research output: Contribution to journalArticle

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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. 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. 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 2 h. 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.

Original languageEnglish
Pages (from-to)457-461
Number of pages5
JournalGynecologic Oncology
Volume119
Issue number3
DOIs
StatePublished - Dec 1 2010

Fingerprint

LHRH Receptors
Gonadotropin-Releasing Hormone
Doxorubicin
Pharmacokinetics
Maximum Tolerated Dose
Neoplasms
Leukopenia
Endometrial Neoplasms
Neutropenia
Ovarian Neoplasms
Half-Life
Immunohistochemistry
Breast Neoplasms
Drug Therapy
lysine(6)-doxorubicin LHRH

Keywords

  • AESZ-108
  • AN-152
  • Doxorubicin
  • LHRH receptors
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors. / Emons, Günter; Kaufmann, Manfred; Gorchev, Grigor; Tsekova, Valentina; Gründker, Carsten; Günthert, Andreas R.; Hanker, Lars C.; Velikova, Maya; Sindermann, Herbert; Engel, Jürgen; Schally, Andrew V.

In: Gynecologic Oncology, Vol. 119, No. 3, 01.12.2010, p. 457-461.

Research output: Contribution to journalArticle

Emons, G, Kaufmann, M, Gorchev, G, Tsekova, V, Gründker, C, Günthert, AR, Hanker, LC, Velikova, M, Sindermann, H, Engel, J & Schally, AV 2010, 'Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors', Gynecologic Oncology, vol. 119, no. 3, pp. 457-461. https://doi.org/10.1016/j.ygyno.2010.08.003
Emons, Günter ; Kaufmann, Manfred ; Gorchev, Grigor ; Tsekova, Valentina ; Gründker, Carsten ; Günthert, Andreas R. ; Hanker, Lars C. ; Velikova, Maya ; Sindermann, Herbert ; Engel, Jürgen ; Schally, Andrew V. / Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors. In: Gynecologic Oncology. 2010 ; Vol. 119, No. 3. pp. 457-461.
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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. 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. 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 2 h. 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.",
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AU - Kaufmann, Manfred

AU - Gorchev, Grigor

AU - Tsekova, Valentina

AU - Gründker, Carsten

AU - Günthert, Andreas R.

AU - Hanker, Lars C.

AU - Velikova, Maya

AU - Sindermann, Herbert

AU - Engel, Jürgen

AU - Schally, Andrew V

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