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Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain†

High rate of thromboembolic events (CALGB 500102)

  1. Susan E. Krown MD1,¶,*,
  2. Donna Niedzwiecki PhD2,
  3. Wen-Jen Hwu PhD, MD1,‡,‖,
  4. Lydia Hodgson MS2,
  5. Alan N. Houghton MD1,
  6. Frank G. Haluska MD, PhD3,§,††,
  7. for the Cancer and Leukemia Group B‡‡

Article first published online: 19 SEP 2006

DOI: 10.1002/cncr.22239

Issue

Cancer

Cancer

Volume 107, Issue 8, pages 1883–1890, 15 October 2006

Additional Information

How to Cite

Krown, S. E., Niedzwiecki, D., Hwu, W.-J., Hodgson, L., Houghton, A. N., Haluska, F. G. and for the Cancer and Leukemia Group B (2006), Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain. Cancer, 107: 1883–1890. doi: 10.1002/cncr.22239

Author Information

  1. 1

    Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

  2. 2

    CALGB Statistical Center, Duke University Medical Center, Durham, North Carolina

  3. 3

    Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts

  1. ‡

    Department of Melanoma Medical Oncology, Department of Medicine, University of Texas, M. D. Anderson Cancer Center, Houston, Texas

  2. §

    Tufts-New England Medical Center, Boston, Massachusetts

  1. Fax: (212) 717-3342

  2. ‖

    Dr. Hwu has served as a consultant to Schering-Plough, the manufacturer of temozolomide, and has received honoraria from Schering-Plough and from Celgene, the manufacturer of thalidomide.

  3. ††

    Dr. Haluska has served as a consultant to Schering-Plough, received honoraria from Schering-Plough, and provided expert testimony concerning temozolomide.

  4. ‡‡

    The following institutions participated in this study: CALGB Statistical Center, Durham, NC (Stephen George, PhD, supported by CA33601); Christiana Care Health Services, CCOP, Wilmington, DE (Stephen Grubbs, MD, supported by CA45418); Duke University Medical Center, Durham, NC (Jeffrey Crawford, MD, supported by CA47577); Georgetown University Medical Center, Washington, DC (Edward Gelmann, MD, supported by CA77597); Massachusetts General Hospital, Boston, MA (Michael L. Grossbard, MD, supported by CA12449); Memorial Sloan-Kettering Cancer Center, New York, NY (Clifford Hudis, MD, supported by CA77651); Mount Sinai Medical Center, Miami, FL (Rogerio Lilenbaum, MD, supported by CA45564); Rhode Island Hospital, Providence, RI (William Sikov, MD, supported by CA08025); Southeast Cancer Control Consortium, CCOP, Goldsboro, NC (James N. Atkins, MD, supported by CA45808); University of Chicago, Chicago, IL (Gini Fleming, MD, supported by CA41287); University of Iowa, Iowa City, IA (Gerald Clamon, MD, supported by CA47642); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO (Michael C Perry, MD, supported by CA12046); and University of North Carolina at Chapel Hill, Chapel Hill, NC (Thomas C. Shea, MD, supported by CA47559).

*Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021

  1. †

    The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Publication History

  1. Issue published online: 3 OCT 2006
  2. Article first published online: 19 SEP 2006
  3. Manuscript Accepted: 9 AUG 2006
  4. Manuscript Revised: 20 JUL 2006
  5. Manuscript Received: 9 MAY 2006

Funded by

  • National Cancer Institute. Grant Numbers: (CA31946), (CA77651), (CA33601), CA12449)

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Keywords:

  • malignant melanoma;
  • brain metastases;
  • temozolomide;
  • thalidomide;
  • thrombosis

Abstract

BACKGROUND.

Preliminary studies suggesting that extended-dose temozolomide with thalidomide is safe and active in patients with metastatic melanoma have led to frequent use of this oral regimen. To confirm these observations the combination was tested in a multicenter Phase II trial in patients with melanoma brain metastases.

METHODS.

Eligible patients had melanoma brain metastases, with or without systemic metastases. The primary endpoint was response rate in brain metastases. Patients received temozolomide at a dose of 75 mg/m2/day for 6 weeks with a 2-week rest between cycles, and thalidomide (escalated to 400 mg/day for patients age <70 years or to 200 mg/day for patients age ≥70 years). A 2-stage design required ≥3 responses in the first 21 patients before enrolling 29 additional patients in the second stage.

RESULTS.

Sixteen eligible patients were enrolled. No objective responses were observed. The median survival was 23.9 weeks. Seven patients withdrew because of tumor progression; 7 were removed during Cycle 1 because of adverse events, including allergic reaction (1 patient), severe fatigue (1 patient), sudden death (1 patient), and thromboembolic events (pulmonary embolism in 3 patients and deep vein thrombosis in 1 patient); 2 patients withdrew when the study was suspended and subsequently closed. No associations could be established between baseline characteristics and toxicity.

CONCLUSIONS.

The proportion of patients with lethal or potentially life-threatening adverse events was high (0.31, 95% confidence interval, 0.11–0.59), and the absence of objective responses made it unlikely that further accrual would demonstrate the efficacy of the regimen. These observations provide little support for the use of this combination for melanoma brain metastases unless safe and effective methods to prevent thrombosis are developed. Cancer 2006. © 2006 American Cancer Society.

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