Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer

Authors

  • Siqing Fu MD, PhD,

    Corresponding author
    1. Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    • Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
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    • Fax: (713) 794-4130

  • Wei Hu MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Revathy Iyer MD,

    1. Department of Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • John J. Kavanagh MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Robert L. Coleman MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Charles F. Levenback MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Anil K. Sood MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Judith K. Wolf MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • David M. Gershenson MD,

    1. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Maurie Markman MD,

    1. Department of Gynecological Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Bryan T. Hennessy MD,

    1. Department of Gynecological Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    2. Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Razelle Kurzrock MD,

    1. Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Robert C. Bast Jr MD

    1. Department of Gynecological Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    2. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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Abstract

BACKGROUND:

Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.

METHODS:

Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease.

RESULTS:

Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%).

CONCLUSIONS:

To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted. Cancer 2011. © 2010 American Cancer Society.

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