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Investigational New Drugs

, Volume 31, Issue 5, pp 1192–1200 | Cite as

Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies

  • Gerald S. FalchookEmail author
  • Siqing Fu
  • Aung Naing
  • David S. Hong
  • Wei Hu
  • Stacy Moulder
  • Jennifer J. Wheler
  • Anil K. Sood
  • Ernesto Bustinza-Linares
  • Kristin L. Parkhurst
  • Razelle Kurzrock
PHASE I STUDIES

Summary

Purpose The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental Design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells. Results Thirty-two patients were treated. The MTD was 75 mg/m2 azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥4 months were achieved by six patients (18.8 %), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥3 were fatigue (81 %) and neutropenia (69 %). Dose-limiting toxicity occurred in six patients (18.8 %), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received. Conclusions Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.

Keywords

Azacitidine Valproic acid Carboplatin Methylation Histone deacetylase inhibition 

Notes

Acknowledgments

We would like to thank Adrienne Howard and Alambardar Khuwaja (Department of Investigational Cancer Therapeutics) for their contributions to this study’s operation and DeYu Shen (Department of Gynecologic Oncology and Reproductive Medicine) for technical assistance.

Grant support

Financial support for this study was provided by Celgene Corporation and UT MD Anderson SPORE in Ovarian (P50 CA083639) and Uterine (P50 CA098258) cancer.

Ethical standards

The research performed complies with the current laws of the country in which it was performed. All patients signed consent in accordance with the guidelines of the M.D. Anderson Cancer Center Institutional Review Board.

Conflict of interest

Dr. Falchook and Dr. Fu received research funding from Celgene. The other authors have no conflict of interest to disclose.

Financial support

Celgene

Supplementary material

10637_2013_3_MOESM1_ESM.doc (54 kb)
ESM 1 (DOC 54 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gerald S. Falchook
    • 1
    Email author
  • Siqing Fu
    • 1
  • Aung Naing
    • 1
  • David S. Hong
    • 1
  • Wei Hu
    • 2
  • Stacy Moulder
    • 3
  • Jennifer J. Wheler
    • 1
  • Anil K. Sood
    • 2
    • 4
    • 5
  • Ernesto Bustinza-Linares
    • 6
  • Kristin L. Parkhurst
    • 1
  • Razelle Kurzrock
    • 7
  1. 1.Department of Investigational Cancer Therapeutics (Phase I Program)The University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Gynecologic OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Department of Cancer BiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  5. 5.Center for RNA Interference and Non-Coding RNAThe University of Texas MD Anderson Cancer CenterHoustonUSA
  6. 6.Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiUSA
  7. 7.Moores Cancer CenterUniversity of California, San DiegoSan DiegoUSA

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