Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies
- 471 Downloads
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.
KeywordsAzacitidine Valproic acid Carboplatin Methylation Histone deacetylase inhibition
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.
Financial support for this study was provided by Celgene Corporation and UT MD Anderson SPORE in Ovarian (P50 CA083639) and Uterine (P50 CA098258) cancer.
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.
- 6.Morgan RJ Jr, Alvarez RD, Armstrong DK, Boston B, Chen LM, Copeland L, Fowler J, Gaffney DK, Gershenson D, Greer BE, Grigsby PW, Havrilesky LJ, Johnston C, Lancaster JM, Lele S, Matulonis U, O’Malley D, Ozols RF, Remmenga SW, Sabbatini P, Schink J, Teng N (2008) Ovarian cancer. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 6:766–794CrossRefGoogle Scholar
- 13.Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL, Levenback CF, Sood AK, Wolf JK, Gershenson DM, Markman M, Hennessy BT, Kurzrock R, Bast RC Jr (2011) 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. Cancer 117:1661–1669. doi: https://doi.org/10.1002/cncr.25701 CrossRefGoogle Scholar
- 15.Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O’Brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271–3279. doi: https://doi.org/10.1182/blood-2006-03-009142 CrossRefGoogle Scholar
- 16.Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S, Talpaz M, Garcia-Manero G, Kantarjian HM (2005) Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 23:3948–3956. doi: https://doi.org/10.1200/JCO.2005.11.981 CrossRefGoogle Scholar
- 17.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefGoogle Scholar
- 18.Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–181. doi: https://doi.org/10.1016/S1053-4296(03)00031-6 CrossRefGoogle Scholar
- 19.Braiteh F, Soriano AO, Garcia-Manero G, Hong D, Johnson MM, Silva Lde P, Yang H, Alexander S, Wolff J, Kurzrock R (2008) Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin Cancer Res 14:6296–6301. doi: https://doi.org/10.1158/1078-0432.CCR-08-1247 CrossRefGoogle Scholar
- 20.Fang F, Balch C, Schilder J, Breen T, Zhang S, Shen C, Li L, Kulesavage C, Snyder AJ, Nephew KP, Matei DE (2010) A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer 116:4043–4053. doi: https://doi.org/10.1002/cncr.25204 CrossRefGoogle Scholar
- 26.Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, Curto J, Siddiqui N, Gabra H, McLeod HL, Strathdee G, Brown R (2005) CpG island methylation of DNA damage response genes in advanced ovarian cancer. Cancer Res 65:8961–8967. doi: https://doi.org/10.1158/0008-5472.CAN-05-1187 CrossRefGoogle Scholar
- 29.Griffiths EA, Gore SD (2008) DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol 45:23–30. doi: https://doi.org/10.1053/j.seminhematol.2007.11.007 CrossRefGoogle Scholar
- 30.Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G (2007) Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 110:2302–2308. doi: https://doi.org/10.1182/blood-2007-03-078576 CrossRefGoogle Scholar
- 31.Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25:3884–3891. doi: https://doi.org/10.1200/JCO.2006.09.4169 CrossRefGoogle Scholar
- 37.Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O’Dorisio MS, Held WA, Cavenee WK, Plass C (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132–138. doi: https://doi.org/10.1038/72785 CrossRefGoogle Scholar
- 39.Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31:141–149. doi: https://doi.org/10.1038/ng892 CrossRefGoogle Scholar