title: Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy.
abstract: BACKGROUND
  Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m(2)/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m(2)/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed.
  
  
  RESULTS
  Thirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 μg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival.
  
  
  CONCLUSIONS
  Oxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration.
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Apostolia M
authors: AM
authors: Tsimberidou
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA ; Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6410 Fannin Street, Suite 722, Houston, TX 77030 USA.
authors: Rabih
authors: R
authors: Said
authors: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Kirk
authors: K
authors: Culotta
authors: Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Ignacio
authors: I
authors: Wistuba
authors: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, PA 19140 USA.
authors: Jaroslav
authors: J
authors: Jelinek
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Siqing
authors: S
authors: Fu
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Gerald
authors: G
authors: Falchook
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Aung
authors: A
authors: Naing
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Sarina
authors: S
authors: Piha-Paul
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Ralph
authors: R
authors: Zinner
authors: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Zahid H
authors: ZH
authors: Siddik
authors: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Guangan
authors: G
authors: He
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 USA.
authors: Kenneth
authors: K
authors: Hess
authors: Division of Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8 L6 Canada.
authors: David J
authors: DJ
authors: Stewart
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX 77030 USA ; Department of Internal Medicine, Moores Cancer Center, University of California, 3855 Health Sciences Dr, La Jolla, CA 92093 USA.
authors: Razelle
authors: R
authors: Kurzrock
authors: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, PA 19140 USA.
authors: Jean-Pierre J
authors: JP
authors: Issa
keywords: Copper/platinum transporter; DNA methylation; Platinum resistance