Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy

Clinical Epigenetics

Jean-Pierre J Issa⁸  Razelle Kurzrock⁷  David J Stewart⁵  Kenneth Hess⁴  Guangan He⁶  Zahid H Siddik⁶  Ralph Zinner³  Sarina Piha-Paul³  Aung Naing³  Gerald Falchook³  Siqing Fu³  Jaroslav Jelinek⁸  Ignacio Wistuba¹  Kirk Culotta⁶  Rabih Said²  Apostolia M Tsimberidou³ 

[1] Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston 77030, TX, USA;Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6410 Fannin Street, Suite 722, Houston 77030, TX, USA;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston 77030, TX, USA;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston 77030, TX, USA;Division of Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, 501 Smyth Road, Ottawa K1H 8 L6, ON, Canada;Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston 77030, TX, USA;Department of Internal Medicine, Moores Cancer Center, University of California, 3855 Health Sciences Dr, La Jolla 92093, CA, USA;Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia 19140, PA, USA

关键词: Copper/platinum transporter;    Platinum resistance;    DNA methylation;   

Others  :  1147817
DOI  :  10.1186/s13148-015-0065-5

 received in 2014-11-25, accepted in 2015-02-24,  发布年份 2015

【 摘 要 】

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/m²/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m²/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 AUC_all 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.

【 授权许可】

   
2015 Tsimberidou et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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