Abstract CT201: Phase I study of 5-azacytidine and oxaliplatin in patients with advanced cancers relapsed or refractory to platinum compounds
Authors: Tsimberidou Apostolia M. , Culotta Kirk , Wistuba Ignacio , Fu Siqing , Naing Aung , Falchook Gerald , Piha-Paul Sarina , Zinner Ralph , Rodriguez-Canales Jaime , He Guangan , Siddik Zahid H. , Jelinek Jaroslav , Chung Woonbok , Ye Yang , Said Rabih , Hess Kenneth , Stewart David J. , Kurzrock Razelle , Issa Jean-Pierre 
Published: May 2015

Abstract
Purpose: To explore whether the hypomethylating agent 5-azacytidine (5-aza) restores platinum sensitivity.
Experimental Design: Patients with advanced cancer relapsed/refractory to platinum compounds were treated with 5-aza 20-50 mg/m2/d IV (D 1-5) and oxaliplatin 15-30 mg/m2/d IV (D 2-5) (“3+3” design escalation phase followed by expansion phase; NCT01039155). PK studies were performed. Global DNA and gene-specific methylation changes (baseline to D12) in blood and tissue, tissue platinum level, and CTR1 (copper transporter involved in platinum uptake) expression were assessed (expansion phase).
Results: Overall, 37 patients were treated (median age, 59 yrs; men, 49%; prior: oxaliplatin, 68%; carboplatin, 30%; cisplatin, 16%) (escalation, n=21; expansion, n=16). No DLT was noted at the maximum dose level tested (5-aza, 50 mg/m2/d; oxaliplatin 30 mg/m2/d; used in expansion phase). The most common adverse events were anemia (49% of pts.) and fatigue (32%). LINE-1 was measured (surrogate for global DNA methylation) in pre- and post-treatment blood samples (9 patients) and in tumor samples (7 patients). All blood samples showed reduction in global DNA methylation (baseline to D12) (median, -22%; range, [-32%, -12%], p&lt;.0001). Paired tumor and blood pre- and post-treatment samples were available in 2 patients. In paired comparison, 1 patient had reduction in global methylation both in tumor and blood (-34% and -32%, respectively); and 1 patient had increased methylation in tumor (+52%) and decreased in blood (-22%).
The mean cytoplasmic CTR1 score was 217.5 and 177.5 on D1 and D12, respectively (mean difference, -40; 95% CI: -69.1,-10.9; p=.02). The respective mean nuclear CTR1 score was 67.5 and 42.5 (mean difference, -25; 95% CI: -55.5,+5.5; p=.08). Oxaliplatin (D2) and 5-aza (D1 and 5) mean systemic exposure based on plasma AUCall resulted in a dose-dependent trend (oxaliplatin 15 to 30 mg/m2, 704.3 to 1149.0 hr·ng/mL; 5-aza 20 to 50 mg/m2, 112.5 to 404.5 [D1] and 143.7 to 426.5 hr·ng/mL [D5]). When the same dose of oxaliplatin was used with increasing doses of 5-aza from 25-50 mg/m2, a reduction in mean oxaliplatin exposure was noted (AUCinf: 1919.4 to 1455.9 hr·ng/mL). No significant differences in other non-compartmental modeled parameters estimated were observed. The total tumor oxaliplatin level was measured in 7 patients. The pre-dose levels ranged from &lt;.25 to 5.8 µg/g tumor (median, .59). The post-dose levels increased 3- to 18-fold (median, 3.8) in 5 post-dose samples (mean difference, 1.48 µg/g; 95% CI: .01,2.95; p=.049). Two patients, having the highest pre-dose level, had unchanged levels. Two (5.4%) patients (colon, n=1; prostate, n=1) had stable disease and received 6 cycles of therapy.
Conclusion: 5-aza combined with oxaliplatin was safe. Hypomethylation was inconsistent in tumor tissue, the CTR1 score decreased and the tumor oxaliplatin level increased.
Citation Format: Apostolia M. Tsimberidou, Kirk Culotta, Ignacio Wistuba, Siqing Fu, Aung Naing, Gerald Falchook, Sarina Piha-Paul, Ralph Zinner, Jaime Rodriguez-Canales, Guangan He, Zahid H. Siddik, Jaroslav Jelinek, Woonbok Chung, Yang Ye, Rabih Said, Kenneth Hess, David J. Stewart, Razelle Kurzrock, Jean-Pierre Issa. Phase I study of 5-azacytidine and oxaliplatin in patients with advanced cancers relapsed or refractory to platinum compounds. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT201. doi:10.1158/1538-7445.AM2014-CT201