A phase I trial of cisplatin plus decitabine, a new DNA-hypomethylating agent, in patients with advanced solid tumors and a follow-up early phase II evaluation in patients with inoperable non-small cell lung cancer.

The authors describe a phase I trial of cisplatin plus decitabine, a novel DNA-hypomethylating agent, in patients with advanced solid tumors, which was followed by an early phase II evaluation of the combination in patients with inoperable non-small cell lung cancer (NSCLC). In the phase I trial, cisplatin was studied at a fixed dose of 33 mg/m2, while decitabine was escalated in four (I-IV) dose escalation levels (45, 67, 90 to 120 mg/m2, respectively) in consecutive groups of at least 3 patients per dose level. Decytabine was administered to the patients as a two-hour intravenous infusion, while cisplatin was given intravenously immediately after the end of decitabine infusion. Both agents were given on days 1-3 every 21 days. Twenty-one patients were included in the phase I trial. Dose level IV (120 mg/m2 decitabine) was considered the maximum tolerated dose (MTD), while the dose-limiting toxicities were neutropenia, thrombocytopenia and mucositis. The recommended doses for phase II trials in good- and poor-risk patients were 90 (level III) and 67 mg/m2 (level II), respectively. One short-lasting partial response was observed in a patient with cervical cancer, while two minor regression were documented in a patients with NSCLC and cervical cancer, respectively. Dose level II was selected for the phase II trial in patients with inoperable NSCLC. Fourteen consecutive patients were included in this part of the study. The median age of the patients was 57 years (range, 39-75), male/female ratio of 11/3 and a median WHO performance status 1 (0-2). The stage of disease were IIIB (5) and IV (9). Prior irradiation to the chest was given in one case. A total of 30 treatment courses were evaluable for toxicity and response, with a median of 2 courses per patient (1-4). Grade 3-4 neutropenia and thrombocytopenia were observed in about half of the cases. Mucositis, diarrhea, nausea and vomiting, and skin rash were also observed in some patients. Three minor responses were documented, which lasted for 4, 16 and 36 weeks. Median survival of patients was 15 weeks (4-38). In conclusion, the cisplatin plus decitabine combination did not exhibit significant antitumor activity in patients with NSCLC at the dose and schedule applied in this trial to justify its further evaluation in this patient population.