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 plusdecitabine, a novel DNA-hypomethylating agent, in patients withadvanced solid tumors, which was followed by an early phase IIevaluation of the combination in patients with inoperablenon-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) doseescalation levels (45, 67, 90 to 120 mg/m²,respectively) in consecutive groups of at least 3 patients perdose level. Decitabine was administered to the patients as atwo-hour intravenous infusion, while cisplatin was givenintravenously 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 trial. Dose levelIV (120 mg/m² decitabine) was considered the maximumtolerated dose (MTD), while the dose-limiting toxicities wereneutropenia, thrombocytopenia and mucositis. The recommendeddoses for phase II trials in good- and poor-risk patients were90 (level III) and 67 mg/m² (level II), respectively.One short-lasting partial response was observed in a patient withcervical cancer, while two minor regression were documented ina patients with NSCLC and cervical cancer, respectively. Doselevel II was selected for the phase II trial in patients withinoperable NSCLC. Fourteen consecutive patients were included inthis part of the study. The median age of the patients was 57years (range, 39–75), male/female ratio of –11/3 anda median WHO performance status 1 (0–2). The stage ofdisease were IIIB (5) and IV (9). Prior irradiation to the chestwas given in one case. A total of 30 treatment courses wereevaluable for toxicity and response, with a median of 2 coursesper patient (1–4). Grade 3–4 neutropenia andthrombocytopenia were observed in about half of the cases.Mucositis, diarrhea, nausea and vomiting, and skin rash were alsoobserved in some patients. Three minor responses were documented,which lasted for 4, 16 and 36 weeks. Median survival of patientswas 15 weeks (4–38). In conclusion, the cisplatin plusdecitabine combination did not exhibit significant antitumoractivity in patients with NSCLC at the dose and schedule appliedin this trial to justify its further evaluation in this patientpopulation.