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, ci...

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Bibliographic Details
Published in:	Investigational new drugs Vol. 18; no. 1; pp. 83 - 91
Main Authors:	SCHWARTSMANN, G, SCHUNEMANN, H, GORINI, C. N. F, FERREIRA, A. F, GARBINO, C, SABINI, G, MUSE, I, DILEONE, L, MANS, D. R
Format:	Journal Article
Language:	English
Published:	Dordrecht Kluwer 01-02-2000 Springer Nature B.V
Subjects:	Abdomen Adult Aged Antimetabolites, Antineoplastic - administration & dosage Antimetabolites, Antineoplastic - adverse effects Antimetabolites, Antineoplastic - therapeutic use Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Azacitidine - administration & dosage Azacitidine - adverse effects Azacitidine - analogs & derivatives Azacitidine - therapeutic use Biological and medical sciences Cancer therapies Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - pathology Cervical cancer Chemotherapy Cisplatin - administration & dosage Cisplatin - adverse effects Cisplatin - therapeutic use Creatinine Cytotoxicity Disease Drug dosages Drug Therapy, Combination Female Follow-Up Studies Gene expression Humans Laboratories Leukemia Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - pathology Male Medical sciences Melanoma Middle Aged Mucositis Neutropenia Patients Pharmacology. Drug treatments Skin cancer Thrombocytopenia Tomography Toxicity Tumors Ultrasonic imaging Antineoplastic agent Human Lung disease Solid tumor Drug combination Intravenous administration Respiratory disease Toxicity Lung Decitabine Malignant tumor Biological activity Cisplatin Alkylating agent Chemotherapy Treatment Phase II trial Phase I trial Non small cell carcinoma Platinum II Complexes
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Summary:	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.
ISSN:	0167-6997 1573-0646
DOI:	10.1023/A:1006388031954