Phase I trial of fixed dose-rate gemcitabine in combination with carboplatin in chemonaive advanced non-small-cell lung cancer: a Cancer Therapeutics Research Group study.
OBJECTIVE
To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m(2) per min in combination with fixed dose carboplatin, to evaluate the toxicity of this regimen and to determine the pharmacokinetics of plasma gemcitabine.


METHODS
Patients with advanced stage non-small-cell lung cancer (NSCLC) received carboplatin (AUC 5) on day 1 followed by gemcitabine at a fixed dose rate of 10 mg/m(2) per min in escalating durations of infusion on days 1 and 8 every 21 days. Pharmacokinetic sampling was obtained on day 1, cycle 1 of treatment.


RESULTS
A total of 15 patients received carboplatin and gemcitabine in cohorts of three to six patients at three dose levels. The doses of gemcitabine studied were 600, 750, and 900 mg/m(2). The MTD was reached at 900 mg/m(2). Dose-limiting toxicities were thrombocytopenia and liver failure, and with repeated dosing neutropenia was commonly observed. The recommended phase II dose of gemcitabine was 750 mg/m(2). Partial responses were observed at 600 and 750 mg/m(2) of gemcitabine. Plasma gemcitabine did not reach steady state except in one patient with the durations of infusion studied. Plasma concentrations, however, were above 10 micro mol/l between 20 and 90 min in all patients.


CONCLUSIONS
Gemcitabine administered as a 75-min infusion at a fixed dose rate of 10 mg/m(2)/min on days 1 and 8 in combination with carboplatin on day 1 every 21 days is tolerable and active in NSCLC. Pharmacokinetic studies demonstrated that the target plasma gemcitabine concentration above 10 micro mol/l was achieved. Further studies are warranted to compare this regimen against standard regimens of carboplatin and gemcitabine.
Soo
Ross A
RA
Department of Hematology-Oncology, National University Hospital, 5 Lower Kent Ridge Road, 119074, Singapore.
Lim
Hong L
HL
Wang
Ling Z
LZ
Lee
How S
HS
Millward
Michael J
MJ
Tok
Lay T
LT
Lee
Soo C
SC
Lehnert
Manfred
M
Goh
Boon C
BC
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D016190:Carboplatin; D000093542:Gemcitabine