Phase I dose-escalating study of raltitrexed ('Tomudex') and cisplatin in metastatic non-small cell lung cancer.
BACKGROUND
The aim of this Phase I, dose-escalation study was to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose-limiting toxicity (DLT) of a raltitrexed ('Tomudex') and cisplatin combination in patients with previously untreated, metastatic non-small cell lung cancer (NSCLC).


METHODS
Patients received raltitrexed (15-min intravenous infusion), followed by cisplatin (1-h intravenous infusion), every 3 weeks at escalating dose levels.


RESULTS
In total, 21 patients entered the study. No DLT was observed up to dose level 4 (raltitrexed 3.0 mg/m(2) plus cisplatin 80 mg/m(2)), or in the first 3 patients who received dose level 5 (raltitrexed 3.5 mg/m(2) plus cisplatin 80 mg/m(2)). However, 1 patient, entered at dose level 6 (raltitrexed 4.0 mg/m(2) plus cisplatin 80 mg/m(2)) experienced severe toxicity (including grade 3 diarrhea), and no further patients were recruited at this level. Of 4 additional patients who received raltitrexed 3.5 mg/m(2) plus cisplatin 80 mg/m(2), 3 also experienced DLTs. The most common adverse events included nausea/vomiting, asthenia, diarrhea, and hematologic toxicities. Of 19 patients evaluated for response, 3 achieved a partial response, 13 had stable disease, and 3 progressed.


CONCLUSIONS
The MTD is raltitrexed 3.5 mg/m(2) plus cisplatin 80 mg/m(2), and the RD for future studies is raltitrexed 3.0 mg/m(2) plus cisplatin 80 mg/m(2); DLTs were diarrhea and asthenia. The combination of raltitrexed and cisplatin shows clinical activity in patients with metastatic NSCLC.
Manegold
C
C
Thorax-Klinik Heidelberg GmbH, Innere Medizin/Onkologie, Amalienstr. 5, Germany. prof.manegold@t-online.de
Buchholz
E
E
Kloeppel
R
R
Kreisel
C
C
Smith
M
M
D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; 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; D009503:Neutropenia / Q000139:chemically induced; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced
D011799:Quinazolines; D013876:Thiophenes; C068874:raltitrexed; D002945:Cisplatin