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Phase I study of
temozolomide in conjunction with gemcitabine
R. Goel, S. Gertler, D. J. Stewart, S. Laurie, G. Goss, N. Reaume, C. Cripps,
D. Bedard, A. Rodgers, D. Cutler
Ottawa Regional Cancer Centre, Ottawa, ON, Canada; MD Anderson
Cancer Center, Houston, TX; Schering Canada Inc., Pointe Claire, Canada;
Schering-Plough Research Institute, Kenilworth, Canada.
Background.
Temozolomide (TZ) is an oral alkylating agent used in the
treatment of brain tumours, and malignant melanoma.
Gemcitabine (GC) is a nucleoside analogue clinically active versus several human
tumors, including pancreatic cancer, breast cancer, non-small cell lung cancer,
bladder cancer etc.
In vitro, these 2 drugs exhibit additive cytotoxic effects against the
astrocytoma U373MG cell line.
Methods.
A phase I clinical study of these 2 drugs in combination was
initiated.
Dose Level (DL) 1 received: TZ 100 mg/m2, days 1-7 and 15-21; GC 750
mg/m2 days 1, 8, and 15; every 28 days.
DL 2 received TZ 125 mg/m2 and GC 750 mg/m2.
DL 3 received TZ 125 mg/m2 and GC 1000 mg/m2.
DL 4 received TZ 150 mg/m2 and GC 1000 mg/m2.
Two Dose-Limiting Toxicities (DLTs) occurred at DL 4; therefore, DL 3 was
considered the maximally tolerated dose.
As per study, 6 more patients were treated at DL 3 (termed DL 3’).
Three prior chemotherapy regimens were allowed .
Results.
Patient characteristics: male 11/female 13; median age 55 (range
26-77); performance status 0 (n=3), 1 (n=14), and 2 (n=7); prior therapy:
chemotherapy 21, radiotherapy 10, no prior anticancer therapy 2; tumour types:
non-small cell lung 8, primary brain tumour 2, miscellaneous 14.
To date, 6 patients were treated at DL 1, 4 at DL 2, 4 at DL 3, 4 at DL 4, and 6
patients at DL 3’.
To date, data analysis has been completed on patients treated on DLs 1-4.
The number of cycles (at these DLs) given: <1 (n=4), 1 (n=3), 2 (n=4), 3
(n=5), 4 (n=2).
The nadir counts (x109/L) after cycle 1: DL 1-white blood cell (wbc)
3.2 (range 2.5-6.5), neutrophil (PMN) 1.7 (range 1.0-3.5), platelets 154 (range
56-228), DL 2-wbc 3.8 (range 2.2-4.2), PMN 1.3 (0.8-1.8), platelets 154
(88-173), DL 3-wbc 2.2 (range 1.3-3.0), PMN 1.5 (0.7-1.7), platelets 104
(64-373), DL 4-wbc 2.6 (0.5-2.6), PMN 1.5 (0.2-2.6), platelet 95 (55-165).
No significant non-hematologic toxicity has been observed.
Conclusions.
This chemotherapy regimen is well-tolerated.
Encouraging activity of the regimen is suggested in this group of heavily
pre-treated patients with resistant tumours; 8 patients received more than 2
courses of therapy.
Supported by Schering-Plough Research Institute.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-003568,00.asp
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