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Phase
I/II trial of gimatecan in patients with recurrent malignant glioma
L.
Alderson, J. Supko, X. Maestri, P. Sampath, E. Benincasa, N. Belonogova, C.
Zanna, P. Carminati, B. Chabner, P. Calabresi
Rhode
Island Hospital, Providence, RI; Massachusetts General Hospital, Boston, MA;
Sigma Tau, Pomezia, Italy
A
phase I/II trial of gimatecan (ST1481), an orally available camptothecin
analogue, was performed in patients with recurrent malignant gliomas.
Objectives were to define the maximum tolerated dose, dose-limiting toxicities,
antitumor activity, and pharmacokinetics of gimatecan given orally once a day
for five conscutive days, every 28 days.
The dose is being independently escalated based upon concurrent use of enzyme
inducing antiepileptic drugs (EIAEDs).
The starting dose was 0.33 mg/m2/day for both cohorts with at least 3
patients evaluated at each dose level (DL).
MRI tumor assessment was performed after every even-numbered cycle.
Twelve adult patients with radiographic evidence of tumor progression after
prior radiotherapy have been enrolled.
In the non-EIAED arm, DL 1 and 2 (0.66 mg/m2/day) have been completed
and 1 patient has received 1.1 mg/m2/day.
In the EIAED arm, 3 patients received the starting dose and 2 have entered DL 2.
The drug has been well tolerated without any dose limiting toxicity.
Four of 7 non-EIAED patients had a radiographic response or disease
stabilization after 2 cycles of therapy, although all but 1 progressed after
cycle 4.
There was no evidence of therapeutic benefit in the EIAED cohort.
Peak drug levels in plasma (Cmax) occurred within 2 h after dosing in
the most patients.
In non-EIAED patients, the Cmax and AUC0-24h for dose 5
were 112% and 179% greater, respectively, than for dose 1 due to a terminal
half-life (t1/2,z) of 71±28h.
Total drug plasma levels 24 h after dose 1 and 5 were 8±4
and 22±18ng/mL,
respectively, for non-EIAED patients in DL 2.
In contrast, patients receiving EIAEDs had a mean t1/2,z of 6.3±4.7h
with minimal accumulation.
The AUC0-24h on day 5 was 81% lower in the EIAED group (74±72ng*h/mL)
than the non-EIAED group (560±175ng*h/mL)
at DL 1.
Gimatecan clearance is markedly enhanced by EIAEDs.
The drug is well tolerated at the doses evaluated and shows initial promising
results for the treatment of malignant glioma.
© Copyright 2003
American Society of Clinical Oncology All rights
reserved worldwide
Source: http://www.asco.org/ac/1,1003,_12-002489-00_18-002003-00_19-00104257-00_29-00A,00.asp?cat=CNS+Tumors&parent=
Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4 |
