|
|
Temozolomide
(TMZ) and irinotecan (CPT-11) for primary brain tumors. A dose escalation study
R.
Stupp, S. Ostermann, A. Calderoni, C. Uhlmann, S. Leyvraz
University
Hospital (CHUV), Lausanne, Switzerland; Department of Medical Oncology,
Inselspital, Bern, Switzerland
Background.
Antitumor activity against malignant glioma has been shown for both temozolomide
and CPT-11.
In vitro studies demonstrated a synergy with prior exposure of glioma cell lines
to TMZ before therapy with CPT-11.
In this trial we investigate the combination of TMZ and CPT-11 at increasing
doses.
As CPT-11 is metabolized by the CYP450 hepatic enzymes, only patients (pts) not
requiring enzyme-inducing antiepileptic therapy (EIAED) nor valproic acid were
eligible.
Methods.
Prospective phase I trial for pts with recurrent or multifocal brain tumors not
receiving EIAED.
TMZ was administered p.o. continuously for 14 days, CPT-11 was given on day 7 or
8 i.v. over 90 minutes.
Cycles were repeated every 21d.
Dose escalation was allowed if no more than 1/3 or 2/6 pts developed DLT defined
as grade 4 neutropenia > 7d, or NF, or gr. 4 thromocytopenia or gr. 3
diarrhea > 48 h.
Twenty-nine pts were included, GBM (20), grade 3 astrocytoma (6), other (3).
All but 4 pts had received prior RT, and 14 pts had also received prior
chemotherapy (of whom prior TMZ: 12).
Median age was 51 yrs (22-66), performance status 1 (0-2).
Results.
(table) Two of the responses were observed in pts who progressed after prior TMZ.
Six additional pts had stable disease.
Median survival for all patients is 10 months (95% c.i: 6.8-13.6), and 9.5 mo
(95% c.i: 4.4-14.6) for recurrent GBM only.
Conclusions.
Both
agents were escalated to their known single agent MTD.
Toxicity was primarily myelosuppression and diarrhea.
Survival and response rate in this usually poor prognosis pretreated patient
group is encouraging.
Further exploration of the association of a camptothecin derivative and TMZ is
warranted.
|
DL
|
n pts
|
n cy
|
TMZ
|
CPT11
|
Toxicity (gr.3/4) during cycle 1 & 2
|
Response
|
|
|
|
|
mg/m2
|
mg/m2
|
ANC
|
Tc
|
non-hemat.
|
|
|
1
|
3
|
10
|
75
|
250
|
|
|
|
|
|
2
|
3
|
18
|
75
|
300
|
|
|
|
1
CR, 1 PR
|
|
3
|
3
|
18
|
85
|
300
|
2
|
|
|
1
PR
|
|
4
|
5
|
29
|
100
|
300
|
|
|
|
1
CR, 1 MR
|
|
5
|
3
|
10
|
100
|
350
|
1
|
|
|
|
|
6
|
12
|
42
|
125
|
350
|
2
/ 1
|
0
/ 1
|
DIA
(2), NF (1)
|
2
PR, 1 MR
|
|
|
|
|
|
|
|
|
|
|
|
all
|
29
|
127
|
|
|
8
/ 6
|
1
/ 1
|
DIA
(4), NF (3)
|
2
CR, 4 PR
|
|
|
|
|
|
|
8 pts
|
2 pts
|
Pneumonitis (1)
|
RR 21 %
|
|
DL, dose level; cy, cycles; ANC, absolute
neutrophil count; Tc, thrombocytes; DIA, diarrhea; NF, neutropenic fever;
CR, complete response; PR, partial response; MR, minor response
|
Supported
in part by Aventis Pharma (Switzerland)
© 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_19-00102334-00_29-00A,00.asp?cat=CNS+Tumors&parent=
Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4 |
