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A phase I/II trial of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis
inhibitor, in combination with either temozolomide or lomustine for patients
with recurrent glioblastoma multiforme (GBM)
D. Reardon, H. Friedman, W. K. A. Yung, M. Brada, C. Conrad, J. Provenzale, E.
Jackson, H. Serajuddin, B. Chen, D. Laurent
Duke University Medical Center, Durham, NC; University of Texas
M. D. Anderson Cancer Center, Houston, TX; Royal Marsden NHS Trust, Surrey,
United Kingdom; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Schering
AG, Berlin, Germany.
Background. VEGF-mediated signaling through VEGF receptors is integral to
GBM neovascularization and therefore an attractive therapeutic target.
PTK/ZK is
an oral, once-daily inhibitor of all known VEGF receptors.
The primary objective
of this trial was to determine the safety profile and maximum tolerated dose
(MTD) of oral once-daily PTK/ZK in combination with either temozolomide (TMZ) or
lomustine (CCNU) in patients (pts) with GBM.
Antitumor activity was also
assessed.
Methods. The starting dose of PTK/ZK was 500 mg/day, escalating
to 1,000, 1,250, and 1,500 mg/day in cohorts of 3 to 6 pts with dose expansion
at 1,500 mg/day in the TMZ treatment arm.
Concurrently, pts also received either
TMZ (200 mg/m2/day for 5 days every 28 days) or CCNU (130 mg/m2
every 6 weeks).
Results. Among 60 pts enrolled, median age was 53 years
(range, 28 - 80 years), median KPS was 90 (range, 70 - 100), and the median
number of prior regimens was 1 (range, 1 - 9).
In 37 pts treated with PTK/ZK +
TMZ, 1 dose-limiting toxicity (DLT) (grade 3 dizziness) was reported at 1,500
mg/day, and the MTD was not reached.
Among 23 pts treated with PTK/ZK + CCNU,
DLTs included grade 3 febrile neutropenia in 1 pt each at the 500- and 1,000-mg
levels and grade 4 transaminase elevation in 1 pt treated at the 1,000-mg level,
which may be related to CCNU.
The PTK/ZK dose level was reduced to 750 mg/day
plus CCNU; accrual is ongoing.
Among 51 pts evaluable for response, 4 had a
partial response (3 with PTK/ZK + TMZ and 1 with PTK/ZK + CCNU) and 27 had
stable disease (19 with PTK/ZK + TMZ and 8 with PTK/ZK + CCNU) as best response.
Median time to progression was 15.7 weeks (95% CI = 8.6, 17.3 weeks) for PTK/ZK
+ TMZ and 10.4 weeks (95% CI = 8.1, 18.7 weeks) for PTK/ZK + CCNU.
The median
TTP for PTK/ZK + TMZ compares favorably with historical reports with TMZ alone (Br
J Cancer 2000;83:588).
Conclusions. Continuous daily dosing of oral
PTK/ZK was well tolerated and demonstrated encouraging antitumor activity when
combined with either TMZ or CCNU, warranting further study.
Accrual is ongoing,
and the respective MTDs have yet to be determined.
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_19-001702,00.asp
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