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Final results of Phase I/II studies of
IL13-PE38QQR administered intratumorally (IT) and/or peritumorally
(PT) via convection-enhanced delivery (CED) in patients undergoing
tumor resection for recurrent malignant glioma
M. Prados, S. Kunwar, F. F. Lang, Z.
Ram, M. Westphal, G. Barnett, J. H. Sampson, D. Croteau, R. K. Puri,
for all participating investigators
Univ of CA, San Francisco, CA; M.D.
Anderson Cancer Ctr, Houston, TX; Tel Aviv Univ, Tel Aviv, Israel;
Univ Hosp Hamburg-Eppendorf, Hamburg, Germany; The Cleveland Cinic
Fdn, Cleveland, OH; Duke Univ Medcl Ctr, Durham, NC; NeoPharm, Inc.,
Lake Forest, IL; CBER U. S. FDA, Bethesda, MD
Background. IL13-PE38QQR
(IL13PE) is a recombinant cytotoxin which binds selectively to the
IL13 receptor that is over-expressed on malignant glioma cells.
CED utilizes positive pressure infusion to achieve loco-regional
delivery of therapeutic agents via intracerebral catheters.
Given the infiltrative nature of malignant glioma, two approaches were
examined in three Phase I/II studies.
Methods. IL13PE was
infused IT before resection, and/or PT after resection.
Safety and tolerability of IL13PE, different dosing regimens, catheter
positioning, and efficacy as measured by overall survival (OS) were
evaluated.
The distribution of an imaging tracer co-infused with IL13PE was also
assessed by SPECT.
Results. Enrollment is
complete; 74 adult patients received IL13PE.
Dose-limiting toxicity consisted of non-specific necrosis of
tumor-infiltrated and normal brain parenchyma which occurred at 1.0 µg/mL
with PT administration.
The maximum tolerated dose for PT infusions was 0.5 µg/mL.
Higher concentrations (up to 3 µg/mL) were tolerated in the IT
setting.
The most common drug related adverse events were headache (31%),
hemiparesis (16%), and fatigue (11%).
SPECT imaging showed that distribution was confined to the solid tumor
with IT infusion, but distribution to parenchyma at risk for tumor
infiltration could be achieved with PT infusion.
Improved OS was observed in patients with glioblastoma multiforme
(GBM) receiving PT infusions (45.9 wks, n=45) as compared to patients
given IT infusion (37.1 wks, n=22).
In the PT setting, OS was 70.3 weeks (n=26) for patients with ≥2
optimally placed catheters compared to 41.4 weeks (n=19) for those
with <2 optimally placed catheters.
Deferred catheter placement led to a greater percentage of optimally
placed catheters.
Conclusions. CED of
IL13PE has a favorable risk/benefit profile for treatment of patients
with GBM undergoing tumor resection.
Based on these results, the design of the ongoing Phase III study
incorporates deferred catheter placement and PT infusion of 0.5 µg/mL
of IL13PE.
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