Trial Information

A Dose Finding Study (Phase I) of the Combination of ZD1839 (Iressa®) and an Oral Formulation of Irinotecan (Camptosar™) in Children With Refractory Solid Tumors

This is a phase I study to estimate the maximum tolerated dose and the dose limiting
toxicities of the intravenous formulation of irinotecan given orally in combination with a
fixed dose of oral gefitinib. This trial will use the EWOC method, which is an adaptive
dose escalation scheme. The method is fully adaptive and makes use of all the information
available at the time of each dose assignment, and directly addresses the ethical need to
control the probability of overdosing. It is designed to approach the maximum tolerated dose
(MTD) as fast as possible.

In this study the intravenous formulation of irinotecan will be given orally on days 1-5 and
days 8-12 (dose level begins at 5 mg/m2 ). One patient will be treated at each dose level
of irinotecan until moderate toxicity is observed. At the level where moderate toxicity is
observed, the cohort size will be increased to 2 patients. Dosages will then be increased
until the development of DLT as guided by the EWOC model. The estimated MTD will be
continually reassessed using all data from preceding patients. The toxicity data of all
patients enrolled in the trial are used to update the dose-toxicity relationship and to
guide the next escalation/de-escalation. The calculation will be carried out with EWOC
software. Patients will be enrolled and the dose assigned is determined based on previous
participants' toxicity. The dose of ZD1839 will be a fixed dose and will be administered
orally on days 1-12 - [150 mg/m2 (maximum 250 mg)] Each course of treatment will consist of
21 days. The administration of irinotecan on day 12 of course 1 and day 2 of course 2 will
be an intravenous administration. All other doses and subsequent courses will consist of an
orally administered dose.

Secondary Objectives Include:

- To describe dose-limiting toxicities (DLTs) of the combination of oral irinotecan and
ZD1839 and to define their duration and reversibility.

- To investigate the pharmacokinetics of oral irinotecan and ZD1839 when given in
combination in children with recurrent malignant solid tumors.

- To describe the relationship between pharmacokinetic parameters and toxicity.

- To describe any antitumor effects within the confines of a phase I study.

- To examine tumor expression of ErbB1 and/or ABCG2 with respect to pharmacokinetics and
response.

- To examine the pharmacogenetic determinants of ZD1839 and irinotecan pharmacokinetics
and pharmacodynamics.