Ph2 PF-00299804 in Relapsed/Recurrent GBM

In this Phase 2 trial, adult recurrent glioblastoma (GBM) patients with available archival
tumor material that demonstrates EGFR gene amplification will be enrolled onto one of three
arms. Arm A will be limited to 10 patients who are candidates for surgical resection that
are at first recurrence and have not had prior anti-VEGF therapy. Arm B will include
patients at first recurrence who are not surgical candidates and who have not had prior
anti-VEGF therapy. Arm C will be limited to patients who are not surgical candidates and are
at first recurrence from a bevacizumab-containing therapeutic regimen. Arm C will be
triggered if a predetermined efficacy threshold is achieved in Stage I of Arm B.

PF 00299804 is an orally available, potent, highly selective, irreversible small molecule
inhibitor of the HER family of tyrosine kinases. EGFR is an attractive therapeutic target
for GBM due to high rates of overexpression and increasing evidence linking EGFR activation
to signal transduction pathways mediating tumor proliferation, survival, angiogenesis and
invasion. Results of malignant glioma clinical trials evaluating first generation,
reversible EGFR inhibitors (mono-HER inhibitors), including gefitinib and erlotinib, yielded
disappointing results. These studies were limited for several reasons but mainly because the
agents were tested in an unselected population. In this study, only an enriched population
of patients who have the greatest potential of responding to HER inhibition (patients with
EGFR amplified tumors) will be enrolled. In addition, we will evaluate a second generation
ErbB inhibitor, PF-00299804, which has greater anti-tumor promise based on its ability to
block multiple ErbB partners, effective inhibition of the constitutively active mutant
EGFRvIII receptor, irreversible target inhibition and its ability to penetrate the
blood-brain barrier. Preclinical data using PF-00299804 have shown that PF-00299804 has
greater activity as shown by IC50 against EGFRvIII, which is found in half of EGFR-amplified
tumors, than the reversible EGFR inhibitor gefitinib.

The primary objective of this study is to assess Progression-Free Survival (PFS) at six
months (PFS6m) in patients with recurrent GBM and EGFR gene amplification in archival tumor
material who are treated with continuous daily dosing of PF-00299804 (Arm B). Secondary
objectives include to 1) assess the ability of PF-00299804 to cross the blood-brain-barrier
(BBB) in GBM patients who are candidates for surgical re-resection (total, or sub-total) in
Arm A, 2) evaluate safety and tolerability of orally administered PF-00299804 on a
continuous dosing schedule in patients with recurrent GBM, 3) document secondary measures of
anti-tumor efficacy of PF-00299804 in patients with recurrent GBM, 4) assess anti-tumor
response in patients in Arm B using MacDonald criteria, 5) assess Overall Survival (OS) in
patients in Arm B 6) Assess the efficacy and safety of PF-00299804 in patients with
recurrent GBM who have previously been treated with bevacizumab therapy (Arm C), 7) Collect
sparse pharmacokinetic (PK) data for population PK, 8) assess pharmacodynamic response to
PF-00299804 in tumor tissue in patients in Arm A, 9) Evaluate potential molecular
determinants of response in tumor tissue and in circulation to PF-00299804, 10) Explore
patient reported outcomes (PRO) of patients in Arm B.