PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated 
by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and 
VEGF overexpression, respectively, drive malignant glioma growth. We 
hypothesized that patients with recurrent glioblastoma would exhibit 
differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated 
with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.
EXPERIMENTAL DESIGN: A phase II study evaluated the antitumor activity of 
pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant 
glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing 
anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg 
design for futility. An independent, parallel phase I component determined the 
maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with 
grade 3/4 glioma receiving EIACs.
RESULTS: The six-month progression-free survival (PFS) rates in phase II (n = 
41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative 
cohorts, respectively, leading to early termination. Two patients (5%) had a 
partial response and 14 patients (34%) had stable disease lasting 8 or more 
weeks. In phase I (n = 34), the MTR was not reached. On the basis of 
pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 
1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced 
exposure to pazopanib and lapatinib.
CONCLUSIONS: The antitumor activity of this combination at the phase II dose 
tested was limited. Pharmacokinetic data indicated that exposure to lapatinib 
was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug 
delivery and activity may be essential for hypothesis-testing trials with 
targeted agents in malignant glioma.