A Phase I/II Trial of Pazopanib in Combination with Lapatinib in Adult Patients with Relapsed Malignant Glioma
Mené sur 41 patients atteints d'un glioblastome récidivant, cet essai de phase II évalue l'activité antitumorale du pazopanib en combinaison avec le lapatinib
Résumé en anglais
Purpose: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGFR (ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that recurrent glioblastoma patients would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib.
Methods: A Phase II study evaluated the antitumor activity of pazopanib 400 mg/day plus lapatinib 1000 mg/day in patients with grade IV malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIACs). The Phase II study used a 2-stage Green-Dahlberg design for futility. An independent, parallel Phase I component determined the maximum tolerated regimen (MTR) of pazopanib and lapatinib in grade III/IV glioma patients receiving EIACs.
Results: The 6-month progression-free survival 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 weeks. In Phase I (n=34), the MTR was not reached. Based on pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1000 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.
