| General information |
| Database: | DB00593 |
| Objective: | 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. They 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. |
| Authors: | Reardon DA, et al |
| Title: | a phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. |
| Journal: | Clin Cancer Res. |
| Year: | 2013 |
| PMID: | 23363814 |
| Trial Design |
| Clinical Trial Id: | NCT00350727 |
| Agent: | pazopanib and lapatinib
|
| Target: | NA
|
| Cancer Type: | Tumors of the nervous system |
| Cancer Subtype: | glioblastoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | pazopanib+ lapatinib |
| Study Type: | a multicenter, openlabel, nonrandomized, phase II study |
| Key Patients Feature: | All eligible patients were at least 18 years of age with anEastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate hematologic, renal, and hepatic function.phase II study patients were additionally required to have grade 4 malignant glioma at first or second recurrence, no concurrent EIAC therapy, and sufficient archival tumor material for analysis of PTEN andEGFRvIII expression.phase I patients were required to havea diagnosis of grade 3/4 malignant glioma at recurrence andto be receiving concurrent treatment with a CYP3A4 EIAC |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | This 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 enzymeinducing anticonvulsants (EIAC). the phase II study used a twostage GreenDahlberg design for futility. An independent, parallelphase I component determined the maximumtolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. |
| Primary End Point: | 6month PFS rate and safety in each stratum. |
| Secondary End Point: | PFS and pharmacokinetics of pazopanib and lapatinib in the absence of an EIAC |
| Patients Number: | 74 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | Median PFS was similar between the 2 groups: 56 days [95% confidence interval (CI), 45-113) in the biomarkernegative stratum and 62 days (95% CI, 56-90) in the biomarkerpositive stratum. |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most frequently reported treatmentrelated adverse events included diarrhea (56%), fatigue (34%), hypertension (24%), and rash (24%). A total of 11 patients (27%) experienced a total of 33 interruptions in pazopanib and/or lapatinib dosing because of adverse events. Treatmentrelated adverse events occurred in 28 patients (82%), were primarily grades 1 or 2, and most frequently included diarrhea (56%), hypertension (26%), fatigue (26%), nausea (24%), thrombocytopenia (15%), and neutropenia (12%). Four patients (12%) permanently discontinued study therapy due to adverse events. |
| Conclusions: | The antitumor activity of this combination at thephase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in thephase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesistesting trials with targeted agents in malignant glioma. |