Pazopanib and lapatinib in patients with relapsed malignant glioma: Results of a phase I/II study

Abstract

2040 Background: Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; and lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER-2 (ErbB2). Combination of VEGFR, PDGFR, and ErbB1 inhibitors may provide synergistic antitumor activity in malignant glioma. Phase I determined the optimally tolerated regimen (OTR) of paz and lap when given with enzyme-inducing anticonvulsants (EIACs). Phase II, which evaluated the efficacy of daily paz/lap (400 mg/1000mg) in relapsed grade 4 glioma without EIACs, was previously reported. Methods: Patients (pts) with grade 3 or 4 glioma, on EIACs, and with adequate organ function were eligible. Doses of paz and lap were escalated in a 3 + 3 design. OTR was defined as the highest dose of paz/lap at which no more than 1 of 6 pts had dose limiting toxicity (DLT) and target concentrations were achieved. Results: 32 pts have been enrolled at doses of paz/lap (mg, daily unless specified) of 200/1500 (N = 4), 800/1500 (N = 6), 800/500 bid (N = 5), 800/750 bid (N = 7), 800/1000 bid (N = 6), and 600 bid/1000 bid (N = 4). Data on 28 pts: the most common adverse events (AEs) were: fatigue (25%); diarrhea (25%); headache (21%); ALT increase (18%); nausea (18%); and insomnia (14%). Hepatobiliary lab abnormalities were reversible, uncomplicated, and included: AST elevation (11%), hyperbilirubinemia (7%), ALT elevation (36%; 7% Gr 3), and Alk phos elevation (14%). DLTs were elevated liver enzymes (800/1500; 1 pt), elevated lipase (800/750 bid; 1 pt) and thrombocytopenia, fatigue, diarrhea, confusion (800/1000 bid; 1 pt). 2 pts dose reduced and 3 pts had a dose interruption. At 600 bid/1000 bid, the target paz Cmin of 17.5 μg/mL was achieved; median lap Cmin of 0.447 μg/mL approached the target of 0.5 μg/mL. Phase I best response (MacDonald criteria) was PR in 3 pts (11%) and SD ≥ 8 weeks in 5 pts (18%). Two pts remain on the phase II, at 21 months (PR) and 23 months (CR) of therapy. Conclusions: The paz/lap combination has a manageable safety profile with a preliminary OTR with EIACs of paz 600 mg bid/ lap 1000 mg bid. EIACs decreased plasma paz and lap concentrations. Responses and lengthy periods without disease progression were seen in some pts in phase I and II. [Table: see text]