C124
Pazopanib and lapatinib in patients with relapsed malignant glioma: results of a Phase I/II study
Martin Forster1, David Olmos1, Sophia Frentzas1, Shahneen Sandhu1, Tim Yap1, Daniel Tan1, Jorge Barriuso1, Michelle Wright1, Morris Groves2, David Reardon3, Martin Curtis4, Jeffrey Hodge4, Ben Suttle4, B Ma4, Joanne Lager4, Johann de Bono1
1Royal Marsden Hospital, Sutton, UK, 2M.D. Anderson, Houston, Texas, USA, 3Duke University Medical Centre, Durham, USA, 4GlaxoSmithKline, Research Triangle Park, USA
Background
Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR and HER2. The combination may provide synergistic activity in malignant glioma. The efficacy of daily paz/lap (400mg/1000mg) in relapsed grade 4 glioma was previously reported. This study determined the optimally tolerated regimen (OTR) of paz/lap when given with enzyme-inducing anticonvulsants (EIACs).
Method
Patients (pts) with Grade 3 or 4 glioma were treated with escalating doses of paz/lap in a 3+3 design. OTR was defined as the highest dose of paz/lap at which <1/6 pts had DLT and target concentrations were achieved.
Results
In Phase I, 34 pts were 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=6). DLTs were transaminitis (2 pts: 800/1500; 800/500 bid), pancreatitis (1pt: 800/750 bid), thrombocytopenia (3 pts: 800/750 bid; 800/1000bid; 600 bid/1000 bid), fatigue (2 pts: 800/1000 bid; 600 bid/1000 bid), seizure (1pt: 800/750 bid), confusion (1pt: 800/1000 bid), diarrhoea (1pt: 800/1000 bid), & neutropaenia (1pt: 600 bid/1000 bid). Common adverse events were diarrhoea (56%), fatigue (41%), headache (31%), nausea (28%), raised ALT (25%) and hypertension (25%). At 600 bid/1000 bid, target paz Cmin of 17.5g/mL was achieved; median lap Cmin of 0.45g/mL approached target of 0.5g/mL. In Phase I, best response was PR in 3 pts (10%; 2.75-8 months) and SD ≥8 wks in 13 pts (43%). In Phase II, best response was PR in 3 pts (7%; 6-22 months) and SD ≥8 wks in 21 pts (51%) by MacDonald criteria.
Conclusion
EIACs decreased plasma paz /lap concentrations and at an OTR of 600mg bid/1000mg bid has a manageable safety profile with responses and prolonged SD seen in some pts.
