This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC0-tand Cmaxof pazopanib was observed. Four partial responses were observed in patients with renal cancer (n = 2), giant-cell tumor of the bone (n = 1), and thyroid cancer (n = 1). Stable disease for ≥18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000.

Lapatinib, Pazopanib, Pharmacokinetic interaction, Phase I, Solid tumors
dx.doi.org/10.1007/s10637-012-9885-8, hdl.handle.net/1765/40693
Investigational New Drugs: the journal of new anti-cancer agents
Erasmus MC: University Medical Center Rotterdam

de Jonge, M.J.A, Hamberg, A.P, Verweij, J, Savage, S, Suttle, A.B, Hodge, J, … Hurwitz, H.I. (2013). Phase i and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Investigational New Drugs: the journal of new anti-cancer agents, 31(3), 751–759. doi:10.1007/s10637-012-9885-8