Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors

• Published in: Investigational new drugs Vol. 31; no. 3; pp. 751 - 759
• Main Authors: de Jonge, Maja J. A., Hamberg, Paul, Verweij, Jaap, Savage, Shawna, Suttle, A. Benjamin, Hodge, Jeffrey, Arumugham, Thangam, Pandite, Lini N., Hurwitz, Herbert I.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biochemistry; Biological and medical sciences; Breast cancer; Cancer therapies; Cell growth; Diarrhea; Drug dosages; Drug interactions; Ejection fraction; Female; Humans; Hypertension; Kinases; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - blood; Neoplasms - drug therapy; Oncology; Pharmacokinetics; Pharmacology/Toxicology; Phase I Studies; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Thyroid gland; Toxicity; Tumors; Vascular endothelial growth factor; Young Adult; Pharmacokinetic interaction; Phase I; Lapatinib; Solid tumors; Pazopanib; Antineoplastic agent; Human; Solid tumor; Drug combination; Enzyme; Tyrosine kinase inhibitor; Toxicity; Transferases; Oral administration; Enzyme inhibitor; Malignant tumor; Phase I trial; Advanced stage; Drug interaction; Combined treatment; Pharmacokinetics; Protein-tyrosine kinase; Cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-012-9885-8

Summary 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 AUC 0-t and C max of 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.