A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Abstract

INTRODUCTION:

Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC.

METHODS:

Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients.

RESULTS:

Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 μg/mL and AUC₂₄ was 4.29 μg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients.

CONCLUSIONS:

Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.

• Authors: Hidehito Horinouchi, Noboru Yamamoto, Hiroshi Nokihara, Takeshi Horai, Makoto Nishio, Fumiyoshi Ohyanagi, Atsushi Horiike, Kazuhiko Nakagawa, Masaaki Terashima, Takafumi Okabe, Hiroyasu Kaneda, Mark D McKee, Dawn M Carlson, Hao Xiong, Tomohide Tamura
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 74 Issue 1 Pg. 37-43 (Jul 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24807459 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Indazoles
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Carboplatin
• linifanib
• Receptors, Platelet-Derived Growth Factor
• Receptors, Vascular Endothelial Growth Factor
• Paclitaxel

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Carboplatin (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma (blood, drug therapy, pathology, secondary)
• Carcinoma, Non-Small-Cell Lung (blood, drug therapy, pathology)
• Chemotherapy-Induced Febrile Neutropenia (physiopathology)
• Cohort Studies
• Dose-Response Relationship, Drug
• Female
• Humans
• Indazoles (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Japan
• Leukopenia (chemically induced, physiopathology)
• Lung (drug effects, pathology)
• Lung Neoplasms (blood, drug therapy, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Paclitaxel (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Phenylurea Compounds (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Severity of Illness Index
• Thrombocytopenia (chemically induced, physiopathology)
• Tumor Burden (drug effects)