A phase I open-label study of the safety, tolerability, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab for relapsed or refractory metastatic colorectal cancer

• Published in: Investigational new drugs 2015-02, Vol.33 (1), p.138-147
• Main Authors: Bennouna, Jaafar, Deslandres, Marion, Senellart, Helene, de Labareyre, Cecile, Ruiz-Soto, Rodrigo, Wixon, Claire, Botbyl, Jeff, Suttle, A. Benjamin, Delord, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - pharmacokinetics; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Cancer therapies; Cetuximab; Chemotherapy; Clinical trials; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Cytotoxicity; Drug dosages; Drug Resistance, Neoplasm; FDA approval; Female; Hematology; Humans; Hypertension; Inhibitor drugs; Kinases; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Monoclonal antibodies; Neutropenia - chemically induced; Oncology; Pharmaceutical sciences; 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; R&D; Recurrence; Research & development; Response rates; Studies; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Thrombocytopenia; Topoisomerase I Inhibitors - administration & dosage; Topoisomerase I Inhibitors - adverse effects; Topoisomerase I Inhibitors - pharmacokinetics; Toxicity; Treatment Outcome; Vascular endothelial growth factor
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0142-1

Summary Background Pazopanib is a multi-targeted tyrosine kinase inhibitor shown to be clinically active in the treatment of various cancer types. This study aimed to evaluate the maximum tolerated regimen (MTR), safety, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab in adult patients with relapsed or refractory metastatic colorectal cancer (mCRC). Patients and methods This was a Phase I, 3 + 3 design, open-label, dose-escalation study (NCT0050943; VEG108925) conducted in sequential cohorts to determine the MTR of pazopanib and irinotecan administered with cetuximab. Twenty-five patients received treatment in three dosing cohorts and were evaluated for safety and tolerability of the combination and pharmacokinetics of individual drugs. Results The MTR was determined to be 400 mg pazopanib per day orally in combination with 150 mg/m 2 irinotecan biweekly and 250 mg/m 2 cetuximab weekly by infusion. Neutropenia was the main dose-limiting toxicity. Pharmacokinetic results suggested that the overall systemic exposure to SN-38, the active metabolite of irinotecan, was affected by pazopanib to a greater extent than was the systemic exposure to irinotecan itself. Conclusions This study provided evidence for the manageable safety profile and feasibility of using the novel triplet combination of pazopanib, irinotecan, and cetuximab in patients with refractory mCRC. Further large-scale Phase II studies are warranted.