Safety of Neratinib (HKI-272) in Combination with Capecitabine in Patients with Solid Tumors: A Phase 1/2 Study.
Authors: Saura C. , Martin M. , Moroose R. , Harb W. , Liem K. , Arena F. , Gressler V. , Cortés J. , Wade M. , Powell C. , Shapiro M. 
Published: December 2010

Abstract
Background: Neratinib (HKI-272) is an oral irreversible pan-ErbB tyrosine kinase inhibitor that blocks downstream signaling of ErbB1, -2, and -4 by binding to the intracellular ATP binding sites of these receptors. Other available ErbB inhibitors include the ErbB2-specific monoclonal antibody trastuzumab and the reversible small molecule inhibitor lapatinib, which is directed against ErbB1 and -2. Neratinib may have advantages over other inhibitors because of its pan-ErbB inhibition and ability to irreversibly inhibit the intracellular tyrosine kinase domains. The objective of this ongoing multicenter, open-label, phase 1/2 study is to evaluate the safety, tolerability, and preliminary antitumor activity of neratinib in combination with capecitabine in patients with solid tumors.Material and Methods: Patients with advanced solid tumors are being enrolled in part 1 of this 2-part study to assess safety and tolerability (ie, adverse events and dose-limiting toxicities [DLTs]) and to determine the maximum tolerated dose (MTD) of neratinib in combination with capecitabine. Part 2 will further assess safety and tolerability, as well as objective response rates and pharmacokinetic parameters at the MTD in patients with metastatic or locally advanced ErbB2+ breast cancer. The dose escalation scheme for part 1 includes 3 ascending dose levels: neratinib 160 or 240 mg/day plus capecitabine 750 mg/m2 twice daily (bid) on days 1-14 of a 21-day cycle (levels 1 and 2) and neratinib 240 mg/day plus capecitabine 1,000 mg/m2 bid on days 1-14 of a 21-day cycle (level 3). Each patient participates at only 1 dose level. If dose level 1 is tolerated, but dose level 2 is not, an intermediate dose level of neratinib 200 mg plus capecitabine 750 mg/m2 bid can be evaluated as a potential MTD.Results: Data as of 1 May 2009 for patients treated at dose levels 1, 2, and 3 (n = 6, 5, and 4, respectively) are presented. Median (range) ages for patients at the respective dose levels were 46 (37-69), 56 (41-58), and 53 (39-80) years. Two DLTs have been observed at dose level 3; one patient each experienced grade 3 elevated alanine aminotransferase and grade 3 diarrhea. Common treatment-emergent adverse events (all grades, ≥10% of patients) included diarrhea (50.0%), nausea (25.0%), vomiting (25.0%), fatigue (16.7%), and pyrexia (16.7%). One patient at dose level 3 experienced a drug-related adverse event of grade ≥3 diarrhea. No patients have withdrawn from the study because of adverse events; 3 patients have died (disease progression, n = 3).Discussion: Based on preliminary results from part 1, the combination of neratinib and capecitabine was well tolerated. Accrual of patients will continue and a fourth cohort of patients (neratinib 200 mg/day plus capecitabine 1,000 mg/m2 bid) will be added to further evaluate this therapeutic combination and establish a recommended dose level for part 2 of this study and for future later-stage clinical studies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5108.