First Study of the Safety, Tolerability, and Pharmacokinetics of CP-724,714 in Patients with Advanced Malignant Solid HER2-Expressing Tumors

Abstract

Purpose: To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2. Experimental Design: A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies. Results:Thirty female patients [median age, 51years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies. Conclusions: Dose-limiting toxicities included hyperbilirubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase II dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.

A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

“…Fluctuations followed the 14-day pattern of drug dosing and were quickly reversible after drug discontinuation. Hepatotoxicity, almost always reversible, is known to occur with another observed AEGFR and HER2 tyrosine kinase inhibitors (Geyer et al, 2006;Munster et al, 2007). In view of cardiac effects of trastuzumab, a decrease in cardiac function was considered to be a potential side effect of BIBW 2992.…”

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

“…Physiologically-based pharmacokinetic (PBPK) models were constructed for bosentan, telmisartan, and CP-724,714 in humans using available in vivo time course data (Weber et al, 1996; Stangier et al, 2000; Munster et al, 2007). For simulations where bosentan metabolism was impaired, the V max for the metabolism of both metabolites was represented as 10% of their baseline value.…”

“… Simulated plasma human concentrations of CP-724,714 after an oral dose of 250 mg (A) and 400 mg (B) compared to data from Munster et al (2007) . The 250 mg dose data represented in this figure are a compilation of the results from the first dose of several different dosing protocols.…”

Trastuzumab-Induced Hepatotoxicity

“…23 Interestingly, in a Phase 1 report of the study drug CP-724,714, which is an oral HER2 tyrosine kinase inhibitor, nearly 30% of the patients experienced dose-limiting hepatotoxicity. 24 The mechanism of hepatic injury caused by trastuzumab is unclear. The clearance of trastuzumab has been reported to occur via the reticuloendothelial system, as with other immunoglobulin G antibodies.…”