Effect of Carboxyamidotriazole Orotate, a Modulator of Calcium-Dependent Signaling Pathways, on Advanced Solid Tumors

• 作者: Alan Sandler Antonio M. P. Omuro Greg S. Gorman Matthew H. Taylor Rashida A. Karmali Walter J. Urba
• 来源期刊: 癌症治疗(英文)
• 学科: 医学
• 关键词: CTO Safety Ca-Dependent Signaling PATHWAYS
• 年，卷（期）: azzlyw_2015,（4）
• 页码范围: 322-333
• 页数: 12页
• 分类号: R73

摘要

Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.