TITLE:
Effect of Carboxyamidotriazole Orotate, a Modulator of Calcium-Dependent Signaling Pathways, on Advanced Solid Tumors
AUTHORS:
Matthew H. Taylor, Alan Sandler, Walter J. Urba, Antonio M. P. Omuro, Greg S. Gorman, Rashida A. Karmali
KEYWORDS:
CTO, Safety, Ca-Dependent Signaling Pathways
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.6 No.4,
April
13,
2015
ABSTRACT:
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.