carboxyamidotriazole orotate + temozolomide

Carboxyamidotriazole orotate (CTO) combined with temozolomide (TMZ) is an investigational oral combination therapy evaluated primarily for the treatment of glioblastoma (GBM) and other high-grade gliomas. CTO is the orotic acid salt of carboxyamidotriazole, a non-voltage-dependent calcium channel inhibitor that modulates multiple cell-signaling pathways, including those involved in angiogenesis and tumor proliferation. It inhibits receptor-operated calcium-channel-mediated influx, affecting VEGF and PI3K signaling, FGF2-induced tyrosine kinase activity, phospholipase Cγ activation, IP3 generation, nitric oxide synthase activation, and can induce apoptosis in resistant cancer cells[1][5]. Temozolomide is an oral alkylating agent that induces DNA damage leading to tumor cell death. The combination has shown synergistic antitumor effects in preclinical models and promising safety/efficacy signals in phase Ib clinical trials for recurrent and newly diagnosed GBM as well as anaplastic gliomas[1][2][3]. The regimen was generally well tolerated; main toxicities included fatigue, constipation, nausea, hypophosphatemia, neutropenia, thrombocytopenia (late), but no dose-limiting toxicities were observed at recommended doses. Pharmacokinetic studies showed no significant drug-drug interaction between CTO and TMZ[1]. In clinical studies combining CTO with standard-dose TMZ—with or without radiotherapy—patients demonstrated improved progression-free survival compared to historical controls on standard chemoradiation alone. Notably high response rates were seen among EGFR-amplified tumors[1][2]. Preclinical data also suggest this combination may allow lower dosing of temozolomide while maintaining efficacy due to enhanced sensitivity conferred by CTO[5].

Other names

CTO + TMZcarboxyamidotriazole orotate and temozolomide