A phase I study of carboxyamidotriazole orotate (CTO) in of advanced solid tumors.

Abstract

2518 Background: CTO is an orotate salt of carboxyamidotriazole (CAI), which is an inhibitor of calcium-dependent intracellular and extracellular signal transduction pathways (presumably affecting VEGF and PI3K) and has tumor anti-proliferative and anti-invasive properties. The activity of CTO alone and in combination with temozolomide or 5Efluorouracil was demonstrated in human glioblastoma, melanoma, and colon tumor xenografts. Methods: This study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics and activity of CTO monotherapy in 34 patients (pts) with advanced solid tumors meeting eligibility criteria with adequate organ function. The CTO study NCT01107522 enrolled pts in 8 cohorts receiving continuous daily oral CTO capsules at doses ranging from 50mg- 555mg/m2/day. The MTD has not been determined. Pharmacokinetic (PK) sampling was performed during cycle 1 at each dose level. CT scans were performed at baseline and after 8 weeks to assess anti-tumor effect. Patients remained on study if they achieved stable disease (SD) or tumor response and did not experience dose limiting toxicities (DLT). Results: The most frequently recorded adverse events (Grade 1 and 2) were fatigue, nausea, vomiting, and dizziness. DLTs of grade 3 fatigue (219 mg/m2) and grade 3 creatine kinase elevation (555 mg/m2) occurred in one pt each. No cardiac QTc prolongations have been recorded. PK data demonstrated therapeutically relevant CAI levels beginning at the 219mg/m2 dose. Nine pts continued CTO dosing beyond 2 cycles. Tumor assessments demonstrated SD at different doses of CTO: i) 75mg/m2 renal carcinoma (1, 12 cycles); ii) 219 mg/m2-small cell lung cancer (1, 4 cycles), squamous cell lung cancer with PIK3CA mutation (1, 10 cycles and continuing), and lung adenocarcinoma with EGFR mutation (1, 10 cycles and, continuing); iii) 285 mg/m2-1 colon cancer with BRAFV600E mutation (1, 6 cycles), and squamous cell carcinoma (tonsil) with PI3KCA and NRAS mutations (1, 9 cycles, and continuing). Conclusions: CTO given as monotherapy up to 555mg/m2/day is safe and tolerable and without MTD. Six patients with different malignancies and genomic markers achieved SD; combinatorial investigations in malignant gliomas have started. Clinical trial information: NCT01107522.