GRCh38 · COSMIC v92


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Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas.
Paper ID
Omuro A, Beal K, McNeill K, Young RJ, Thomas A, Lin X, Terziev R, Kaley TJ, DeAngelis LM, Daras M, Gavrilovic IT, Mellinghoff I, Diamond EL, McKeown A, Manne M, Caterfino A, Patel K, Bavisotto L, Gorman G, Lamson M, Gutin P, Tabar V, Chakravarty D, Chan TA, Brennan CW, Garrett-Mayer E, Karmali RA and Pentsova E
Antonio Omuro, University of Miami, Miami, FL; Kathryn Beal, Robert J. Young, Thomas J. Kaley, Lisa M. DeAngelis, Mariza Daras, Igor T. Gavrilovic, Ingo Mellinghoff, Eli L. Diamond, Andrew McKeown, Malbora Manne, Andrew Caterfino, Krishna Patel, Philip Gutin, Viviane Tabar, Debyani Chakravarty, Timothy A. Chan, Cameron W. Brennan, and Elena Pentsova, Memorial Sloan Kettering Cancer Center; Rashida A. Karmali, Tactical Therapeutics, Inc, New York; Katharine McNeill, Montefiore Medical Center, Bronx, NY; Alissa Thomas, University of Vermont, Burlington, VT; Xuling Lin, National Neuroscience Institute, Singapore; Robert Terziev, University Hospital, Zurich, Switzerland; Linda Bavisotto, Porta Clinica PLLC, Seattle, WA; Greg Gorman, Samford University McWhorter School of Pharmacy, Birmingham, AL; Michael Lamson, Nuventra Pharma Sciences, Durham, NC; and Elizabeth Garrett-Mayer, Medical University of South Carolina, Charleston, SC.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018:JCO2017769992
ISSN: 1527-7755
PMID: 29683790 (view at PubMed or Europe PMC)
Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m<sup>2</sup> once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m<sup>2</sup> 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m<sup>2</sup>/d once daily) with radiotherapy and TMZ 75 mg/m<sup>2</sup>/d, followed by TMZ 150 mg to 200 mg/m<sup>2</sup> 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O<sup>6</sup>-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.
Paper Status