TY - JOUR
T1 - Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas
AU - Omuro, Antonio
AU - Beal, Kathryn
AU - McNeill, Katharine
AU - Young, Robert J.
AU - Thomas, Alissa
AU - Lin, Xuling
AU - Terziev, Robert
AU - Kaley, Thomas J.
AU - DeAngelis, Lisa M.
AU - Daras, Mariza
AU - Gavrilovic, Igor T.
AU - Mellinghoff, Ingo
AU - Diamond, Eli L.
AU - McKeown, Andrew
AU - Manne, Malbora
AU - Caterfino, Andrew
AU - Patel, Krishna
AU - Bavisotto, Linda
AU - Gorman, Greg
AU - Lamson, Michael
AU - Gutin, Philip
AU - Tabar, Viviane
AU - Chakravarty, Debyani
AU - Chan, Timothy A.
AU - Brennan, Cameron W.
AU - Elizabeth, Garrett Mayer
AU - Karmali, Rashida A.
AU - Pentsova, Elena
N1 - Funding Information:
We thank the patients and their families and caregivers for participating in the study. Third-party medical writing assistance, under the direction of the authors, was provided by J. Abbott and was funded by Tactical Therapeutics.
Funding Information:
Supported by Tactical Therapeutics and National Institutes of Health P30-CA008748. We thank the patients and their families and caregivers for participating in the study. Third-party medical writing assistance, under the direction of the authors, was provided by J. Abbott and was funded by Tactical Therapeutics.
Publisher Copyright:
© 2018 by American Society of Clinical Oncology.
PY - 2018/6/10
Y1 - 2018/6/10
N2 - 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 2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m 2 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 2 /d once daily) with radiotherapy and TMZ 75 mg/m 2 /d, followed by TMZ 150 mg to 200 mg/m 2 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 6 -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.
AB - 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 2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m 2 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 2 /d once daily) with radiotherapy and TMZ 75 mg/m 2 /d, followed by TMZ 150 mg to 200 mg/m 2 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 6 -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.
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U2 - 10.1200/JCO.2017.76.9992
DO - 10.1200/JCO.2017.76.9992
M3 - Article
C2 - 29683790
AN - SCOPUS:85048191778
SN - 0732-183X
VL - 36
SP - 1702
EP - 1709
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 17
ER -
