Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas

Antonio Omuro, Kathryn Beal, Katharine A. McNeill, Robert J. Young, Alissa Thomas, Xuling Lin, Robert Terziev, Thomas J. Kaley, Lisa M. DeAngelis, Mariza Daras, Igor T. Gavrilovic, Ingo Mellinghoff, Eli L. Diamond, Andrew McKeown, Malbora Manne, Andrew Caterfino, Krishna Patel, Linda Bavisotto, Greg Gorman, Michael LamsonPhilip Gutin, Viviane Tabar, Debyani Chakravarty, Timothy A. Chan, Cameron W. Brennan, Garrett Mayer Elizabeth, Rashida A. Karmali, Elena Pentsova

Research output: Contribution to journalArticle

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Abstract

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/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 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 O6-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.

Original languageEnglish (US)
Pages (from-to)1702-1709
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number17
DOIs
StatePublished - Jun 10 2018

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temozolomide
carboxyamido-triazole
Glioblastoma
Glioma
Hypophosphatemia
DNA Mismatch Repair
Survival
Methyltransferases
Constipation
Calcium Channels
Brain Neoplasms
Nausea
Genes
Disease-Free Survival
Fatigue
Neoplasms
Appointments and Schedules
Radiotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas. / Omuro, Antonio; Beal, Kathryn; McNeill, Katharine A.; Young, Robert J.; Thomas, Alissa; Lin, Xuling; Terziev, Robert; Kaley, Thomas J.; DeAngelis, Lisa M.; Daras, Mariza; Gavrilovic, Igor T.; Mellinghoff, Ingo; Diamond, Eli L.; McKeown, Andrew; Manne, Malbora; Caterfino, Andrew; Patel, Krishna; Bavisotto, Linda; Gorman, Greg; Lamson, Michael; Gutin, Philip; Tabar, Viviane; Chakravarty, Debyani; Chan, Timothy A.; Brennan, Cameron W.; Elizabeth, Garrett Mayer; Karmali, Rashida A.; Pentsova, Elena.

In: Journal of Clinical Oncology, Vol. 36, No. 17, 10.06.2018, p. 1702-1709.

Research output: Contribution to journalArticle

Omuro, A, Beal, K, McNeill, KA, 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, Elizabeth, GM, Karmali, RA & Pentsova, E 2018, 'Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas', Journal of Clinical Oncology, vol. 36, no. 17, pp. 1702-1709. https://doi.org/10.1200/JCO.2017.76.9992
Omuro, Antonio ; Beal, Kathryn ; McNeill, Katharine A. ; Young, Robert J. ; Thomas, Alissa ; Lin, Xuling ; Terziev, Robert ; Kaley, Thomas J. ; DeAngelis, Lisa M. ; Daras, Mariza ; Gavrilovic, Igor T. ; Mellinghoff, Ingo ; Diamond, Eli L. ; McKeown, Andrew ; Manne, Malbora ; Caterfino, Andrew ; Patel, Krishna ; Bavisotto, Linda ; Gorman, Greg ; Lamson, Michael ; Gutin, Philip ; Tabar, Viviane ; Chakravarty, Debyani ; Chan, Timothy A. ; Brennan, Cameron W. ; Elizabeth, Garrett Mayer ; Karmali, Rashida A. ; Pentsova, Elena. / Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 17. pp. 1702-1709.
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title = "Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas",
abstract = "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/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 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 O6-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.",
author = "Antonio Omuro and Kathryn Beal and McNeill, {Katharine A.} and Young, {Robert J.} and Alissa Thomas and Xuling Lin and Robert Terziev and Kaley, {Thomas J.} and DeAngelis, {Lisa M.} and Mariza Daras and Gavrilovic, {Igor T.} and Ingo Mellinghoff and Diamond, {Eli L.} and Andrew McKeown and Malbora Manne and Andrew Caterfino and Krishna Patel and Linda Bavisotto and Greg Gorman and Michael Lamson and Philip Gutin and Viviane Tabar and Debyani Chakravarty and Chan, {Timothy A.} and Brennan, {Cameron W.} and Elizabeth, {Garrett Mayer} and Karmali, {Rashida A.} and Elena Pentsova",
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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 A.

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

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/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 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 O6-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/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 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 O6-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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