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.

Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation

“…Moreover, the anti-tumoral effect of this combination could explain the mild efficacy of CAI when it was used as a single agent in clinical trials, as the sole inhibition of Mcl-1 is not sufficient to induce apoptosis in ovarian cancer [ 45 ]. CAI has been tested in combination with several compounds and has been shown to potentiate the anti-tumoral activity of sorafenib [ 63 ], LM-1685, a celecoxib analogue [ 79 ], 2-deoxyglucose [ 80 ] and Temozolomide [ 48 ]. In this recent phase IB clinical trial conducted in cohorts of recurrent or newly diagnosed glioblastoma, patients were treated with increasing doses of the oral derivative of this calcium channel blocker (Carboxyamidotriazole orotate - CTO) in combination with temozolomide ± radiotherapy.…”

“…The results showed, on the one hand, that CTO is well tolerated by patients confirming results observed in previous clinical trials and on the other hand that treatment was effective on these aggressive cancers. This clinical trial showed that CAI has to be combined with another anti-neoplastic molecule in order to have a good therapeutic efficacy and it should be noted that the best clinical responses were obtained for tumors with EGFR amplification as well as mutations of the Akt / mTOR, PTEN and PI3KCA pathway [ 48 ]. Therefore these results strongly support all those we have obtained in ovarian cancer.…”

“…One of them, carboxyamidotriazole (CAI), was shown to have anti-tumoral and anti-angiogenic properties in vitro and in vivo through its ability to inhibit calcium channels such as Store-Operated Calcium Channels (SOC) [ 32 – 40 ]. CAI and its pro-drug salt form (carboxyamidotriazole orotate - CTO) have reached several clinical trials in various solid cancers including ovarian carcinoma, cervical cancer, renal cell carcinoma, melanoma or glioblastoma [ 41 – 48 ]. Reported results showed that CAI used as a single agent or in combination with paclitaxel or temozolomide has a well-tolerated toxicity profile with low grade side-effects such as fatigue, nausea or reversible peripheral neuropathy.…”

“…Reported results showed that CAI used as a single agent or in combination with paclitaxel or temozolomide has a well-tolerated toxicity profile with low grade side-effects such as fatigue, nausea or reversible peripheral neuropathy. CAI exhibited mild anticancer properties in some clinical trials, however it was described to stabilize 31% of patients with relapsed ovarian cancer for more than 6 months and its combination with Temozolomide displayed effective antitumor activity in glioblastoma [ 45 , 48 ]. As we previously showed that Mcl-1 is a target for calcium signaling, we investigated whether CAI could modulate the expression of Mcl-1, with a special attention to the molecular mechanism involved and whether it could sensitize platinum-refractory ovarian cancer cells to anti-Bcl-x L strategies.…”

Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis

“…Despite the combined therapeutic approach, including aggressive surgery, adjuvant postoperative radio/chemotherapy, the 5-year survival rate of glioblastoma patients is less than 5% [1][2][3][4]. Resistance to traditionally chemo/radiotherapy or targeted therapy is the crucial factor to result in therapy failure in glioblastoma [5][6][7].…”