Phase IB trial of carboxyamidotriazole orotate (CTO) and radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ) in newly diagnosed glioblastoma (GBM).

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Abstract
2060 Background: CTO is an oral inhibitor of non-voltage-dependent calcium signaling achieving simultaneous modulation of several receptor-mediated signaling pathways. A single-agent phase I trial determined the maximum tolerated dose (MTD) at 427 mg/m2, with a safe toxicity profile. A phase IB in combination with TMZ for TMZ-refractory glioma found therapeutic brain tissue concentrations and early evidence of activity, prompting this study in newly diagnosed GBM. Methods: Following a 3+3 design, pts received escalating doses of daily CTO (219-481mg/m2) added to the standard GBM RT regimen (60 Gy concurrent with TMZ 75 mg/m2 daily, followed by adjuvant TMZ 150-200 mg/m2 x 5/28 days). Results: Accrual is complete. All pts (N = 15) had GBM (methylated MGMT: 33%; unmethylated: 67%). ChemoRT was well tolerated at CTO doses of 219-481 mg/m2. CTO-related adverse events ( > 10%) included fatigue, nausea, constipation, ALT, rash, and headache; in addition to these, AE likely-related to TMZ included decreased platelets and neutrophils. No dose-limiting toxicities (DLT) were observed up to 481 mg/m2 (maximum administered dose- MAD), but cumulative toxicities emerging after the DLT evaluation period prompted de-escalation to 370 mg/m2, which was better tolerated. Exploratory efficacy analysis shows median PFS of 17m, and median OS not reached (median follow-up of survivors: 15m). The 1-y OS is 92% (95% CI 57-99%). Three pts have already completed 12+ cycles. One MGMT unmethylated completed cycle 12, discontinued CTO and has not recurred after 3+ months. One patient continuing CTO is on cycle 17 and has had a durable partial response for 12+ months. One patient continuing CTO has stable disease after 15+ cycles. PK data confirmed therapeutic levels starting at 219 mg/m2. One patient operated during study (481 mg/m2 cohort) showed tumor concentration of 5900 ng/g, with a plasma level of 3460 ng/mL. Conclusions: CTO combined with RT and TMZ is safe and well tolerated. The MAD was 481 mg/m2 and recommended phase II dose is 370 mg/m2. Given encouraging preliminary signals of activity including durable disease control, a randomized study is warranted. Clinical trial information: NCT01107522.