Carboxyamidotriazole Orotate Demonstrates Promising Efficacy in Brain Cancers

Elena Pentsova, MD

Elena Pentsova, MD

In a recent phase Ib study, the combination of carboxyamidotriazole orotate (CTO) and temozolomide (Temodar) produced positive safety and efficacy results in patients with glioblastoma (GBM) or anaplastic gliomas, with or without treatment with radiotherapy.

In the trial, 42 patients were divided into 2 cohorts and received treatment. Cohort 1 included 27 patients with recurrent, temozolomide-refractory anaplastic gliomas or GBM. Twenty-one patients were assigned to a regimen of 219 to 812.5 mg/m²of once-daily CTO in escalating doses and 6 were assigned to a fixed daily dose of 600 mg of CTO. All 27 patients received 150 mg/m²of temozolomide on days 1 to 5 of each 28-day cycle.

Cohort 2 included 15 patients with newly diagnosed GBM. This group was assigned to 219 to 481 mg/m²of once-daily CTO in escalating doses along with 60 Gy radiotherapy in 2 Gy fractions and 75 mg/m2 of daily temozolomide. CTO was continued after radiotherapy. Temozolomide discontinued for 4 weeks following radiotherapy, then restarted at 150 mg/m²/day in cycle 1 and increased to 200 mg/m²/day starting in cycle 2.

Following pharmacokinetic analysis, investigators established 600 mg/day of CTO once daily as the recommended phase II dose for both cohorts.

“On the basis of the favorable toxicity profile, brain penetration, and encouraging activity observed in this difficult-to-treat population of patients with GBM and [anaplastic gliomas], randomized phase II trials with CTO in combination with temozolomide or chemoradiation are planned,” corresponding author Elena Pentsova, MD, Department of Neurology, Memorial Sloan Kettering Cancer Center, and colleagues wrote.

Most (59%) of patients in cohort 1 were diagnosed with WHO grade IV GBM or WHO grade III anaplastic astrocytoma (30%). Fourteen patients (93%) in cohort 2 had WHO grade IV GBM. One patient (7%) in that cohort was diagnosed with WHO grade III anaplastic astrocytoma.

Fourteen (52%) patients in cohort 1 had experienced at least 2 recurrences, including 5 who had 3 to 8 recurrences and were heavily pretreated as a result. Temozolomide (93%) was the most commonly used previous systemic treatment.

Patients in cohort 1 were aged a median of 49 years (range, 28-78). Patients in cohort 2 were aged a median of 57.5 years (range, 24-77).

All 27 patients in cohort 1 were evaluable for response. The clinical benefit rate was 67% (95% CI, 46-83) and the objective response rate was 26% (95% CI, 11-46). One patient had complete response (CR), 6 had a partial response (PR), and 11 (41%) had stable disease. Investigators observed disease progression in 9 (33%) patients.

Included among the responders were 4 patients with IDH wild-type, MGMT unmethylated tumors and 2 with GBM that recurred after failure of anti-VEGF therapy, tumors that are usually chemoresistant.

The 1-year overall survival (OS) rate was 46% (95% CI, 31-70) and median OS was 10.2 months (95% CI, 8-30). The 6-month progression-free survival (PFS) rate was 37% (95% CI, 12-62) and the median PFS was 3.1 months (95% CI, 2.5-6.8).

Investigators observed no dose limiting toxicities (DLTs) in cohort 1 and the maximum-tolerated dose was not reached. Grade 1/2 fatigue (51.8%), nausea, (40.7%), constipation (40.7%), and vomiting (25.9%) were the most common treatment-related adverse events (TRAEs). There were no grade ≥3 TRAEs observed.

In cohort 2, the 2-year PFS rate was 35% (95% CI, 11-61), the 1-year PFS rate was 52% (95% CI, 23-75), and the median PFS was 15 months (95% CI, 5-infinity). The OS rate at 2 years was 62% (95% CI, 31-82) and 93% (95% CI, 61-99) at 1 year. At a median follow-up of 28 months, the median OS was not reached.

Nine patients were evaluable for response. One patient had a CR, 2 had a PR, and 3 had stable disease. Three patients had progressive disease.

Investigators expected to see a greater incidence of AEs in cohort 2 due to the higher dose of temozolomide and concomitant radiotherapy, but found that treatment was well tolerated. Fatigue (66.7%), nausea (46.7%), constipation (46.7%), radiotherapy-related dermatitis (33.3%), skin rash (20.0%), and headache (20%) were the most common grade 1/2 AEs reported.

Investigators observed no DLTs at doses up to 481 mg/m²of CTO. Grade 3/4 febrile neutropenia (n = 2), neutropenia (n = 1), platelets (n = 1), and ALT (n = 1) developed after DLT observation, however, and investigators stopped dose escalation at 481 mg/m². There were no DLTs observed in 6 patients assigned to 370 mg/m²of CTO, the next lower dose level.

Reference:

Omuro A, Beal K, McNeill K, et al. Multicenter phase ib trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas [published online April 23, 2018].J Clin Oncol. 2018 Apr 23:JCO2017769992. doi: 10.1200/JCO.2017.76.9992.