Background Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). Methods Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose‐limiting toxicities (DLTs) were determined, using a 3 + 3 study design. Results Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2‐year survival rate was 43%. Conclusions Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

LITT and RT treatment in close succession can induce cerebral edema, which can usually be managed successfully with steroids, although the treatment period may be prolonged. A minority of patients may require more aggressive treatment, such as bevacizumab. Lasers Surg. Med. 50:917-923, 2018. © 2018 Wiley Periodicals, Inc.

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Background Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound 1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. Methods A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1=375 mg) on days 1-21, in combination with TMZ 150 mg/m 2/5 days, per 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Results Eighteen patients were enrolled (13 GBM, IDH-wildtype; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (i.e., PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, MGMT promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Conclusions Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m 2/5 days per 28-day cycle. The MTD was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

NEURO-ONCOLOGY • NOVEMBER 2017survival in glioblastoma. METHODS: We retrospectively evaluated 127 consecutive patients with newly diagnosed GBM treated at our institution. Forty-seven (37%) had circumferential resection (CR) by the senior author and the other 80(63%) had debulking/piecemeal ("non-circumferential") resection(NCR). All patients underwent adjuvant chemoradiotherapy as per the Stupp protocol. Tumor volumetric analysis was performed using Osirix software. Overall survival and survival as stratified by treatment and extent of resection (EOR) were evaluated using Kaplan-Meier survival analysis. RESULTS: Clinical characteristics between CR and NCR cohorts were similar. Mean age at diagnosis was 59 years and 81(63.9%) were male. Preoperative tumor volume was 31.8 cm 3 vs. 40.6 cm 3 (p=0.05) for CR vs. NCR respectively. Patients who had CR had higher median EOR (100.0 vs. 90.4, p<0.0001). The median OS for the entire cohort was 13.2 months. Median OS for CR and NCR was 17.7 and 11.0 months respectively (p<0.0001). EOR significantly impacted survival. Among the CR cohort, median survival was 22.5 and 11.5 months for >98% and <98% EOR respectively while median survival for the NCR cohort was 14.4 and 9.6 months for >98% and <98% EOR respectively. Post-operative Karnofsky Performance Scale (median, interquartile range) was 80(70-90) and 70(70-90) for CR and NCR patients respectively (p=0.43). CONCLUSION: Circumferential resection helps maximise the extent of resection in glioblastoma surgery and significantly prolongs survival without compromise to functional status.

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