Reverse swing‐M, phase 1 study of repurposing mebendazole in recurrent high‐grade glioma

Abstract

BackgroundRelapsed high‐grade glioma has dismal outcomes. Mebendazole has shown promising activity against glioma in in‐vitro and in‐vivo studies. Hence, we undertook a phase 1 study to repurpose mebendazole in the treatment of glioblastoma.MethodsWe conducted a phase 1 study (accelerated titrated design 4) of mebendazole in patients with recurrent glioblastoma (GBM). Patients eligible for re‐irradiation were enrolled in arm A1 (radiation with concurrent temozolomide 75 mg/m2 daily during the course of radiation+mebendazole) while patients who were ineligible were enrolled in either arm B1 (CCNU 110 mg/m2 day 1, every 6 weekly + mebendazole) or arm C1 (temozolomide 200 mg/m2 day 1‐5, every 4 weekly + mebendazole). The primary endpoint of phase 1 was to identify the MTD of mebendazole in each combination.Findings11 patients were enrolled in the whole study. MTD of mebendazole was not reached in arm A1 and C1 and hence the recommended dose for phase 2 was 1600 mg TDS (4800 mg) per day. The MTD of mebendazole in combination with CCNU was 1600 mg TDS (4800 mg) per day and the dose recommended for phase 2 was 800 mg TDS (2400 mg) per day. The three most common adverse events seen in the study were anemia (n = 9, 81.8%), nausea (n = 7, 63.6%), and fatigue (n = 6, 55.5%).InterpretationThe recommended phase 2 dose of mebendazole is 1600 mg TDS with temozolomide and temozolomide‐radiation combination while the dose of 800 mg TDS needs to be used with single‐agent CCNU.

Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways

“…We demonstrated that MBZ exerted more potent anti-proliferation activity than cisplatin in human HNSCC cells, and effectively inhibited cell proliferation, cell cycle progression and cell migration, and induced apoptosis in HNSCC cells [ 18 ]. Other studies indicate that MBZ and its derivatives exerted potent anticancer effect in non-small cell lung cancer [ 19 , 20 ], adrenocortical carcinoma [ 22 ], medulloblastoma [ 28 ], melanoma [ 21 ], leukemia and myeloma [ 24 ], glioblastoma multiform [ 23 , 34 ], colon cancer [ 26 ], cholangiocarcinoma [ 27 ], breast cancer [ 25 , 29 ], gastric cancer [ 30 ], mouse hepatoma [ 31 ], and thyroid cancer [ 32 ]. In this study, our results are the first to demonstrate that MBZ can overcome cisplatin resistance and synergize with cisplatin in inhibiting cell proliferation and inducing apoptosis in cisplatin-resistant ovarian cancer cells.…”

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

“…Its anticancer properties were notably demonstrated in gliomas [11,14,34], and there are currently three ongoing clinical trials in high‐grade gliomas in both adult and pediatric patients (NCT01729260, NCT02644291, and NCT01837862). Furthermore, a recent phase I trial demonstrated that administration of MBZ concomitantly with radiotherapy and temozolomide chemotherapy was safe in high‐grade glioma patients [35].…”

Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia

“…Consequently, this would be a suitable approach to achieve an improved treatment for the elderly who cannot tolerate higher doses. [ 38 , 39 ]. The prognosis for elderly, unfit patients is still bleak with current treatments.…”