What completed phase‑1 studies have defined maximum tolerated doses of mebendazole in cancer patients and what dosing schedules did they use?

1. The Johns Hopkins Phase I: fixed high‑dose chewable tablets on a 28‑day cycle

A Phase I open‑label study run out of Johns Hopkins treated newly diagnosed high‑grade glioma patients receiving temozolomide using specially manufactured 500 mg polymorph C chewable mebendazole tablets, given in a 28‑day cycle and initially described as 500 mg three times daily; the primary endpoint was to determine the maximum tolerated dose in combination with temozolomide and the regimen was reported as safe and tolerable in the published trial report ^{[1] [2]}.

2. Pediatric/young‑adult Phase I with bevacizumab and irinotecan: weight‑based escalation up to 200 mg/kg/day

A phase I trial (NCT01837862) in children and young adults with high‑grade gliomas tested mebendazole together with bevacizumab and irinotecan and escalated doses to very high weight‑based levels, reporting that dosing up to approximately 200 mg/kg/day was administered and considered tolerable in the study population; dose‑limiting toxicities noted across cohorts included neutropenia and lymphopenia and some hepatotoxicity, and several patients required dose reductions ^{[3] [5]}.

3. Other phase‑1/dose‑escalation data and how MTD was described

Clinical summaries and reviews of early human studies describe dose‑escalation ranges from roughly 25 mg/kg/day to 200 mg/kg/day (divided into three daily doses with meals) and also document the 500 mg three‑times‑daily fixed schedule used in the Johns Hopkins protocol; these sources frame the practical “maximally tolerated” operational ceiling near 200 mg/kg/day in the cancer context, but emphasize variability in tolerability between adult and pediatric patients and across combination regimens ^{[4] [1] [6]}.

4. Safety signals that shaped dose‑limits: hepatotoxicity and cytopenias

Across the published reports and reviews, the adverse events that most commonly forced dose reductions or caution were reversible elevated transaminases (hepatotoxicity) and hematologic toxicities such as neutropenia and lymphopenia; in the Johns Hopkins adult study most patients tolerated the fixed 500 mg TID schedule, but combination studies and pediatric cohorts reported that a minority required lower dosing because of biochemical or hematologic toxicity ^{[2] [4] [3]}.

5. What “defined MTD” means in the available reports and remaining gaps

The phrase “maximum tolerated dose” is applied differently across the small studies: Johns Hopkins defined and tested a fixed high tablet dose (500 mg TID) within a chemotherapy cycle context and reported tolerability, while the pediatric combination trial used formal dose escalation to identify tolerability up to ~200 mg/kg/day; however, none of the sources present a single, universal MTD across all cancer indications, formulations, and combination regimens — and published sample sizes are small, limiting generalizability ^{[2] [3] [4]}.

6. Bottom line for clinical interpretation

Completed early‑phase work shows mebendazole can be given at high oral doses in cancer patients: commonly as 500 mg three times daily in the adult temozolomide study, and in weight‑based escalation trials up to about 200 mg/kg/day divided into three doses with meals in combination regimens — but tolerability varies, hepatotoxicity and cytopenias are the main dose‑limiting signals, and no single definitive, universally applicable MTD across cancers and combinations has been established in large cohorts ^{[1] [2] [3] [4]}.