Assessment of N-methylformamide (NMF) administered orally on a three times weekly schedule: a phase I study

This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m², determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m², however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m². Although NMF peak plasma concentrations (C_max) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m² dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m². C_maxs and AUCs at this dose were significantly lower than those that were demonstrated to induce cytotoxicity, and differentiating, chemosensitizing, and radiosensitizing effects in preclinical studies suggesting that further clinical evaluations of NMF may not be warranted.