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Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion
Abstract:
A Phase I study of pentamethylmelamine (PMM) was conducted, administering the drug as a 24-hr i.v. infusion once weekly for 3 weeks. Doses ranged from 80 to 3000 mg/sq m/week. Twenty-six evaluable patients received a total of 30 courses of PMM. The median performance status of the patients was 60% (range, 40 to 90%), and the median age was 58 years (range, 43 to 72 years). The highest tolerated dose was 2000 mb/sq m/week. Nausea and vomiting were the dose-limiting toxicities; myelosuppression was neither consistent nor severe. One objective response lasting 10 months was noted in a patient with renal cancer. Pharmacokinetic studies using [ring-14C]PMM demonstrated a postinfusion half-life of 14C of approximately 12 hr, with the majority of the radiolabel excreted in the urine. PMM was introduced as a parenteral form of hexamethylmelamine. The present schedule does not permit administration of PMM in a dose greater than the tolerated dose of hexamethylmelamine and does not appear to offer an advantage over the p.o. use of the parent compound.
Insights
Pentamethylmelamine (PMM) Phase I study found the highest tolerated dose to be 2000 mg/sq m/week. Nausea and vomiting were dose-limiting, with no significant advantage over oral hexamethylmelamine.
Area of Science:
- Oncology
- Pharmacology
Background:
- Pentamethylmelamine (PMM) was developed as a parenteral form of hexamethylmelamine.
- Investigating novel administration routes for existing chemotherapeutics is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the safety and tolerability of pentamethylmelamine (PMM) administered via intravenous infusion.
- To determine the maximum tolerated dose (MTD) of PMM in patients with advanced cancer.
Main Methods:
- Phase I clinical trial design.
- Administered PMM as a 24-hour intravenous infusion weekly for 3 weeks.
- Dose escalation from 80 to 3000 mg/sq m/week in 26 evaluable patients.
Main Results:
- The maximum tolerated dose (MTD) was determined to be 2000 mg/sq m/week.
- Dose-limiting toxicities included nausea and vomiting; myelosuppression was minimal.
- One objective response was observed in a patient with renal cancer.
- Pharmacokinetic analysis showed a 14C half-life of approximately 12 hours, with renal excretion.
Conclusions:
- The current intravenous dosing schedule for PMM did not exceed the tolerated dose of oral hexamethylmelamine.
- PMM administered via this schedule does not appear to offer advantages over the oral administration of hexamethylmelamine.
- Further investigation into alternative PMM dosing or formulations may be warranted.