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Early clinical trial of a 1-day intermittent schedule for pentamethylmelamine
Abstract:
An early clinical trial of pentamethylmelamine (PMM) the monodemethylated derivative of hexamethylmelamine, was conducted in 22 adults with solid tumors. PMM was administered as a 2-hour iv infusion every 4 weeks at doses ranging from 40 to 2400 mg/m2. A combination of gastrointestinal and neurologic (CNS) toxicity was dose-limiting. Nausea and vomiting began at a dose of 265 mg/m2 and became progressively worse until it became life-threatening at doses of 1800-2400 mg/m2. CNS toxic effects consisting of agitation, confusion, drowsiness, and loss of consciousness were first noted at a dose of 1200 mg/m2 and were seen in varying degrees at all higher dose levels. No other toxic effects were noteworthy except two instances of thrombocytopenia at low doses. No antitumor activity was observed. We do not recommend the further use of this schedule of administration for PMM.
Insights
Pentamethylmelamine (PMM) showed dose-limiting gastrointestinal and central nervous system (CNS) toxicity in adults with solid tumors. No antitumor activity was observed, and further use of this PMM administration schedule is not recommended.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Hexamethylmelamine (HMM) is an antineoplastic agent.
- Pentamethylmelamine (PMM) is a derivative of HMM.
- Early clinical trials are essential for evaluating novel cancer therapeutics.
Purpose of the Study:
- To evaluate the safety and tolerability of pentamethylmelamine (PMM) in adult patients with solid tumors.
- To determine the dose-limiting toxicities of PMM.
- To assess any potential antitumor activity of PMM.
Main Methods:
- A Phase I clinical trial was conducted involving 22 adult patients with solid tumors.
- PMM was administered intravenously over 2 hours every 4 weeks.
- Doses ranged from 40 to 2400 mg/m2, with toxicity and antitumor activity monitored.
Main Results:
- Dose-limiting toxicities included gastrointestinal (nausea, vomiting) and central nervous system (CNS) effects (agitation, confusion, drowsiness, loss of consciousness).
- Severe nausea and vomiting occurred at doses of 1800-2400 mg/m2.
- CNS toxic effects were observed at doses of 1200 mg/m2 and higher.
- No significant antitumor activity was observed.
- Two instances of thrombocytopenia were noted at lower doses.
Conclusions:
- Pentamethylmelamine (PMM) demonstrated significant dose-limiting gastrointestinal and CNS toxicities.
- The observed toxicities suggest that the tested administration schedule for PMM is not clinically viable.
- Further investigation into PMM using this specific dosing regimen is not recommended due to lack of efficacy and significant toxicity.