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Phase I study of N(1),N(11)-diethylnorspermine in patients with non-small cell lung cancer
Hillary A Hahm1, David S Ettinger, Kathy Bowling
1The Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Purpose:
Polyamines are essential for tumor growth; consequently, agents that interfere with their metabolisms have been developed as antineoplastic agents. Diethylnorspermine (DENSPM) is one such agent. A focused Phase I clinical trial in patients with advanced non-small cell lung cancer was undertaken.
Experimental Design:
Twenty-nine patients were treated with DENSPM using a dosing schedule of once daily for 5 days. Doses ranged from 25 mg/m(2)/day to 231 mg/m(2)/day.
Results:
The dose-limiting toxicity was determined to be gastrointestinal including asthenia, abdominal cramps, diarrhea, and nausea. The maximal tolerated dose was 185 mg/m(2)/day for 5 days. At drug dosages for which it was possible to estimate, serum half-life ranged from 0.5 to 3.7 h without apparent dose dependence. Maximal serum concentrations increased with dosage. However, the increase was greater than the proportional increase of the administered dose. There were no objective disease responses observed during the Phase I trial.
Conclusions:
The results of the Phase I clinical trial suggest that DENSPM can safely be administered to patients with minimal toxicity. Furthermore, the observed dose-limiting toxicity is unique to DENSPM, thus underscoring the potential for DENSPM to be a suitable agent for chemotherapy in combination with agents possessing different spectrums of toxicities.
Insights
Diethylnorspermine (DENSPM), an antineoplastic agent, showed minimal toxicity in a Phase I trial for advanced non-small cell lung cancer. The maximal tolerated dose was 185 mg/m(2)/day, with gastrointestinal issues as the dose-limiting toxicity.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Polyamines are crucial for tumor proliferation.
- Diethylnorspermine (DENSPM) is an investigational antineoplastic agent targeting polyamine metabolism.
- Phase I trials are essential for evaluating novel cancer therapeutics.
Purpose of the Study:
- To assess the safety and tolerability of Diethylnorspermine (DENSPM) in patients with advanced non-small cell lung cancer.
- To determine the dose-limiting toxicity and maximal tolerated dose of DENSPM.
- To explore the pharmacokinetic profile of DENSPM in this patient population.
Main Methods:
- A focused Phase I clinical trial was conducted.
- Twenty-nine patients with advanced non-small cell lung cancer received DENSPM.
- Dosing ranged from 25 mg/m(2)/day to 231 mg/m(2)/day, administered once daily for 5 days.
Main Results:
- The maximal tolerated dose of DENSPM was determined to be 185 mg/m(2)/day for 5 days.
- Dose-limiting toxicities were primarily gastrointestinal, including asthenia, abdominal cramps, diarrhea, and nausea.
- Serum half-life ranged from 0.5 to 3.7 hours, with maximal serum concentrations increasing disproportionately with dose; no objective responses were observed.
Conclusions:
- Diethylnorspermine (DENSPM) can be safely administered to patients with advanced non-small cell lung cancer with manageable toxicity.
- The unique dose-limiting toxicity profile of DENSPM suggests potential for combination chemotherapy.
- Further investigation into DENSPM as a component of combination cancer therapy is warranted.