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Phase II trial of amonafide in advanced colorectal cancer: a SouthWest Oncology Group study
T D Brown1, P J Goodman, T Fleming
1Duke University Medical Center, Durham, NC 27710.
Abstract:
Amonafide is a substituted benzisoquinolinedione that exerts its cytotoxicity through effects on macromolecular synthesis and intercalation of DNA. In this trial, 44 patients with advanced colorectal cancer and without prior chemotherapy received amonafide at a starting dose of 300 mg/m2 intravenously over one hour, on a daily x 5 schedule every 3 weeks. Toxicities of grade 3 or above included granulocytopenia, thrombocytopenia, sepsis, anaphylaxis and transient aphasia. Forty-seven % of patients had grade 3 or higher toxicity of any type. There were no complete or partial responses for an overall response rate of 0%, with a 95% confidence interval of 0-9%. The level of toxicity observed on this trial suggests an appropriate dose intensity of amonafide, despite lack of knowledge of patients' acetylator phenotypes.
Insights
Amonafide, a DNA intercalator, showed significant toxicity in advanced colorectal cancer patients. This trial found no complete or partial responses, indicating limited efficacy for this chemotherapy-naive group.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Amonafide is a benzisoquinolinedione derivative with demonstrated cytotoxicity.
- Its mechanism involves inhibiting macromolecular synthesis and DNA intercalation.
Purpose of the Study:
- To evaluate the efficacy and toxicity of amonafide in patients with advanced colorectal cancer.
- To determine an appropriate dose intensity for amonafide therapy.
Main Methods:
- A phase II trial involving 44 chemotherapy-naive patients with advanced colorectal cancer.
- Amonafide was administered intravenously at 300 mg/m2 daily for 5 days every 3 weeks.
- Toxicity and response rates were meticulously monitored.
Main Results:
- Grade 3 or higher toxicities occurred in 47% of patients, including granulocytopenia, thrombocytopenia, sepsis, anaphylaxis, and transient aphasia.
- No complete or partial responses were observed, yielding an overall response rate of 0% (95% CI: 0-9%).
Conclusions:
- The observed toxicity profile suggests that the dose intensity used was appropriate, despite the lack of patient acetylator phenotype data.
- Amonafide demonstrated significant toxicity without efficacy in this patient population, warranting further investigation into alternative therapeutic strategies.