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Phase I study of recombinant human tumor necrosis factor
K Kimura1, T Taguchi, I Urushizaki
1Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Cancer Chemotherapy and Pharmacology
|January 1, 1987
Summary
Recombinant human tumor necrosis factor (rH-TNF) showed dose-dependent toxicities like hypotension and thrombocytopenia in advanced cancer patients. The maximum tolerated dose was established based on these safety findings.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with potential anti-cancer activity.
- Phase I studies are crucial for determining safety and optimal dosing of novel therapeutics.
Purpose of the Study:
- To evaluate the safety and pharmacokinetics of single-dose intravenous rH-TNF in patients with advanced cancer.
- To determine the maximum tolerated dose (MTD) of rH-TNF in this patient population.
Main Methods:
- A phase I dose-escalation study using a modified Fibonacci scheme.
- 33 patients with advanced cancer received single intravenous infusions of rH-TNF.
- Pharmacokinetic parameters and toxicities were closely monitored.
Main Results:
- Common toxicities included fever, nausea, and anorexia (non-dose-dependent), and hypotension, leukocytosis, and elevated transaminases (dose-dependent).
- Dose-limiting toxicities were identified as hypotension, thrombocytopenia, and hepatotoxicity.
- The maximum tolerated dose was estimated at 12 x 10^5 units/m2, or 5 x 10^5 units/m2 if hypotension was included.
Conclusions:
- Single-dose rH-TNF exhibits dose-dependent toxicities in advanced cancer patients.
- Careful dose selection is necessary to mitigate risks such as hypotension and thrombocytopenia.
- Further investigation into the therapeutic potential and optimized dosing of rH-TNF is warranted.