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Phase I study of recombinant human tumor necrosis factor-alpha in patients with advanced malignancies
H H Bartsch1, G A Nagel, R Mull
1Department of Internal Medicine, University of Göttingen, FRG.
Abstract:
A clinical phase I trial with recombinant human tumor necrosis factor-alpha (rTNF-alpha) was performed in 30 patients with advanced malignancies. The maximal tolerated dose (MTD) by 3 times weekly intramuscular (i.m.) application was 150 micrograms m-2. Main subjective toxicities including chills, fever, hypotension, fatigue, and anorexia were dose-related. In addition, transient changes in hematologic parameters and lipid metabolism were noted. Two out of 25 evaluated patients showed a minor tumor response after eight weeks of therapy. There was evidence for an improvement of in vivo immuneresponsiveness as revealed from positive delayed type hypersensitivity (DTH) skin tests of 3 out of 6 pretherapeutically anergic patients. We conclude from this phase I trial that rTNF-alpha can be safely administered at doses up to 150 micrograms m-2 i.m., 3 times weekly, without evidence of cumulative toxicity in long-term treatment.
Insights
Recombinant human tumor necrosis factor-alpha (rTNF-alpha) is safe for advanced cancer patients at doses up to 150 mcg/m² i.m. three times weekly. This phase I trial showed dose-related toxicities and potential immune response improvements.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Advanced malignancies present significant treatment challenges.
- Recombinant human tumor necrosis factor-alpha (rTNF-alpha) is a potential therapeutic agent.
- Understanding the safety and efficacy of novel cancer therapies is crucial.
Purpose of the Study:
- To evaluate the safety and tolerability of rTNF-alpha in patients with advanced malignancies.
- To determine the maximal tolerated dose (MTD) of rTNF-alpha administered intramuscularly.
- To explore preliminary signs of anti-tumor activity and immunomodulatory effects.
Main Methods:
- A Phase I clinical trial involving 30 patients with advanced cancers.
- Intramuscular administration of rTNF-alpha three times weekly.
- Monitoring of dose-limiting toxicities, hematologic parameters, lipid metabolism, and immune responses (DTH skin tests).
Main Results:
- The MTD was established at 150 micrograms m-2 for thrice-weekly i.m. rTNF-alpha.
- Common toxicities included dose-related chills, fever, hypotension, fatigue, and anorexia.
- Transient hematologic and lipid metabolism changes were observed.
- Minor tumor responses were noted in 2/25 patients; 3/6 anergic patients showed improved DTH responses.
Conclusions:
- rTNF-alpha can be safely administered at doses up to 150 mcg/m² i.m., thrice weekly.
- No cumulative toxicity was observed with long-term treatment.
- rTNF-alpha demonstrates potential immunomodulatory effects in cancer patients.