title: Phase I trial of recombinant interleukin-2 followed by recombinant tumor necrosis factor in patients with metastatic cancer.
abstract: In this Phase I trial, the feasibility of sequential administration of continuous intravenous recombinant interleukin-2 (rIL-2) at 18 x 10(6) IU/m2/day for 6 days, followed by three daily bolus intravenous recombinant tumor necrosis factor (rTNF) infusions at doses escalating between 10 and 120 micrograms/m2/day, was investigated in 31 patients with metastatic malignancies. Prophylactic use of indomethacin prior to and during rTNF administration was found to significantly reduce toxicity. However, despite prophylactic indomethacin, a maximum tolerated dose of rTNF of 120 micrograms/m2 was reached. The limiting toxicity was hypotension. Predictable flu-like toxicities (i.e., fever/chills, hypotension, gastrointestinal toxicity, edema, malaise) were seen in most patients. These started during the rIL-2 infusion and continued during rTNF administration, particularly in the absence of indomethacin. Hematological, renal, and hepatic toxicities were not dose limiting. These toxicities were all reversible after treatment interruption. Pulmonary toxicity [i.e., anaphylactic-like reactions, bronchospasms, and adult respiratory distress syndrome (ARDS)] was seen in several patients immediately after rTNF infusions, irrespective of the rTNF dose or treatment cycle, and mainly in patients with extensive pulmonary metastases. The combined effect of treatment-related ARDS, lung metastases, and a Guillain-Barré syndrome led to the death of one patient. Two partial responses were seen in this study (i.e., breast and renal cancer). Based on these results, a Phase II trial of rIL-2 followed by rTNF has been initiated in metastatic breast cancer patients.
authors.affiliation: Intensive Care Unit, Hôpital E. Herriot, Lyon, France.
authors.forename: M S
authors.initials: MS
authors.lastname: Negrier
authors.forename: C N
authors.initials: CN
authors.lastname: Pourreau
authors.forename: P A
authors.initials: PA
authors.lastname: Palmer
authors.forename: J Y
authors.initials: JY
authors.lastname: Ranchere
authors.forename: A
authors.initials: A
authors.lastname: Mercatello
authors.forename: P
authors.initials: P
authors.lastname: Viens
authors.forename: D
authors.initials: D
authors.lastname: Blaise
authors.forename: C
authors.initials: C
authors.lastname: Jasmin
authors.forename: J L
authors.initials: JL
authors.lastname: Misset
authors.forename: C R
authors.initials: CR
authors.lastname: Franks
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001774:Blood Chemical Analysis; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin