A Phase I trial of escalating doses of trastuzumab combined with daily subcutaneous interleukin 2: Report of cancer and leukemia group B 9661

Purpose: The purpose of this study was to determine the toxicity of escalating doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)-2. Experimental Design: Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that over-expressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m² (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m² (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m² after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-over-expressing cell lines. Results: Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response. Conclusions: A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.