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A Phase I Study of Interleukin 12 with Trastuzumab in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressing Malignancies

Analysis of Sustained Interferon Production in a Subset of Patients

Departments of ¹ Molecular Virology, Immunology, and Medical Genetics, ² Hematology and Oncology, ³ Surgery, ⁴ Pathology, and ⁵ Biostatistics, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio

Purpose: On the basis of preclinical studies, we hypothesized that interleukin (IL)12 would potentiate the antitumor actions of an antihuman epidermal growth factor receptor-2 (HER2) monoclonal antibody (trastuzumab). We conducted a Phase I trial to determine the safety and optimal biological dose of IL-12 when given in combination with trastuzumab.

Patients and Methods: Patients with metastatic HER2-positive malignancies received trastuzumab on day 1 of each weekly cycle. Beginning in week 3, patients also received intravenous injections of IL-12 on days 2 and 5. The IL-12 component was dose-escalated within cohorts of 3 patients (30, 100, 300, or 500 ng/kg). Correlative assays were conducted using serum samples and peripheral blood cells obtained during the course of therapy.

Results: Fifteen patients were treated, including 12 with HER2 2+ or 3+ breast cancer. The regimen was well tolerated with IL-12-induced grade 1 nausea and grade 2 fatigue predominating. Evaluation of dose-limiting toxicity and biological end points suggested that the 300 ng/kg dose was both the maximally tolerated dose and the optimal biological dose of IL-12 for use in combination with trastuzumab. Two patients with HER2 3+ breast cancer within the 500 ng/kg dose level experienced grade 1 asymptomatic decreases in left ventricular ejection fraction of 12% and 19% after 3 and 10 months of therapy, respectively. There was one complete response in a patient with HER2 3+ breast cancer metastatic to the axillary, mediastinal, and supraclavicular nodes, and 2 patients with stabilization of bone disease lasting 10 months and >12 months, respectively. Correlative assays showed sustained production of interferon (IFN) by natural killer cells only in those patients experiencing a clinical response or stabilization of disease. Elevated serum levels of macrophage inflammatory protein-1, tumor necrosis factor-, and the antiangiogenic factors IFN- inducible protein-10 and monokine induced by were also observed in these patients. Patient genotyping suggested that a specific IFN- gene polymorphism might have been associated with increased IFN- production. The ability of patient peripheral blood cells to conduct antibody-dependent cellular cytotoxicity against tumor targets in vitro did not correlate with clinical response or dose of IL-12.

Conclusions: The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment. Sustained production of IFN- and other cytokines were observed in three patients: One who exhibited a complete response and two others who had stabilization of disease lasting over 6 months. Given the small sample size and heterogeneity of the patient population, the effects of IL-12 on the innate immune response to trastuzumab therapy should be further explored in the context of a larger clinical trial.

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