Phase I trial of interleukin-12 with trastuzumab and paclitaxel in HER2-overexpressing malignancies

Abstract

2531 Background: Our pre-clinical work suggested dramatic synergy between trastuzumab-coated HER2-positive cancer cells and interleukin-12 (IL-12) for stimulation of natural killer (NK) cell cytokine secretion and cytotoxicity. Our previous phase I trial of trastuzumab in combination with IL-12 in patients with Her2-expressing cancers showed that interferon-gamma (IFN-g) production by NK cells occurred only in patients who exhibited a favorable response to therapy (Clin CA Res, 2004). Methods: Given the widespread use of trastuzumab with cytotoxic agents, we conducted a phase I trial that employed IL-12 in combination with trastuzumab/paclitaxel (NCI 84). Trastuzumab was given on day 1 of the weekly cycle (4 mg/kg initially and 2 mg/kg thereafter) in combination with i.v. injections of IL-12 on days 2 and 5 starting in week 3. Paclitaxel was given at a dose of 175 mg/m2every 3 weeks. Results: This trial accrued 21 patients (10 female, 11 male) with metastatic 2+ and 3+ HER2-positive tumors (breast-7, colon-6, esophageal-4, gastric-2, pancreas-1, thyroid-1). Average age was 57.7 years. 17/21 patients had prior surgery and 16/21 had prior chemotherapy. The IL-12 was dose-escalated in cohorts of 3 patients (100 and then 300 ng/kg), but because of dose-limiting grade 3 fatigue at the 300 ng/kg dose level, the IL-12 component was reduced to 200 ng/kg subcutaneously. Grade 1 fever/chills associated with IL-12 were common, but easily managed. There have been partial responses (PR) in 5 patients (breast-3, esophageal-2) and stabilization of disease (SD) in 5 others (breast-2, gastric-2, colon-1). All but one response occurred in patients with HER2 3+ disease. Two SD patients (breast-1, gastric-1) completed 1 year of therapy and went on to receive trastuzumab alone. 9 patients had progression of disease (average of 2.9 cycles). Two patients were inevaluable for response due to dose-limiting fatigue. Correlative studies showed increased circulating levels of IFN-g in 5/5 PR patients and 5/5 SD. No patient with progressive disease had measurable levels of IFN-g. Conclusions: These findings suggest that the addition of IL-12 to trastuzumab/paclitaxel may lead to enhanced efficacy through the induction of anti-tumor immunity. No significant financial relationships to disclose.