A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies.
A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies.
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DOI：
10.1158/1535-7163.mct-09-0820
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发表时间：
2009-11
影响因子：
5.7
通讯作者：
Carson WE 3rd
中科院分区：
文献类型：
--
作者：
Bekaii-Saab TS;Roda JM;Guenterberg KD;Ramaswamy B;Young DC;Ferketich AK;Lamb TA;Grever MR;Shapiro CL;Carson WE 3rd
我们的临床前工作表明，白细胞介素-12（IL-12）和曲妥珠单抗刺激自然杀伤细胞细胞因子分泌之间有显着的协同作用。我们的目的是确定IL-12与曲妥珠单抗和紫杉醇联合治疗转移性HER 2过表达癌症患者的安全性。紫杉醇以175 mg/m2每3周一次静脉给药。从第2周期开始，每周第1天给予曲妥珠单抗（最初为4 mg/kg，此后为2 mg/kg），并在第2天和第5天注射IL-12。该试验招募了21例转移性HER 2阳性肿瘤患者（乳腺，7例;结肠，6例;食管，4例;胃，2例;胰腺，1例;甲状腺，1例）。IL-12组分在三名患者的队列中剂量递增。在300 ng/kg剂量水平下，2例患者的剂量限制性毒性为3级疲劳。推荐的II期剂量为200 ng/kg，皮下给药。1例乳腺癌患者完全缓解，4例患者部分缓解（乳腺癌，2例;食管癌，2例），6例其他患者疾病稳定持续3个月或更长时间（SD）。除1例缓解外，所有缓解均发生在HER 2 3+疾病患者中。2例SD患者完成了1年的治疗。10例患者出现疾病进展。在有临床获益（完全缓解、部分缓解或SD）的患者中，外周血单个核细胞中细胞外信号调节激酶的活化增加，IFN-γ和几种趋化因子的水平升高，但在疾病进展的患者中则没有。因此，IL-12与曲妥珠单抗和紫杉醇的组合表现出可接受的毒性特征，并且在HER 2过表达癌症患者中具有活性。
Our preclinical work showed a dramatic synergy between interleukin-12 (IL-12) and trastuzumab for stimulation of natural killer cell cytokine secretion. We aimed to determine the safety profile of IL-12 when given in combination with trastuzumab and paclitaxel to patients with meta-static HER2-overexpressing cancers. Paclitaxel was given i.v. at 175 mg/m2 every 3 weeks. Trastuzumab was given on day 1 each week (4 mg/kg initially and 2 mg/kg thereafter) in combination with injections of IL-12 on days 2 and 5 starting in cycle 2. This trial accrued 21 patients with metastatic HER2-positive tumors (breast, 7; colon, 6; esophagus, 4; stomach, 2; pancreas, 1; thyroid, 1). The IL-12 component was dose-escalated in cohorts of three patients. The dose-limiting toxicity was grade 3 fatigue at the 300 ng/kg dose level in two patients. The recommended phase II dose was 200 ng/kg administered s.c. There was one complete response in a patient with breast cancer, partial responses in 4 patients (breast, 2; esophageal, 2), and stabilization of disease lasting 3 months or greater (SD) in 6 other patients. All but one response occurred in patients with HER2 3+ disease. Two SD patients completed 1 year of therapy. Ten patients had progressive disease. There was increased activation of extracellular signal–regulated kinase in peripheral blood mononuclear cells and increased levels of IFN-γ and several chemokines in patients with clinical benefit (complete response, partial response, or SD), but not in patients with progressive disease. IL-12 in combination with trastuzumab and paclitaxel therefore exhibits an acceptable toxicity profile and has activity in patients with HER2-overexpressing cancers.