Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma
Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma
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DOI：
10.1002/cncr.10631
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发表时间：
2002-07-01
期刊：
影响因子：
6.2
通讯作者：
Benjamin, RS
中科院分区：
文献类型：
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作者：
Eton, O;Rosenblum, MG;Benjamin, RS
背景白细胞介素-2（IL-2）在通过静脉（IV）途径以高剂量给药时对转移性黑色素瘤具有活性，但其在通过皮下（SC）途径以中高剂量给药时的副作用和有效性尚未得到充分研究。本研究试图确定IL-2通过SC途径每日一次给药的最大耐受剂量（MTD）。在化疗后患有进行性转移性黑素瘤的门诊患者被招募到IL-2每天SC施用持续每周5天持续4周的I期试验中，以6周的间隔重复。指导患者每天至少饮用2 L液体。在两个最高剂量水平下进行IL-2药代动力学研究。使用国家癌症研究所通用毒性标准每周记录毒性。每6周评估一次缓解情况。3名患者、6名患者、6名患者和4名患者分别接受了中位数为2个疗程的SC IL-2，剂量水平分别为6 MIU/m2、9 MIU/m2、12 MIU/m2和15 MIU/m2。未能维持足够的液体摄入是在9 MIU/m2剂量水平下发生2次晕厥和在15 MIU/m2剂量水平下发生2次可逆性肾前性氮质血症的原因。在这些患者中重新开始IL-2治疗，没有发生任何事件。在15 MIU/m2剂量水平，2名患者出现严重头痛、抑郁和幻视，需要停止治疗。在15 MIU/m2剂量水平的第三和第四周结束时，咳嗽和液体潴留与按相同时间表以9 MIU/m2连续IV输注治疗的住院患者报告的症状相似。在12 MIU/m2和15 MIU/m2剂量水平下，皮下疾病分别有部分反应和完全反应，各持续< 2个月。SC注射1000-5000 pg/mL后的血浆IL-2水平在3小时达到最大值，并且在给药后长达48小时可检测到。SC IL-2吸收和清除的半衰期分别为1.6小时和5.2小时，计算的曲线下面积为30，584 pg/mL ×小时。SC IL-2耐受性良好，在研究的较高剂量下具有高持续生物利用度。每日SC方案的MTD为12 MIU/m2，建议用于未来研究。
BACKGROUND. Interleukin-2 (IL-2) has activity in metastatic melanoma when given in high doses by the intravenous (IV) route, but its side effects and effectiveness when given in intermediate to high doses by the subcutaneous (SC) route have not been studied adequately. This study sought to determine the maximum tolerated dose (MTD) of IL-2 administered once daily by the SC route.METHODS. Outpatients with progressive metastatic melanoma after chemotherapy were enrolled in a Phase I trial of IL-2 administered SC daily for 5 days per week for 4 consecutive weeks, repeated at 6-week intervals. Patients were instructed to drink at least 2 L of fluid daily. IL-2 pharmacokinetic studies were performed at the two highest dose levels. Toxicity was recorded weekly using the National Cancer Institute Common Toxicity Criteria. Response was assessed at 6-week intervals.RESULTS. Three patients, 6 patients, 6 patients, and 4 patients received a median of 2 courses of SC IL-2 at dose levels of 6 MIU/m(2), 9 MIU/m(2), 12 MIU/m(2), and 15 MIU/m', respectively. Failure to maintain adequate fluid intake was responsible for 2 episodes of syncope at the 9 MIU/m' dose level and for 2 incidents of reversible prerenal azotemia at the 15 MIU/m(2) dose level. IL-2 treatment was resumed in these patients without incident. At the 15 MIU/m(2) dose level, 2 patients had severe headaches, depression, and visual hallucinations requiring discontinuation of treatment. Cough and fluid retention at the end of the third and fourth weeks at the 15 MIU/m(2) dose level approximated the symptoms reported by inpatients treated by continuous IV infusion at 9 MIU/m(2) on the same schedule. There was a partial response and a complete response in subcutaneous disease at the 12 MIU/m' and 15 MIU/m(2) dose levels, respectively, each lasting < 2 months. Plasma IL-2 levels after SC injection of 1000-5000 pg/mL reached maximum by 3 hours and were detectable for up to 48 hours after administration. The half-lives for SC IL-2 absorbance and clearance were 1.6 hours and 5.2 hours, respectively, and the calculated area under the curve was 30,584 pg/mL X hour.CONCLUSIONS. SC IL-2 was well tolerated and had high sustained bioavailability at the higher doses studied. The MTD for a daily SC regimen was 12 MIU/m(2) and is recommended for future studies.