Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma.
Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma.
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发表时间：
1998-05
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通讯作者：
R. Motzer;A. Rakhit;L. Schwartz;T. Olencki;T. Malone;K. Sandstrom;R. Nadeau;H. Parmar;R. Bukowski
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作者：
R. Motzer;A. Rakhit;L. Schwartz;T. Olencki;T. Malone;K. Sandstrom;R. Nadeau;H. Parmar;R. Bukowski
在I期试验中，在每个28天周期的第1、8和15天给予递增剂量的重组人白细胞介素-12（rHuIL-12）治疗晚期肾细胞癌患者。初始剂量方案中的治疗包括固定剂量，剂量水平为0.1、0.5和1.0 μ g/kg，给予由3名或6名患者组成的队列。基于毒性特征，进行第二方案（向上滴定），其中从第1周至第2周，将每名患者的rHuIL-12递增至第3周及之后给予的目标剂量;群组目标剂量水平为0.5、0.75、1.0、1.25和1.5微克/千克。51例患者接受了治疗：32例（63%）既往接受过细胞因子治疗，19例（37%）既往未接受过全身治疗。固定剂量方案的最大耐受剂量为1.0 μ g/kg。剂量限制性毒性包括转氨酶浓度升高、肺毒性和白细胞减少症。最严重的毒性发生在第一次注射时，在进一步治疗时较轻。在剂量上调方案中，最大耐受剂量达到1.5 μ g/kg，剂量限制性毒性包括血清转氨酶水平升高。在最大耐受剂量1.5 μ g/kg时，血清IL-12水平升高至平均峰值水平706 pg/ml。IFN-γ的血清水平在1.5 μ g/kg的首次维持剂量后24小时增加至约200 pg/ml的平均峰值水平。最佳缓解情况如下：1例患者完全缓解，34例患者稳定，14例患者显示进展，1例患者无法评估。总之，当通过皮下施用时，rHuIL-12耐受性相对良好。注射对于II期试验，根据rHuIL-12（微克/千克）的向上滴定时间表的推荐剂量如下：周期1，0.1（第1天），0.5（第8天），1.25（第15天）;周期2开始，1.25。在先前未经治疗的肾细胞癌患者和黑素瘤患者中启动rHuIL-12的II期试验。
Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.