Motzer R J, Rakhit A, Schwartz L H, Olencki T, Malone T M, Sandstrom K, Nadeau R, Parmar H, Bukowski R
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 1998 May;4(5):1183-91.
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.
晚期肾细胞癌患者在一项I期试验中接受治疗，每28天为一个周期，在第1、8和15天给予递增剂量的重组人白细胞介素-12（rHuIL-12）。初始剂量方案的治疗包括固定剂量，剂量水平分别为0.1、0.5和1.0μg/kg，给予由3名或6名患者组成的队列。根据毒性情况，采用了第二种方案（剂量递增），即rHuIL-12从第1周开始为每位患者递增剂量，至第3周及之后给予目标剂量；队列目标剂量水平分别为0.5、0.75、1.0、1.25和1.5μg/kg。共治疗了51名患者：32名（63%）曾接受过细胞因子治疗，19名（37%）未曾接受过全身治疗。固定剂量方案的最大耐受剂量为1.0μg/kg。剂量限制性毒性包括转氨酶浓度升高、肺部毒性和白细胞减少。最严重的毒性发生在首次注射时，后续治疗时症状较轻。采用剂量递增方案时，最大耐受剂量为1.5μg/kg，剂量限制性毒性为血清转氨酶水平升高。在1.5μg/kg的最大耐受剂量下，血清IL-12水平升至平均峰值水平706pg/ml。在首次给予1.5μg/kg维持剂量后24小时，血清IFN-γ水平升至平均峰值水平约200pg/ml。最佳反应如下：1例患者完全缓解，34例患者病情稳定，14例患者病情进展，1例患者无法评估。总之，rHuIL-12皮下注射给药时耐受性相对良好。根据rHuIL-12的剂量递增方案（μg/kg），II期试验的推荐剂量如下：第1周期，0.1（第1天），0.5（第8天），1.25（第15天）；从第2周期起，1.25。rHuIL-12的II期试验已在既往未接受治疗的肾细胞癌患者和黑色素瘤患者中启动。
