Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.-猫眼课题宝

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1997-03

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Clinical cancer research : an official journal of the American Association for Cancer Research

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其他

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作者：

Michael B. Atkins;Michael J. Robertson;M. Gordon;M. T. Lotze;Michelle DeCoste;Jon S. Dubois;J. Ritz;Alan B. Sandler;H. Edington;Pamela D. Garzone;J. Mier;C. Canning;L. Battiato;Hideaki Tahara;M. L. Sherman

重组人白细胞介素12 （rhIL-12）进行了I期剂量递增试验，以确定其毒性、最大耐受剂量（MTD）、药代动力学、生物学和潜在的抗肿瘤作用。4 - 6例晚期癌症患者，Karnofsky表现>/=70%，器官功能正常，作为住院患者，通过静脉注射逐渐增加剂量（3-1000 ng/kg/天）rhIL-12 (Genetics Institute, Inc.)，然后在休息2周后，作为门诊患者，每天一次，每3周5天。3级毒性（4级高胆红素血症或中性粒细胞减少症）暂停治疗，如果6名患者中有3名出现剂量限制性毒性（DLT），则停止剂量递增。建立MTD后，又入组了8名患者，进一步评估该剂量的安全性、药代动力学和免疫生物学。40名患者入组，包括20名肾癌患者、12名黑色素瘤患者和5名结肠癌患者；25例患者先前接受过全身治疗。常见的毒性包括发烧/发冷、疲劳、恶心、呕吐和头痛。在3 ng/kg剂量水平下首次观察到发热，通常发生在给药后8-12小时，非甾体抗炎药不完全抑制发热。常规实验室变化包括贫血、中性粒细胞减少、淋巴细胞减少、高血糖、血小板减少和低白蛋白血症。dlt包括口腔口炎和肝功能检查异常，主要是转氨酶升高，在1000 ng/kg剂量水平下，4名患者中有3名出现转氨酶升高。确定500 ng/kg剂量水平为MTD。按照该方案给药的该剂量与3例患者无症状肝功能检查异常和1例研究中因产气荚膜梭菌败血症死亡相关，但在剂量递增和安全阶段接受治疗的14例患者在其他方面耐受良好。计算出rhIL-12的T1/2消除时间为5.3-9.6 h。生物效应包括循环ifn - γ的剂量依赖性增加，随着后续周期的增加而衰减。血清新蝶呤以可重复的方式上升，无论剂量或周期。ELISA未检测到肿瘤坏死因子α。40名患者中有一人产生了低效价的rhIL-12抗体。在所有剂量水平下均观察到淋巴细胞减少，在完成治疗后几天内恢复，无反弹淋巴细胞增多。有一个部分缓解（肾细胞癌）和一个短暂的完全缓解（黑色素瘤），都是在以前未经治疗的患者。另外4名患者接受了所有建议的治疗，没有疾病进展。根据该方案给药的rhIL-12在大多数门诊患者可耐受的剂量下具有生物学和临床活性。尽管如此，在进行第二阶段测试之前，还需要进行额外的第一阶段研究，检查不同的时间表和特定dlt的机制。

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.

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