BACKGROUND Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. METHODS Three chronomodulation schedules (5:00-13:00, 13:00-21:00, and 21:00-5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). RESULTS Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00-13:00, 15 at 13:00-21:00, and 13 at 21:00-5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2-107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1-2), MSKCC score (0-2 vs. ≥ 3), IMDC risk score (0-2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. CONCLUSION IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

中文翻译：

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白细胞介素 2 时间疗法治疗转移性肾细胞癌：I-II 期研究结果

背景白细胞介素2（IL-2）是转移性肾细胞癌（RCC）治疗的基石，直到酪氨酸激酶抑制剂问世，但它仍然具有治疗价值。由于单次注射 IL-2 会引起毒性，因此人们对具有更好耐受性和有效性的给药方案感兴趣。时间疗法是根据昼夜节律对免疫和激素系统的影响进行治疗。该 I-II 期试验评估了 IL-2 计时疗法在转移性 RCC 患者中的安全性，并确定了最大耐受剂量。次要目标是确定生存的预后因素。方法 测试了三种时间调节时间表（5:00-13:00、13:00-21:00 和 21:00-5:00）。每个时间表是 8 小时 IL-2 输注，药物浓度的高斯分布在 4 小时达到峰值。为了确定最大耐受剂量，不同患者的剂量从 2 MIU/m2（I 级）增加到 18.6 MIU/m2（VI 级）。结果 30 名患者入组并完成治疗。5:00-13:00治疗2例，13:00-21:00治疗15例，21:00-5:00治疗13例。7 名患者在最高剂量（18.6 MIU/m2）时发生 9 例 3 级毒性；没有发生 4 级毒性。最大耐受剂量为 14.0 MUI/m2。患者的中位随访时间为 16 个月（范围，2-107）。1名患者失访，3名患者在最后一次接触时存活，26名患者死亡。6 名患者实现了长期生存（≥48 个月）。完全缓解1例，部分缓解4例，病情稳定11例，疾病进展14例。反应率为 16% (5/30)，疾病控制率为 53% (16/30)。中位无进展生存期为 4.5 个月，中位总生存期为 14.5 个月。Kaplan-Meier 分析显示总生存期与 ECOG 表现评分（0 对 1-2）、MSKCC 评分（0-2 对 ≥ 3）、IMDC 风险评分（0-2 对 ≥ 3）、IL- 2 剂量水平（IV-VI 与 I-III）和催乳素（增加与不增加），但不适用于计时疗法。结论 IL-2 时间疗法在转移性 RCC 中似乎是安全、中等毒性和活性的。对于这些患者，它可能代表了一种新的 IL-2 给药方式。I-III）和催乳素（增加与不增加），但不适用于时间疗法计划。结论 IL-2 时间疗法在转移性 RCC 中似乎是安全、中等毒性和活性的。对于这些患者，它可能代表了一种新的 IL-2 给药方式。I-III）和催乳素（增加与不增加），但不适用于时间疗法计划。结论 IL-2 时间疗法在转移性 RCC 中似乎是安全、中等毒性和活性的。对于这些患者，它可能代表了一种新的 IL-2 给药方式。