Lessons learned: The maximum tolerated dose of the combination of linsitinib and irinotecan is linsitinib 450 mg daily on days 1-3 every 7 days and irinotecan 125 mg/m2 days 1 and 8 of a 21-day cycle.The adverse effects associated with the combination are not significantly increased beyond what is expected of each drug as a single agent.Multiple negative trials of insulin-like growth factor-1 receptor inhibitors performed in unselected patient populations led to the early discontinuation of linistinib development and this trial.Earlier integration of assessment of potential predictive biomarkers into clinical trials, as was planned in this study, is vital to the development of targeted therapies in oncology.
Background: This phase I dose-escalation study was designed to evaluate the safety and tolerability of the combination of irinotecan and insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib in patients with advanced cancer refractory to standard therapy.
Methods: Dose escalation in three specified dose levels was performed according to a standard 3 + 3 design. Dose levels were as follows: (a) linsitinib 400 mg and irinotecan 100 mg/m2, (b) linsitinib 450 mg and irinotecan 100 mg/m2, and (c) linsitinib 450 mg and irinotecan 125 mg/m2. Linisitinib was administered once daily on days 1-3, 8-10, and 15-17, and irinotecan on days 1 and 8. Assessment of a candidate predictive biomarker was planned in all patients, with further evaluation in an expansion cohort of advanced colorectal cancer.
Results: A total of 17 patients were treated, with 1 patient in both cohort 2 and 3 experiencing dose-limiting toxicity. Linsitinib 450 mg and irinotecan 125 mg/m2 was the maximum tolerated dose. Sixteen (94%) patients experienced at least one treatment-related adverse event. Neutropenia was the only grade >3 toxicity (4%). No significant hyperglycemia or QT interval prolongation was noted. No objective responses were observed; 47% (n = 8) had stable disease with median duration of 5.25 months.
Conclusion: Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.
背景。本次 I 期剂量递增研究旨在评估标准疗法耐药的晚期癌症患者采用伊立替康和胰岛素样生长因子 1 受体 (IGF‐1R) 抑制剂 Linsitinib 联合治疗的安全性和耐受性。
方法。按照标准的 3 + 3 设计,实施 3 种特定剂量水平的剂量递增。剂量水平如下:(a) Linsitinib 400 mg 和伊立替康 100 mg/m2,(b) Linsitinib 450 mg 和伊立替康 100 mg/m2 以及 (c) Linsitinib 450 mg 和伊立替康 125 mg/m2。Linisitinib 在第 1–3 天、第 8–10 天及第 15–17 天每天给药一次,伊立替康在第 1 天和第 8 天给药。计划在所有患者中对候选的预测性生物标志物进行评估,并对一个扩展的晚期结直肠癌队列实施进一步评估。
结果。一共有 17 名患者接受治疗,在第 2 队列和第 3 队列中分别有 1 名患者出现剂量限制性毒性。Linsitinib 450 mg 和伊立替康 125 mg/m2 为最大耐受剂量。16 名 (94%) 患者至少出现一种与治疗相关的不良反应。中性粒细胞减少症是唯一的 >3 级毒性 (4%)。未发现显著的高血糖症或 QT 间期延长。未观察到客观缓解;在为期 5.25 个月的中位持续时间内,47% (n = 8) 的患者病情稳定。
结论。尽管已经确定这种联合治疗安全无虞,但是,本研究因 Linsitinib 研发终止而停止,未实施生物标记物测试
Trial registration: ClinicalTrials.gov NCT01016860.
© AlphaMed Press; the data published online to support this summary are the property of the authors.