Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 ( P < 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.

中文翻译：

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MPS1 抑制剂 (BAY 1217389) 与紫杉醇联用的 I 期研究，使用新的随机持续重新评估方法进行剂量递增

目的：单极纺锤体 1 (MPS1) 激酶抑制剂 BAY 1217389 (BAY) 与紫杉醇协同作用。这项 I 期研究使用一种新的随机连续重新评估方法 (rCRM) 评估了 BAY 与紫杉醇的组合，以改进剂量确定。患者和方法：实体瘤患者在第 1 周期随机接受口服 BAY（每日 2 次，每天 2 次，连用 5 天）联合紫杉醇（90 mg/m2）每周一次或紫杉醇单药治疗。 CRM 建模。主要目标是评估安全性，建立 BAY 的 MTD，并评估两种化合物的药代动力学特征。进行模拟以确定 rCRM 对剂量确定的贡献。结果：总共有 75 名患者入组。主要的剂量限制性毒性是血液学毒性（55.6%）。BAY 的 MTD 设定为 64 mg，每天两次，使用紫杉醇。纳入控制组可以将≥3 级中性粒细胞减少症明确归因于较高的 BAY 暴露 [AUC0-12 ( P < 0.001)]。在确定 MTD 后，我们纳入了 19 名该剂量的乳腺癌患者进行剂量扩展。其他常见的毒性是恶心 (45.3%)、疲劳 (41.3%) 和腹泻 (40.0%)。在 31.6% 的可评估患者中看到了总体确认的反应。模拟表明，rCRM 在确定真正的 MTD 方面优于传统设计。结论：BAY 与紫杉醇的组合与相当大的毒性相关，没有治疗窗。然而，使用 rCRM 设计使我们能够确定 BAY 的暴露-毒性关系。所以，