Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Urology, University of California, Irvine, California, USA.
Clin Transl Med. 2024 Mar;14(3):e1627. doi: 10.1002/ctm2.1627.
Our preclinical studies showed that lycopene enhanced the anti-prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer.
Subjects were treated with 21-day cycles of 75 mg/m docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out.
Twenty-four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose-limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of .106 and thus was chosen as the MTD. Lycopene increased the AUC and C of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose-related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin-like growth factor 1R phosphorylation, associated with lycopene therapy.
The combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity-dependent MTD definition.
The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients. Small increases in plasma exposure to docetaxel were observed with lycopene co-administration. Mechanistically significant effects were seen on angiogenesis and insulin-like growth factor 1 signalling by lycopene co-administration with docetaxel/ADT.
我们的临床前研究表明，番茄红素增强了多西紫杉醇在动物模型中抗前列腺癌的疗效。进行了一项 I 期临床试验（NCT0149519），以确定番茄红素与多西紫杉醇（联合雄激素阻断[雄激素剥夺疗法，ADT]）联合使用的最佳剂量，并评估其对转移性前列腺癌患者多西紫杉醇安全性和药代动力学的影响。
受试者接受 21 天周期的 75mg/m2多西紫杉醇（联合 ADT）治疗，同时每天服用 30、90 或 150mg 番茄红素。采用贝叶斯模型平均连续评估方法指导剂量递增。进行了多西紫杉醇的药代动力学和多项相关性研究。
共纳入 24 名受试者，18 名参加剂量递增队列以确定最大耐受剂量（MTD），6 名参加药代动力学队列。多西紫杉醇/ADT 加 150mg/天合成番茄红素导致 12 名参与者中的 1 名出现剂量限制毒性（肺栓塞），估计概率为.106，因此被选为 MTD。番茄红素使血浆多西紫杉醇的 AUC 和 C 分别增加了 9.5%和 15.1%。相关性研究表明，与番茄红素治疗相关的循环内皮细胞和血管内皮生长因子 A 发生剂量相关性变化，胰岛素样生长因子 1R 磷酸化减少。
多西紫杉醇/ADT 联合合成番茄红素具有低毒性和良好的药代动力学特性。番茄红素对生物标志物的影响为基于毒性的 MTD 定义提供了额外支持。
确定了多西紫杉醇/ADT 联合番茄红素的最大耐受剂量为 150mg/天，用于治疗转移性前列腺癌患者。与番茄红素联合使用时，观察到多西紫杉醇的血浆暴露量略有增加。与多西紫杉醇/ADT 联合使用时，番茄红素观察到对血管生成和胰岛素样生长因子 1 信号传导具有显著的机制作用。
