Abstract

Background

The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.

Methods

Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.

Results

Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m² daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.

Conclusion

Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

中文翻译：

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奥拉帕尼和替莫唑胺治疗复发性胶质母细胞瘤的药代动力学、安全性和耐受性：I 期 OPARATIC 试验的结果。

摘要

背景

聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂奥拉帕尼增强了临床前胶质母细胞瘤模型中的放射和替莫唑胺 (TMZ) 化疗，但脑渗透性较差。临床上，PARP 抑制剂加剧了 TMZ 的血液学副作用。进行 OPARATIC 试验以测量奥拉帕尼对复发性胶质母细胞瘤的渗透性，并评估其与 TMZ 组合的安全性和耐受性。

方法

临床前药代动力学研究评估了奥拉帕尼在大鼠和荷瘤小鼠中的组织分布。患有复发性胶质母细胞瘤的成年患者在 3 + 3 设计中接受了不同剂量和时间表的奥拉帕尼和低剂量 TMZ。合适的患者在神经外科切除前接受了奥拉帕尼；通过质谱法测量血浆、肿瘤核心和肿瘤边缘标本中的奥拉帕尼浓度。一个剂量扩展队列测试了推荐的 II 期剂量 (RP2D) 的耐受性和有效性。通过胶质母细胞瘤细胞系中的克隆形成存活率测量奥拉帕尼的放射增敏作用。

结果

奥拉帕尼是多药耐药蛋白 1 的底物，在大鼠中未显示出脑渗透，但在原位胶质母细胞瘤异种移植物中检测到。临床上，在 71/71 例肿瘤核心标本（27 例患者；中位值，496 nM）和 21/21 例肿瘤边缘标本（9 例患者；中位值，512.3 nM）中检测到奥拉帕尼。奥拉帕尼加剧了 TMZ 相关的血液学毒性，需要间歇给药。RP2D 是 olaparib 150 mg（3 天/周）和 TMZ 75 mg/m ²每天 42 天。39 名可评估患者中有 14 名 (36%) 在 6 个月时无进展。Olaparib 在 100 和 500 nM 的临床相关浓度下放射增敏 6 种胶质母细胞瘤细胞系。

结论

奥拉帕尼在放射增敏浓度下可靠地穿透复发性胶质母细胞瘤，支持进一步的临床开发，并强调需要更好的临床前模型。