克唑替尼联合细胞毒化疗治疗儿童难治性实体瘤或间变大细胞淋巴瘤（ALCL）的安全性、耐受性和药代动力学：一项儿童肿瘤学组 1 期联盟研究（ADVL1212）。
Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212).
机构信息
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
St Jude Children's Research Hospital, Memphis, TN, USA.
出版信息
Cancer Chemother Pharmacol. 2020 Dec;86(6):829-840. doi: 10.1007/s00280-020-04171-4. Epub 2020 Oct 23.
PURPOSE
This phase 1 study aimed to determine the safety, tolerability and recommended phase 2 dose (RP2D) of crizotinib in combination with cytotoxic chemotherapy for children with refractory solid tumors and ALCL.
METHODS
Pediatric patients with treatment refractory solid tumors or ALCL were eligible. Using a 3 + 3 design, crizotinib was escalated in three dose levels: 165, 215, or 280 mg/m/dose BID. In Part A, patients received crizotinib oral solution (OS) in combination with topotecan and cyclophosphamide (topo/cyclo); in Part B, crizotinib OS was administered with vincristine and doxorubicin (vcr/dox). In Parts C and D, patients received topo/cyclo in combination with either crizotinib-formulated capsules (FC) or microspheres (cMS), respectively. Crizotinib pharmacokinetic evaluation was required.
RESULTS
Forty-four eligible patients were enrolled, 39 were evaluable for toxicity. Parts A and B were terminated due to concerns regarding palatability and tolerability of the OS. In Part C, crizotinib, FC 215 mg/m/dose BID, in combination with topo/cyclo was tolerated. In Part D, the maximum tolerated dose (MTD) was exceeded at 165 mg/m/dose of crizotinib cMS. Pharmacokinetics of crizotinib in combination with chemotherapy was similar to single-agent crizotinib and exposures were not formulation dependent.
CONCLUSIONS
The RP2D of crizotinib FCs in combination with cyclophosphamide and topotecan was 215 mg/m/dose BID. The oral solution of crizotinib was not palatable in this patient population. Crizotinib cMS was palatable; however, patients experienced increased toxicity that was not explained by the relative bioavailability or exposure and warrants further investigation.
CLINICAL TRIAL REGISTRY
The trial is registered as NCT01606878 at Clinicaltrials.gov.
目的
本 1 期研究旨在确定克唑替尼联合细胞毒化疗治疗耐药性实体瘤和 ALCL 患儿的安全性、耐受性和推荐 2 期剂量（RP2D）。
方法
符合条件的患儿为治疗耐药性实体瘤或 ALCL。采用 3+3 设计，克唑替尼分三个剂量水平递增：165、215 或 280mg/m/剂量 BID。在 A 部分，患者接受克唑替尼口服液（OS）联合拓扑替康和环磷酰胺（topo/cyclo）；在 B 部分，克唑替尼 OS 与长春新碱和多柔比星（vcr/dox）联合给药。在 C 和 D 部分，患者分别接受 topo/cyclo 联合克唑替尼胶囊（FC）或微球（cMS）。需要进行克唑替尼药代动力学评估。
结果
共纳入 44 名合格患儿，39 名患儿可评估毒性。由于 OS 的适口性和耐受性问题，A 部分和 B 部分提前终止。在 C 部分，克唑替尼 215mg/m/剂量 BID，与 topo/cyclo 联合使用可耐受。在 D 部分，165mg/m/剂量的 crizotinib cMS 超过最大耐受剂量（MTD）。与单药克唑替尼相比，化疗联合克唑替尼的药代动力学相似，且暴露水平与剂型无关。
结论
克唑替尼 FC 联合环磷酰胺和拓扑替康的 RP2D 为 215mg/m/剂量 BID。该患者人群对克唑替尼口服液的口感不佳。克唑替尼 cMS 口感较好；然而，患者出现了无法用相对生物利用度或暴露来解释的毒性增加，需要进一步研究。
临床试验注册
该试验在 Clinicaltrials.gov 上注册为 NCT01606878。
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