I-间碘苄胍联合地努图希单抗±伏立诺他治疗复发或难治性神经母细胞瘤的I期研究：神经母细胞瘤治疗新方法试验

Phase I Study of I-Metaiodobenzylguanidine With Dinutuximab ± Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial.

作者信息

Cash Thomas, Marachelian Araz, DuBois Steven G, Chi Yueh-Yun, Baregamyan Anahit, Groshen Susan G, Jonus Hunter C, Shamirian Anasheh, Crowley Mary, Goodarzian Fariba, Acharya Patricia T, Pawel Bruce, Erbe Amy K, Shahi Ankita, Zaborek Jen, Kennedy Eleanor, Asgharzadeh Shahab, Villablanca Judith G, Pinto Navin, Weiss Brian D, Mosse Yael P, Desai Ami V, Macy Margaret E, Granger Meaghan, Vo Kieuhoa T, Sondel Paul M, Matthay Katherine K, Park Julie R, Goldsmith Kelly C

机构信息

Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.

Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.

出版信息

J Clin Oncol. 2025 Jun 23:JCO2402612. doi: 10.1200/JCO-24-02612.

DOI:10.1200/JCO-24-02612

PMID:40549985

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12226806/

Abstract

PURPOSE

We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory neuroblastoma (rNBL).

METHODS

In part A, patients with MIBG-avid rNBL received MIBG intravenously (IV) on day 1 at 12, 15, or 18 mCi/kg per the rolling six design and dinutuximab (17.5 mg/m once daily) IV on days 8-11 and 29-32 and granulocyte-macrophage colony-stimulating factor (250 mcg/m once daily) subcutaneously on days 8-17 and 29-38. Autologous stem cells were infused on day 15. In part B, vorinostat at 180 mg/m once daily was given orally on days 0-13 in combination with the part A recommended phase II dose (RP2D). Patients could receive two courses.

RESULTS

Forty-five eligible patients enrolled, of whom 31 were evaluable. The median age was 7.5 (range, 2.9-24.1) years. For part A (n = 19), no dose-limiting toxicities (DLTs) occurred across all dose levels and courses, establishing the RP2D of MIBG to be 18 mCi/kg. In part B (n = 12), 1 DLT (grade 3 hypokalemia) occurred during course 1, and 3 of 11 patients who received a second course experienced DLT: grade 3 ALT increase, grade 4 hypoxia and grade 5 pneumonitis, and grade 3 fatigue. The best overall response rate (BORR; complete response [CR] + partial response [PR]) on part A was 42% with a CR/PR/minor response (MR) rate of 46%, and 19% progressive disease (PD) rate. For part B, the BORR was 42% with a CR/PR/MR rate of 75% and 0% PD rate.

CONCLUSION

MIBG combined with dinutuximab was well tolerated with encouraging antitumor activity. Vorinostat added to this combination may augment responses in this heavily pretreated patient population.

摘要

目的

我们开展了一项I期试验，以确定1-间碘苄胍（MIBG）联合抗GD2抗体迪努图希单抗，无论是否联合组蛋白去乙酰化酶抑制剂伏立诺他，在复发/难治性神经母细胞瘤（rNBL）患者中的安全性、耐受性及初步抗肿瘤活性。

方法

在A部分，MIBG摄取阳性的rNBL患者按照滚动六剂量设计，于第1天静脉注射（IV）MIBG，剂量为12、15或18 mCi/kg，于第8 - 11天和第29 - 32天静脉注射迪努图希单抗（17.5 mg/m²每日1次），并于第8 - 17天和第29 - 38天皮下注射粒细胞巨噬细胞集落刺激因子（250 mcg/m²每日1次）。于第15天输注自体干细胞。在B部分，于第0 - 13天口服伏立诺他，剂量为180 mg/m²每日1次，联合A部分的推荐II期剂量（RP2D）。患者可接受两个疗程。

结果

45例符合条件的患者入组，其中31例可评估。中位年龄为7.5岁（范围2.9 - 24.1岁）。对于A部分（n = 19），所有剂量水平和疗程均未发生剂量限制性毒性（DLT），确定MIBG的RP2D为18 mCi/kg。在B部分（n = 12），第1疗程期间发生1例DLT（3级低钾血症），接受第2疗程的11例患者中有3例发生DLT：3级ALT升高、4级低氧血症和5级肺炎，以及3级疲劳。A部分的最佳总体缓解率（BORR；完全缓解[CR] + 部分缓解[PR]）为42%，CR/PR/微小缓解（MR）率为46%，疾病进展（PD）率为19%。对于B部分，BORR为42%，CR/PR/MR率为75%，PD率为0%。