Modak Shakeel, Kushner Brian H, Basu Ellen, Roberts Stephen S, Cheung Nai-Kong V
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Pediatr Blood Cancer. 2017 Aug;64(8). doi: 10.1002/pbc.26448. Epub 2017 Jan 23.
The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy.
We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m /day IV) and temozolomide (150 mg/m /day orally) on days 4-8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles.
Thirty-three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT-treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti-NB therapy post-BIT.
BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT.
研究贝伐单抗、伊立替康和替莫唑胺（BIT）联合方案用于神经母细胞瘤（NB）的依据如下：（i）血管内皮生长因子（VEGF）表达与侵袭性表型相关；（ii）抗VEGF抗体贝伐单抗可增强伊立替康对NB异种移植瘤的抑制作用；（iii）贝伐单抗的安全性已在儿科I期研究中得到证实；（iv）伊立替康+替莫唑胺（IT）是标准的挽救性化疗方案。
我们对可测量/可评估的难治性或复发性高危NB患者开展了BIT的II期研究（www.clinicaltrials.gov，NCT01114555）。每个周期包括第1天和第15天静脉注射（IV）贝伐单抗（15mg/kg），以及第4 - 8天静脉注射伊立替康（50mg/m²/天）和口服替莫唑胺（150mg/m²/天）。患者此前可以接受过IT治疗，但未出现复发。早期终止规则规定，仅当27例可评估患者中有超过5例在4个周期后达到部分缓解（PR）或完全缓解（CR）时，才继续治疗。
33例经过大量预处理的患者（9例原发难治性；24例复发性）接受了1至8个周期的BIT治疗。毒性反应为预期的且为一过性。4级毒性反应为中性粒细胞减少（30%）和血小板减少（24%）。3级毒性反应包括肝转氨酶升高（15%）、蛋白尿（9%）和腹泻（3%）。总体反应如下：3例CR（均为既往接受过IT治疗的患者），18例无反应，12例疾病进展。在23例可根据疗效早期终止规则进行评估的患者中，只有1例达到PR/CR，因此停止入组患者。无进展生存期和总生存期的中位数分别为7.7±1.7个月和31.5±5.6个月；所有患者在BIT治疗后继续接受抗NB治疗。
BIT耐受性良好，但与IT的历史数据相比，添加贝伐单抗并未提高耐药NB的缓解率。
