A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors.
A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors.
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第一阶段的研究研究了pexidartinib和sirolimus靶向不可切除的肉瘤和恶性周围神经鞘瘤中与肿瘤相关的巨噬细胞的组合。
DOI：
10.1158/1078-0432.ccr-21-1779
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发表时间：
2021-10-15
期刊：
影响因子：
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通讯作者：
Schwartz GK
中科院分区：
文献类型：
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作者：
Manji GA;Van Tine BA;Lee SM;Raufi AG;Pellicciotta I;Hirbe AC;Pradhan J;Chen A;Rabadan R;Schwartz GK
目的：评价集落刺激因子-1受体抑制剂培西达替尼和mTOR抑制剂西罗莫司I期联合治疗软组织肉瘤中肿瘤相关巨噬细胞()极化的安全性和耐受性。这项多中心I期研究使用事件发生时间持续再评估方法(TITE-CRM)来研究西罗莫司(剂量从2到6毫克)和培西达替尼(剂量从600到1000毫克)在晚期肉瘤患者中的组合，这两种药物都是以28天为周期连续提供的。入选患者24例，其中恶性周围神经鞘膜瘤8例，腱鞘巨细胞瘤3例，平滑肌肉瘤5例，其他肉瘤亚型8例。中位年龄为46岁，其中56%为男性，61%曾接受过两次治疗。推荐的第二阶段剂量为每天2毫克西罗莫司和1000毫克培西达替尼。在18名可评估的受试者中，5人出现剂量限制性毒性(2人天冬氨酸氨基转移酶/丙氨酸氨基转移酶升高，2人西罗莫司谷值升高，1人出现5级脱水)。最常见的2级或更高级别的治疗相关不良事件包括贫血、疲劳、中性粒细胞减少和淋巴细胞减少。18例可评估受试者中有12例(67%)观察到临床受益，其中3例部分缓解(均在TGCT中)，9例病情稳定。组织染色显示，治疗后肿瘤样本中活化的M2巨噬细胞比例降低。西罗莫司可以安全地给予培西达替尼。这些发现支持对这种组合的进一步研究，以确定临床疗效。ClinicalTrials.gov标识符NCT02584647。
To evaluate the safety and tolerability in phase I first-in-human combination therapy with pexidartinib, an inhibitor of colony-stimulating factor-1 receptor, and sirolimus, an mTOR inhibitor, to target tumor-associated macrophage (TAM) polarization in soft tissue sarcomas (STS). This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) to study the combination of sirolimus, doses ranging from 2 to 6 mg, with pexidartinib, doses ranging from 600 to 1,000 mg, both provided continuously on a 28-day cycle, in patients with advanced sarcoma. A total of 24 patients [8 malignant peripheral nerve sheath tumor, 3 tenosynovial giant cell tumor (TGCT), 5 leiomyosarcoma, and 8 with other sarcoma subtypes] were enrolled. The median age was 46 years, 56% were male, and 61% had >2 prior lines of therapy. The recommended phase II dose was 2 mg of sirolimus combined with 1,000 mg of pexidartinib daily. Of the 18 evaluable subjects, 5 experienced dose-limiting toxicities (2 elevated aspartate aminotransferase/alanine aminotransferase, 2 elevated sirolimus trough levels, and 1 grade 5 dehydration). Most common grade 2 or higher treatment-related adverse events included anemia, fatigue, neutropenia, and lymphopenia. Clinical benefit was observed in 12 of 18 (67%) evaluable subjects with 3 partial responses (all in TGCT) and 9 stable disease. Tissue staining indicated a decreased proportion of activated M2 macrophages within tumor samples with treatment. Pexidartinib can be safely administered with sirolimus. These findings support further investigation of this combination to determine clinical efficacy. Clinicaltrials.gov identifier NCT02584647.