Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors

PLX3397和西罗莫司联合治疗恶性周围神经鞘肿瘤中肿瘤相关巨噬细胞的2期研究

• 批准号: 9444352
• 负责人: Gulam Abbas Manji
• 金额: $ 50万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-05 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444352
• 关键词: Phase; study; combination; therapy; PLX3397

Project Summary/Abstract This Orphan Drug Grant application is for a phase 2 clinical trial of combination therapy with a novel receptor tyrosine kinase (RTK) inhibitor and mammalian target of rapamycin inhibitor against malignant peripheral nerve sheath tumors (MPNSTs). No efficacious treatment options currently exist in this chemotherapy-resistant fatal disease. This is an investigator-initiated, multicenter, first in man study with preclinical data spanning over seven years which identified MPNST as a specific disease indication for PLX3397 (PLX), a potent and specific RTK inhibitor that inhibits five kinases of the over 200 tested. PLX specifically inhibits CSF1R, c-KIT, and PDGFRβ in vitro and in an MPNST xenograft model. We have shown that combination therapy with PLX and sirolimus resulted in sustained tumor growth inhibition and a marked depletion of tumor-associated macrophages and a shift from M2 (tumor promoting) to M1 (tumor inhibiting) macrophages. Therefore, this drug combination, by potently blocking RTKs and by altering tumor macrophage infiltration, represents a novel drug combination for MPNSTs. The phase 1 portion of the phase 1/2 study has been approved by the FDA (IND #125719) and CUMC IRB (#AAAO6059) and has to date enrolled four patients using an adaptive design to identify the recommended phase 2 dose (RP2D). All three evaluable patients have experienced clinical benefit (1 response and 2 stable disease by RECIST) which includes a patient with MPNST. Two patients have surpassed the dose limiting toxicity (DLT) period and one DLT was observed at dose level 4, which is thought to be disease related in the fourth patient who remains on study. The phase 2 portion of the study, and the focus of this application, will require pre-treatment, on-treatment, and on-progression biopsies in patients treated with the RP2D in hopes to demonstrate efficacy. The goal of the study is to (1) demonstrate a performance free survival benefit, (2) determine the response rate and overall survival, (3) correlate inhibition of target pathways and macrophage infiltration with efficacy, and (4) identify pathways of resistance by determining RTK phosphorylation status and level of macrophage infiltration in tumor samples from patients at time of progression compared to that on-treatment. Proof of efficacy of combination therapy with PLX and sirolimus in MPNST would be invaluable in the treatment of patients with MPNST and lead to improved medical management of this incurable and highly fatal disease.

项目概要/摘要 该孤儿药补助金申请用于与新型受体联合治疗的 2 期临床试验 酪氨酸激酶（RTK）抑制剂和雷帕霉素抑制剂针对恶性周围神经的哺乳动物靶点 对于这种化疗耐药的致命性鞘膜瘤（MPNST），目前尚无有效的治疗方案。 这是一项由研究者发起的、多中心的、首次针对人体的研究，其临床前数据涵盖了多个领域。 七年来，将 MPNST 确定为 PLX3397 (PLX) 的特定疾病适应症，PLX3397 是一种有效且特异性强的药物。 RTK 抑制剂可抑制 200 多种测试的 PLX 中的 5 种激酶，特别抑制 CSF1R、c-KIT 和 我们已经在体外和 MPNST 异种移植模型中证明了与 PLX 和 PDGFRβ 的联合治疗。 西罗莫司导致持续的肿瘤生长抑制和肿瘤相关的显着耗竭 巨噬细胞和从 M2（肿瘤促进）到 M1（肿瘤抑制）巨噬细胞的转变。 药物组合通过有效阻断 RTK 和改变肿瘤巨噬细胞浸润，代表了一种新的 MPNST 的药物组合。 1/2 期研究的 1 期部分已获得 FDA (IND #125719) 和 CUMC IRB 的批准 (#AAAO6059)，迄今为止已使用自适应设计招募了四名患者来确定推荐的治疗方案 2 期剂量 (RP2D) 所有三名可评估患者均获得了临床获益（1 例缓解，2 例稳定）。 RECIST 疾病），其中包括一名 MPNST 患者，已超过剂量限制。 毒性（DLT）期，并且在剂量水平 4 时观察到一种 DLT，这被认为与疾病相关 第四位患者仍在研究中。 该研究的第 2 阶段部分以及本申请的重点将需要预处理、治疗中和 对接受 RP2D 治疗的患者进行进展活检，希望证明其疗效。 研究的目的是（1）证明无绩效生存获益，（2）确定缓解率和总体 生存，(3) 将靶途径的抑制和巨噬细胞浸润与疗效相关联，以及 (4) 确定 通过测定 RTK 磷酸化状态和巨噬细胞浸润水平来确定耐药途径 与治疗时相比，来自患者进展时的肿瘤样本的疗效证明。 在 MPNST 中使用 PLX 和西罗莫司联合治疗对于治疗以下患者具有不可估量的价值： MPNST 并导致改善这种无法治愈且高度致命的疾病的医疗管理。