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

项目总结/摘要 这个孤儿药补助申请是一个2期临床试验的联合治疗与一种新的受体 酪氨酸激酶（RTK）抑制剂和雷帕霉素哺乳动物靶点抑制剂抗恶性外周神经病变 鞘瘤（MPNSTs）。在这种化疗耐药致死性肿瘤中，目前没有有效的治疗选择。 疾病这是一项由制药商发起的多中心首次人体研究，临床前数据涵盖 7年，将MPNST确定为PLX 3397（PLX）的特定疾病适应症， RTK抑制剂，可抑制200多种测试激酶中的5种。PLX特异性抑制CSF 1 R、c-KIT和 体外和MPNST异种移植模型中的PDGFRβ。我们已经证明，PLX和 西罗莫司导致持续的肿瘤生长抑制和显著的肿瘤相关的细胞因子消耗。 巨噬细胞和转移从M2（肿瘤促进）到M1（肿瘤抑制）巨噬细胞。因此本 药物组合，通过有效地阻断RTKs和改变肿瘤巨噬细胞浸润，代表了一种新的 MPNST的药物组合。 I/II期研究的I期部分已获得FDA（IND #125719）和CANCIRB的批准 （#AAAO6059），迄今为止已招募了4名患者，使用自适应设计来确定推荐的 II期剂量（RP 2D）。所有3例可评价患者均经历了临床获益（1例缓解，2例稳定 疾病），其中包括MPNST患者。两名患者已超过剂量限制 在剂量水平4下观察到1例DLT，认为其与研究中的疾病相关。 第四位患者仍在接受研究。 研究的II期部分和本申请的重点将需要治疗前、治疗中和 在接受RP 2D治疗的患者中进行进展期活检，希望证明疗效。的目标 研究旨在（1）证明无性能生存获益，（2）确定缓解率和总体 存活，（3）将靶途径和巨噬细胞浸润抑制与功效相关联，和（4）鉴定 通过确定RTK磷酸化状态和巨噬细胞浸润水平， 与治疗期间相比，来自进展时患者的肿瘤样品。有效性证明 在MPNST中PLX和西罗莫司的联合治疗在治疗 MPNST和导致改善医疗管理这种不治之症和高度致命的疾病。

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.