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

项目摘要/摘要 这项孤儿药物补助申请是针对与一种新型受体联合治疗的第二阶段临床试验 酪氨酸激酶(RTK)抑制剂和雷帕霉素抑制剂抗恶性周围神经的哺乳动物靶点 鞘肿瘤(MPNSTs)。对于这种化疗耐药的死亡病例，目前还没有有效的治疗选择 疾病。这是一项由研究人员发起的多中心人类首例研究，临床前数据涵盖了 七年来，MPNST被确定为PLX3397(PLX)的特异性疾病适应症，PLX是一种有效和特异的 RTK抑制剂，可抑制200多个受试者中的五个激酶。PLX特别抑制CSF1R、c-kit和 β在体外和MPNST异种移植模型中的表达。我们已经证明，PLX和PLX联合治疗 西罗莫司导致持续的肿瘤生长抑制和肿瘤相关基因的显著耗竭 巨噬细胞和从M2(促肿瘤)向M1(肿瘤抑制)巨噬细胞的转变。因此，这 药物组合，通过有效地阻断RTK和改变肿瘤巨噬细胞的浸润，代表了一种新的 治疗MPNST的药物组合。 1/2期研究的1期部分已获得食品和药物管理局(IND#125719)和CUMC IRB的批准 (#AAAO6059)，到目前为止已经招募了四名患者，使用适应性设计来确定推荐的 第2期剂量(RP2D)。所有三名可评估的患者都经历了临床受益(1名有效，2名稳定 疾病由RECIST)，包括一名MPNST患者。两名患者已超过剂量限制 毒性(DLT)期和一个DLT被观察到在剂量水平4，这被认为是与疾病有关的 第四位仍在研究中的患者。 研究的第二阶段部分，也是本应用的重点，将需要预治疗、继续治疗和 在接受RP2D治疗的患者中进行活组织检查，希望证明其疗效。的目标是 研究的目的是(1)证明一种无表现生存的益处，(2)确定有效率和总体 存活率，(3)抑制靶通路和巨噬细胞浸润与疗效的相关性，以及(4)识别 RTK磷酸化状态和巨噬细胞浸润水平检测耐药途径的研究 患者进展时的肿瘤样本与正在治疗的患者的肿瘤样本进行比较。药效的证明 联合应用PLX和西罗莫司治疗MPNST将是非常有价值的治疗 MPNST并导致改善对这种不治之症和高度致命疾病的医疗管理。

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.