Targeting the c-Met/HGF Axis in Acute Myeloid Leukemia

描述（由申请人提供）：急性髓性白血病（AML）是一种侵袭性恶性肿瘤，长期预后不良。所有人的存活率仍然低于50%。复发性或难治性疾病的患者可以对二线治疗作出反应，但只能达到10%的五年生存率。因此，AML是一种临床需求未得到满足的疾病，迫切需要新的药物来改善结局。最近，几项研究表明c-Met/肝细胞生长因子（HGF）途径在介导耐药性和促进不同肿瘤类型（从上皮到血液恶性肿瘤）的肿瘤生长方面的重要性13，25，30。在AML中，高血清HGF水平与更具侵袭性的病程以及生存期缩短相关10，11，14，28。最近，使用抗HGF抗体或c-Met的小分子抑制剂对HGF进行基因耗竭，在体外和体内有效抑制了表达HGF的AML母细胞的生长和存活13。 基于这些数据和c-Met抑制剂在胃腺癌和肺癌II期研究中的成功，我们推测，联合使用高剂量阿糖胞苷（HIDAC）和ficlatuzumab（一种抗HGF抗体）将通过废除下游c-Met信号传导途径改善复发性/难治性AML患者的临床结局，从而降低白血病克隆的生存率。我们提出了一项Ib期研究，采用3+3设计，以发现这些药物联合治疗的最大耐受剂量（MTD），并描述该方案的初步活性和对生活质量的影响。主要终点是联合用药的安全性/耐受性。次要终点包括CR率、OS、PFS和生活质量变化。计划的相关因素包括：治疗前和治疗后的血清HGF水平、原始细胞计数和c-Met的下游靶点（p-ERK、p-AKT和p-STAT 3）。此外，将通过免疫组织化学（IHC）与骨髓活检标本上的基质和干细胞标志物共染色评估c-Met和HGF表达，以探索造血生态位旁分泌信号传导的作用。 如果成功，这项研究将 成为第一个利用合理选择的抗体为这一高风险人群提供更有效和毒性更小的治疗选择的人。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is an aggressive malignancy with a poor long-term prognosis. Survival rate for all comers remains less than 50%. Patients with either relapsed or refractory disease can respond to second-line therapy but only achieve a five-year survival of 10%. Thus, AML represents a disease with an unmet clinical need, and novel agents are urgently needed to improve outcomes. Recently, several studies have shown the importance of the c-Met/hepatocyte growth factor (HGF) pathway in mediating drug resistance and fueling tumor growth across distinct tumor types ranging from epithelial to hematological malignancies 13, 25, 30. In AML, high serum HGF levels have correlated with a more aggressive disease course as well as shortened survival 10, 11, 14, 28. More recently, genetic depletion of HGF using anti-HGF antibodies or a small molecule inhibitor of c-Met potently suppressed the growth and survival of HGF expressing AML blasts in vitro and in vivo 13. Based on these data and the success of c-Met inhibitors in phase II studies for gastric adenocarcinomas and lung cancer, we surmise that combining high-dose cytarabine (HIDAC) with ficlatuzumab (an anti-HGF antibody) will improve clinical outcomes in patients with relapsed/refractory AML through abrogation of the downstream c-Met signaling pathway, resulting in decreased survival of the leukemia clones. We propose a phase Ib study using the 3+3 design to discover the maximally tolerated dose (MTD) of these agents in combination and describe the preliminary activity and effect on quality of life afforded by this regimen. The primary endpoint is the safety/tolerability of the combination. Secondary endpoints consist of CR rate, OS, PFS, and changes in quality of life. Planned correlatives include: serum HGF levels, blast counts, and downstream targets of c-Met (p-ERK, p-AKT, and p-STAT3) pre- and post-treatment. In addition, c-Met and HGF expression will be assessed by immunohistochemistry (IHC) co-staining with stromal and stem cell markers on bone marrow biopsy specimen to explore the role of paracrine signaling by the hematopoietic niche. If successful, this study will be the first to offer a more potent and less toxic treatment option for this high-risk population utilizing a rationally selected antibody.