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

点击翻译按钮获取中文摘要

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.