"A PHASE I STUDY INVESTIGATING THE SAFETY & EFFICACY OF DANVATIRSEN AS MONOTHERAPY FOLLOWED BY COMBINATION WITH VENETOCLAX IN PATIENTS WITH RELAPSED/REFRACTORY MDS & AML."

项目摘要/摘要 髓系恶性肿瘤，如骨髓增生异常综合征(MDS)和急性髓系白血病 (AML)通过致病变异的扩大而出现和传播 造血干细胞。尽管新批准的治疗方法在这些方面的结果有所改善 疾病，复发仍然是侵袭性髓系死亡的最常见原因 R/R、HR-MDS和R/R预后不良的恶性肿瘤(MDS和AML) AML。引发疾病的白血病干细胞是疾病复发的来源，需要 以潜在的治疗策略为目标。信号换能器和激活器 转录因子3(STAT3)属于转录因子STAT家族。 在几种恶性肿瘤中被不适当地激活。我们的初步数据表明STAT3是 MDS/AML干细胞中去甲基化和过表达，并与不利的 在一大群患者中的预后(Shastri等人，JCI 2018)。我们还展示了 STAT3控制着几个重要的白血病驱动因素，如抗凋亡蛋白 髓系白血病细胞分化1(MCL1)。MCL1的过度表达是一种重要的调节因子 在R/R AML/MDS中对bcl2抑制(Ventoclax)的抗性。Danvatirsen(AZD9150)是一种 选择性反义STAT3抑制剂，可靶向恶性干细胞，而不损害健康 控制造血干细胞和祖细胞(HSPC)，从而确定其为潜在的 MDS/AML的治疗策略(Shastri等人，JCI 2018)。 通过这项拨款计划，我们将研究该药物的安全性、有效性和靶向性。 Danvatirsen作为单一疗法&与Ven联合进行的I期临床试验 R/R高危MDS和R/R AML。我们的目标也是评估STAT3抑制的生物标志物 作为下游的MCL1抑制与正在进行的临床试验并行。 通过AIM。1我们将确定STAT3的安全性、有效性和达标效果 Danvatirsen抑制剂作为抗白血病干细胞治疗的早期临床试验 在R/R高危MDS和AML中。我们将采用第一阶段剂量升级方案， 包括2项子研究，以评估安全性并确定最大耐受量 (MTD)：a)丹伐替罗单用，b)丹伐替森和万乃馨联合使用一次 Danvatirsen单一疗法的安全性已经确立。这项研究的主要目的是 确定安全性、最大耐受量(MTD)和推荐第二阶段剂量(RP2D) 丹参单药联合万乃近治疗R/R INT/高/极高风险IPSS-R MDS或R/R AML。这项研究的次要目标是 确定应答持续时间(DOR)、无事件生存期(EFS)、总生存期(OS)、30 以及60天全因死亡率、应答者最低残留疾病清除率(基于 多参数流式细胞术，数量桥接干细胞移植)。 为了这项研究的目的2.我们将确定反应的生物标记物，并对 相关研究中针对白血病干细胞的靶向性研究。我们的探索目标 是确定治疗前和治疗中的临床、突变和干细胞反应的相关性 为了抑制STAT3以及了解STAT3相关基因表达的变化 异常的MDS/AML LSC。为此，我们将从患者身上分离干细胞和祖细胞 在治疗前和治疗前的预定时间点评估摄取和分子水平 Danvatirsen对MDS/AML细胞中STAT3表达/磷酸化的影响 LSC。我们已经从FDA那里获得了拟议试验的IND以及一封支持信 在整个临床试验期间提供Flamingo Treateutics的Danvatirsen。

Project Summary/Abstract Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) emerge and are propagated through expansion of disease-initiating aberrant hematopoietic stem cells. Although newer approved therapies have improved outcomes in these diseases, relapse continues to be the most common cause of death in aggressive myeloid malignancies (MDS & AML) with a dismal prognosis of 4-10 months in R/R HR-MDS and R/R AML. Disease-initiating leukemic stem cells are a source of disease relapse and need to be targeted for potentially curative therapeutic strategies. Signal transducer and activator of transcription 3 (STAT3) belongs to the STAT family of transcription factors that are inappropriately activated in several malignancies. Our preliminary data indicate that STAT3 is demethylated and overexpressed in MDS/AML stem cells and was associated with an adverse prognosis in a large cohort of patients (Shastri et al, JCI 2018) . We have also demonstrated that STAT3 controls several important leukemic drivers such as the antiapoptotic protein myeloid leukemia cell differentiation 1 (MCL1). MCL1 overexpression is an important mediator of resistance to BCL2 inhibition (venetoclax) in R/R AML/MDS. Danvatirsen (AZD9150) is a selective antisense inhibitor of STAT3 that can target malignant stem cells while sparing healthy control hematopoietic stem and progenitor cells (HSPC), thus identifying it as a potential therapeutic strategy in MDS/AML (Shastri et al, JCI 2018). Through the means of this grant proposal we will study the safety, efficacy & target-selectivity of danvatirsen as monotherapy & in combination with Ven in a phase I clinical trial for patients with R/R high-risk MDS & R/R AML. We also aim to evaluate biomarkers of STAT3 inhibition as well as downstream MCL1 inhibition in parallel with the ongoing clinical trial. Through Aim. 1 we will determine the safety, efficacy & on-target effect of the STAT3 inhibitor danvatirsen as an antileukemic stem cell therapy in an early-phase clinical trial in R/R high-risk MDS and AML. We will employ a phase I dose escalation protocol that includes 2 sub-studies to evaluate the safety profile and determine the maximum tolerated dose (MTD) of : a) danvatirsen as monotherapy, b) combination of danvatirsen and venetoclax once safety of danvatirsen monotherapy is established. The primary objective of the study is to establish the safety, the maximum tolerated dose (MTD) & recommended phase 2 dose (RP2D) of danvatirsen monotherapy followed by combination with venetoclax for the treatment of R/R Int/high/very-high-risk IPSS-R MDS or R/R AML. The secondary objective of the study is to determine the duration of response (DOR), event-free survival (EFS), overall survival (OS), 30- and 60-day all cause mortality, minimal residual disease clearance in responders (based on multiparametric flow-cytometry, number bridged to stem cell transplantation). For Aim 2. of the study, we will determine biomarkers of response as well as evaluate on- target efficacy against leukemic stem cells in correlative studies. Our exploratory objectives are to identify pretherapy and on-therapy clinical, mutational and stem cell correlates of response to STAT3 inhibition as well as understand the STAT3-associated gene expression changes in aberrant MDS/AML LSC’s. To this end, we will isolate stem and progenitor cells from patients prior to treatment and at pre-specified time points on therapy to assess the uptake and molecular effects of danvatirsen including on STAT3 expression/phosphorylation in aberrant MDS/AML LSCs. We have obtained an IND for the proposed trial from the FDA as well as a letter of support for provision of danvatirsen from Flamingo therapeutics for the entire duration of the clinical trial.