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

“第一阶段研究的安全性

• 批准号: 10730723
• 负责人: Aditi Shastri
• 金额: $ 65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730723
• 关键词: PHASE; STUDY; INVESTIGATING; SAFETY; EFFICACY

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.

项目总结/摘要 骨髓恶性肿瘤，如骨髓增生异常综合征（MDS）和急性髓性白血病 (AML)出现并通过引发疾病的异常细胞的扩张而传播 造血干细胞。虽然新批准的疗法改善了这些患者的结局， 疾病，复发仍然是最常见的死亡原因，在积极的骨髓 恶性肿瘤（MDS & AML），R/R HR-MDS和R/R中预后不良4-10个月 急性髓细胞白血病疾病引发的白血病干细胞是疾病复发的来源，需要 针对潜在的治愈性治疗策略。信号转导和转录激活 转录因子3（STAT 3）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，STAT 3是 在MDS/AML干细胞中去甲基化和过表达，并与不良反应相关。 在大型患者队列中的预后（Shastri et al，JCI 2018）。我们还证明 STAT 3控制着几种重要的白血病驱动因子，如抗凋亡蛋白， 髓样白血病细胞分化1（MCL 1）。MCL 1过表达是一种重要的介导因子， 在R/R AML/MDS中对BCL 2抑制（维奈托克）的耐药性。Danvatirsen（AZD 9150）是一种 STAT 3的选择性反义抑制剂，可以靶向恶性干细胞，同时保留健康 对照造血干细胞和祖细胞（HSPC），从而将其鉴定为潜在的 MDS/AML的治疗策略（Shastri et al，JCI 2018）。 通过这项拨款申请，我们将研究的安全性，有效性和目标选择性 丹伐他汀作为单药治疗和与Ven联合治疗的I期临床试验， R/R高危MDS和R/R AML。我们还旨在评估STAT 3抑制的生物标志物以及 作为下游MCL 1抑制与正在进行的临床试验平行。 通过瞄准。1我们将确定STAT 3的安全性、有效性和靶向作用 抑制剂Danvatirsen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I期剂量递增方案， 包括2项子研究，以评价安全性特征并确定最大耐受剂量 (MTD)其中：a）丹伐替森单药治疗，B）丹伐替森和维奈托克联合给药一次 确立了Danvatirsen单一疗法的安全性。这项研究的主要目的是 确定安全性、最大耐受剂量（MTD）和推荐的II期剂量（RP 2D） 单药治疗后与维奈托克联合治疗R/R 国际/高/极高风险IPSS-R MDS或R/R AML。研究的次要目的是 确定缓解持续时间（DOR）、无事件生存期（EFS）、总生存期（OS）、30- 和60天全因死亡率，应答者的最小残留疾病清除率（基于 多参数流式细胞术，桥接至干细胞移植的数量）。 目标2。在这项研究中，我们将确定反应的生物标志物，并评估- 相关研究中对白血病干细胞的靶向疗效。我们的探索目标 是为了确定治疗前和治疗中的临床，突变和干细胞相关的反应， STAT 3抑制以及了解STAT 3相关基因表达的变化， 异常MDS/AML LSC。为此，我们将从病人身上分离出干细胞和祖细胞 在治疗前和治疗中预先规定的时间点， 丹伐他汀对异常MDS/AML中STAT 3表达/磷酸化的影响 LSC。我们已经从FDA获得了拟议试验的IND以及支持信 用于在整个临床试验期间提供来自Flamingo therapeutics的danvatirsen。