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