A Phase 1 Study Investigating the Safety and Efficacy of Danvatirsen As Monotherapy Followed By Combination with Venetoclax in Patients with Relapsed/Refractory MDS and AML

Background: In spite of the emergence of targeted & novel therapies, only 30% of patients with newly diagnosed acute myeloid leukemia (AML) enjoy long-term survival, while the majority still succumb to their illness. Even patients with MRD negative complete remissions may relapse due to chemotherapy-resistant leukemic stem cells (LSCs). Eradication of residual disease at the LSC level is the ultimate goal of anti-leukemia therapy. STAT3 belongs to the STAT family of seven transcription factors. STAT3 is activated in the cytoplasm when growth factors & cytokines bind to the upstream Janus activating kinase (JAK) and serine kinase receptors. Inappropriate activation of STAT3 dysregulates cellular processes leading to leukemogenesis. Even though STAT3 is recognized as an important therapeutic target, there has been a dearth of clinically safe,effective and specific STAT3 therapeutics. We have previously demonstrated that STAT3 is overexpressed in LSC's and have also successfully demonstrated that a selective antisense oligonucleotide inhibitor of STAT3, danvatirsen, is rapidly incorporated into MDS/AML hematopoietic stem & progenitor cells (HSPCs) and induces selective apoptosis and down regulation of STAT3 in these cells compared with healthy control HSPCs. In addition, we demonstrated a strong correlation between STAT3 & MCL1 overexpression (Shastri et al, JCI 2018). MCL1 emergence is closely tied to therapy resistance to the BCL2 inhibitor venetoclax. Aims : The current study (1R01FD007836-01, NCT05986240) is a phase I dose escalation protocol that includes 2 sub-studies to evaluate the safety profile and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of : 1) danvatirsen as monotherapy, 2) danvatirsen in combination with venetoclax, once the safety and RP2D of danvatirsen monotherapy is established; for the treatment of relapsed /refractory Int/high/very-high-risk IPSS-R myelodysplastic syndromes or relapsed/refractory AML. The secondary objective of the study is to determine the overall response rate defined as CR + CRi + PR based on the revised IWG response criteria for AML (Cheson B et al, JCO 2003). For MDS, the overall response rate (ORR) is defined as CR +CRh + HR the based on the IWG revised criteria for hematologic response in MDS ( Platzbecker U et al, Blood 2019). To evaluate the on-target activity of danvatirsen in hematopoietic stem & progenitor cells (HSPC's), to correlate responses observed to a STAT3 gene expression signature, 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, and number bridged to SCT. Methods : In each of the sub-studies, we have employed the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; Yuan et al., 2016), with the 3+3 design run-in, to find the MTD. Sub-study 1 employs a dose escalation through 3 dose levels ranging from 1 mg/kg to 3 mg/kg. Cycle 1 consists of 1 week of a loading dose on days 1, 3 and 5 followed by a weekly infusion for 3 weeks. Thereafter, each cycle consists of weekly treatment for 4 weeks. There are no premedications required prior to treatment. In sub-study 2, up to 2 dose levels of danvatirsen will be evaluated, while dose for venetoclax is fixed at 400 mg daily equivalent (with azole based dose adjustments per venetoclax label) except where dose modifications are indicated in the protocol. The two doses of danvatirsen used will be determined based on aggregate review of safety/efficacy/PK/PD data from the single-agent experience. Dose 1 will be one level lower than the dose with expected target activity. A total of 9-12 DLT evaluable patients will be enrolled into sub-study 1 and sub-study 2 respectively. Conclusion: Recruitment is currently ongoing at the Montefiore Einstein Comprehensive Cancer Center, Bronx, NY and the M.D Anderson Cancer Center, Houston, TX. As of 1 August 2024, 3 patients have been enrolled onto the study into sub study 1, dose level 1 of 1 mg/kg of danvatirsen. At this time sub study 1 cohort is still enrolling. Samples for biomarker analysis are collected and being analyzed. Updated data will be reported at the ASH Annual Meeting.