Application of a Phenotype-Based Predictive Analytic in a Phase Ib Study of Selinexor and Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia
Authors: Ball Somedeb , Byrne Michael T. , Fischer Melissa A , Awan Farrukh T. , Tomlinson Ben K. , Stopczynski Tess , Patil Lokesh , Gu Christine J. , Leonardi Chris , Walsh Katherine J. , Ayers Gregory Dan , Kishtagari Ashwin , Fedorov Kateryna , Lacher Markus D. , Wagner Joseph , Mohan Sanjay R , Savona Michael R. 
Published: December 2024

Introduction
Selective inhibitor of nuclear export (SINE) compounds block XPO1/elF4E-mediated nuclear-cytoplasmic transport, and lead to nuclear retention and activation of tumor suppressor proteins (e.g., p53) and impaired translation of oncogenic proteins (e.g., c-MYC, MCL1). Our preclinical studies showed synergistic antileukemia activity with selinexor (SEL) and venetoclax (VEN) combination, with the potential to overcome VEN resistance by reducing MCL1(Fischer MA, Blood Advances, 2020). A phase Ib study (NCT03955783) evaluated SEL-VEN in relapsed or refractory (r/r) high-risk hematologic malignancies. Notable Labs has developed an automated predictive analytic (PA) for high throughput assessment of drug sensitivity on bone marrow (BM) or blood samples. Here we report clinical trial data from patients (pts) with acute myeloid leukemia (AML) and retrospective application of the PA on pt samples.
Methods
In this investigator-sponsored, open-label phase Ib study, adult pts with r/r AML with adequate performance status and organ function were enrolled. Primary objectives were to determine safety, recommended phase II dose, and preliminary response rate of SEL-VEN. After the dose escalation phase, SEL 80 mg po weekly plus VEN (ramp-up followed by 400 mg/d continuous) was deemed the recommended dose for expansion phase. Treatment-emergent adverse events (TEAE) were graded with CTCAE v5.0, and responses in the AML cohort were assessed with IWG 2003 and ELN 2022 criteria. Pretreatment pt samples were treated ex vivo with drugs of interest, followed by multiparameter flow cytometry-based blast enumeration.
Results
From September 2019 to December 2022, 19 pts with r/r AML were enrolled. Median age at enrollment was 67.2 (range, 21.1-83.8) years; 18/19 pts were white and 53% were male. Overall, 62% of pts had received ³3 prior lines of therapies. Eight (42%) pts each had prior allogeneic stem cell transplant (allo-SCT) and prior VEN exposure. Baseline next generation sequencing (n=11) revealed mutations in NPM1 (n=3; 23%), IDH2 (n=3; 23%), NRAS (n=2; 15%), TP53 (n=2; 15%), and FLT3-ITD (n=1; 8%).
Pts received a median of 3 (range, 1-8) cycles of study treatment, with a median duration of 1.9 (range, 0.3-8.1) months. Seven (37%) pts were in SEL 60 mg/week and the rest in 80 mg/week cohorts. The primary reason for study treatment discontinuation was disease progression (n=9; 47%).
Most common grade 3-5 TEAEs were anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Non-hematologic AEs of any grade (³ 20%) included vomiting (50%), nausea (44%), anorexia (44%), diarrhea (39%), fatigue (33%), dyspnea (33%), limb edema (28%), hyponatremia (22%) and dysgeusia (22%), with the majority being grade 1-2 AEs.
Overall response rate with SEL-VEN was 21%. Two (11%) pts, one with prior allo-SCT and one with prior VEN and both treated with SEL 80 mg/week, experienced complete remissions (CR), with duration of response of 7 and 9.1 months, respectively. One (5%) pt experienced morphologic leukemia free state, and one other had medullary response (BM blast &lt;5%) but extramedullary disease persisted. After a median follow up of 3.02 (range, 0.62-15.4) months, median event free survival was 2.4 (95% CI: 1.9-12.1) months and median overall survival was 6.4 (95% CI: 2.5-12.1) months.
Using commercially available, fresh remnant AML samples (n=12), ex vivo blast reductions with SEL and eltanexor (ELTA) showed SINE activity on our PA platform. From one clinical responder and one non-responder on the SEL-VEN trial, dose-response curves could be derived from cryopreserved samples, with SEL EC50 values of 8.79 nM and 17.08 nM, respectively, indicating a correlation between PA results and clinical response. Similarly, ex vivo treatment with SEL-VEN yielded lower blast levels in the sample from the responder than the one from non-responder. Further analysis is ongoing to explore potential phenotypic predictors of response to SEL-VEN.
Conclusions
SEL-VEN was feasible in a heavily pretreated AML cohort, with no new toxicity signal. Two pts experienced durable CR, confirming activity of SEL-VEN. Second-generation SINE compound ELTA with VEN could further improve outcomes in an ongoing study (NCT06399640) and provide a more tolerable SINE regimen to overcome VEN resistant AML. Analysis is ongoing to establish a flow-based PA for selection of participants in future AML clinical trials.