Initial Results of a Phase Ib/II Study Evaluating Navitoclax after Failure of Hypomethylating Agent and Venetoclax for Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome
Authors: Keiffer Gina , Wilde Lindsay , Jeurkar Chetan , Kasner Margaret , Palmisiano Neil D. 
Published: December 2024

We initiated a phase Ib/II dose escalation and expansion study to evaluate the combination of DEC/VEN/NAV in R/R HR-MDS. Pts with R/R HR-MDS after HMA with or without prior VEN and adequate performance status and organ function were eligible. Pts were treated with escalating doses of NAV (25 mg, 50 mg or 100 mg daily for 7-14 days) in combination with standard dose VEN (400 mg daily days 1-14) and DEC (20 mg/m2 days 1-5). During cycle 1, a 2-day dose ramp-up of VEN was initiated prior to NAV and DEC (NCT05564650). The primary objective of the phase Ib portion of the study is to evaluate the safety profile and determine the recommended phase II dose (RP2D) of NAV in the combination. Bayesian optimal interval design was utilized to identify the maximum tolerated dose and RP2D of NAV. Correlative studies to determine the impact of treatment on molecular targets, including profiling of BCL-2 family members and single cell gene expression patterns pre- and post-treatment and at relapse, were planned. Here, we report the initial results from the Phase Ib portion of the study.
RESULTS
Six pts were enrolled between February 2023 and April 2024. 3 pts (50%) were female. 2 pts (33%) identified as Black and the remainder as Caucasian. Median age was 73 yrs (range 37-76) and baseline performance status was 1 (range 1-2, 1 missing). Median IPSS-R at time of enrollment was 5.25 (range 4-6). 2 pts (33%) were red blood cell transfusion-dependent and 3 pts (50%) were platelet transfusion-dependent at baseline. Pts had a median of 1.5 prior lines of treatment (range 1-6). All pts had received prior HMA, 2 pts (33%) had received prior VEN and 2 pts (33%) had received prior allogeneic stem cell transplant.
The first 3 pts were treated with NAV 25 mg daily for 14 days in combination with DEC/VEN. One pt experienced a DLT of prolonged grade 4 thrombocytopenia and the dose was reduced to dose level -1 (NAV 25 mg for 7 days). An additional 3 pts were treated at dose level -1. No pts in dose level -1 experienced a DLT. Serious adverse events deemed possibly, probably or definitely related to the study drug were febrile neutropenia (2), platelet count decreased (1), hematoma (2). After a median of 1 cycle (range 1-2) of treatment, best response by IWG 2006 criteria was marrow complete response (1), partial response (1), stable disease (1). Two pts developed progressive disease and one was not evaluable due to withdrawal of consent. One of the 2 VEN-exposed pts achieved a partial response and the other was not evaluable. The study was subsequently closed to accrual due to withdrawal of sponsor funding.
CONCLUSIONS
The addition of NAV to treatment with HMA and VEN is a logical strategy to treat R/R HR-MDS due to heterogeneous patterns of BCL-2 family protein expression to promote apoptosis and limit resistance to BCL-2 inhibition. We report the initial results of a planned phase Ib/II study employing this strategy, which suggest that at a dose of 25 mg for 7 days, NAV was tolerable and showed early evidence of clinical activity in this refractory population. Two of the 6 pts achieved a response, including 1 pt with prior VEN exposure, suggesting this strategy can be effective in VEN-refractory pts. Further studies are needed to evaluate the impact of broad inhibition of BCL-2 family members in the treatment of MDS.