A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia

Abstract

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, multicenter, open-label study in 16 adults with relapsed/ refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at doses of 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. The median time to best response was 50 (range, 23-77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

Figure 1.

Impact of treatment on protein and mRNA levels. (A) Whole cell lysates harvested before (0 h) or at the indicated times after chemotherapy administration on day 1 or on progression (Prg) were subjected to immunoblotting for the indicated antigens. LMNB1 or GAPDH served as a loading control. Response is indicated above each patient’s number. Dashed lines indicate juxtaposition of different exposures of the same blot (upper panels) or a different loading control (bottom panels). (B) mRNA levels determined by quantitative reverse transcriptase polymerase chain reaction at the indicated time points were compared to mRNA levels in the pretreatment samples. Pt #: patient’s number; NR: no response; NE: not evaluable; CR: complete response; MLFS: morphological leukemia-free state.

Figure 2.

Relative survival of cells with a hematopoietic stem cell-like immunophenotype after 24 hours of exposure to the indicated treatments ex vivo. Bone marrow mononuclear cells isolated prior to treatment from the indicated study patient (various shades of blue) or from normal individuals (red shades) were incubated for 24 hours with the indicated concentrations of pevonedistat (pevo) and/or venetoclax and subjected to multiparameter flow cytometry as described in the Online Supplementary Methods. Results for each patient were normalized to those of the diluent control. NR: no response; NE: not evaluable; CR: complete remission; pevo: pevonedistat.

Figure 3.

Potential predictive markers of response.