Phase 1b/2 Study of Escalating Doses of the NEDD8 Activating Enzyme Inhibitor Pevonedistat Administered in Combination with Standard Induction Therapy (Cytarabine and Idarubicin) in Newly Diagnosed High Risk Acute Myeloid Leukemia

Introduction: Pevonedistat is a potent and selective small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated clinical activity in acute myeloid leukemia (AML). Preclinical studies suggest that pevonedistat synergistically enhances the activity of cytarabine in AML. We investigated the safety and efficacy of pevonedistat in combination with 7+3 cytarabine and idarubicin induction chemotherapy in adults with high-risk AML.

Methods: This open-label, multicenter phase 1b/2 study (NCT03330821) enrolled patients aged ≥18 years with newly diagnosed high-risk AML, defined as therapy-related AML, AML with antecedent myelodysplastic syndrome or AML with myelodysplasia-related changes, the presence of adverse genetic features per ELN 2017 guidelines, or being age ≥55. Eligible patients had an ECOG status of 0-2. Patients were administered pevonedistat on days 1, 3, and 5 of each 28-day cycle in combination with cytarabine 100 mg/m ² on days 1-7 and idarubicin 12 mg/m ² on days 1-3. In the phase 1b dose-escalation part of the study, a standard 3+3 design was used to evaluate 2 dose levels of pevonedistat: 15 and 20 mg/m ². Consolidation consisted of up to 4 cycles of cytarabine (1-3 g/m ² q12h) on days 1, 3, and 5 or transplant. For pharmacodynamic (PD) assessment, RT-PCR assays were performed on peripheral blood samples to measure expression levels of 7 NRF-2 target genes (ATF3, GCLM, GSR, NQ01, SLC7A11, SRXN1, and TXNRD1).

The primary objective for the phase 1b study was to determine the RP2D of pevonedistat in combination with cytarabine and idarubicin. The primary objective for the phase 2 study was to determine the composite complete response rate (CRc; CR+CRi). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and safety and tolerability.

Results: A total of 28 patients were enrolled at 5 sites in the US between August 2018 and August 2021. Six patients were enrolled in the phase 1b study and 22 patients in phase 2. Baseline patient characteristics are shown in Table 1. The median age was 61 years (range 47-74). Per the 2017 ELN risk classification, 8 of 28 patients (29%) had favorable risk, 8 (29%) had intermediate risk, and 12 (43%) had adverse risk.

All 28 patients were included for safety and response assessments. In phase 1b, none of the 6 patients experienced dose-limiting toxicity at 15 or 20 mg/m ². Thus, the RP2D of pevonedistat was determined to be 20 mg/m ². The CRc rate was 64% (95% CI 44-81) with 17 patients achieving CR and 1 patient achieving CRi. Of the 18 patients who achieved CR or CRi, 16 (89%) achieved MRD negativity by multiparameter flow cytometry, and 7 (39%) proceeded to HSCT. The CRc rates for patients in the ELN 2017 favorable, intermediate, and adverse risk groups were 100% (95% CI 63-100), 63% (95% CI 29-89), and 42% (95% CI 18-71), respectively.

Eight patients were included in the interim PD analysis. Among patients who achieved CR or CRi (n=6), 4 (ATF3, GSR, SLC7A11, and SRXN1) of the 7 NRF-2 target genes measured were significantly upregulated at 5 hours post-pevonedistat induction compared to baseline. There was no significant increase in NRF-2-regulated gene transcript levels among patients with refractory disease (n=2).

The median follow-up was 31.1 months (range 19.1-55.9). The median RFS was 24.4 months (95% CI 7-54.3+) and median OS was 25 months (95% CI 11.9-55.9+). The estimated 1-year and 2-year RFS were 72% (95% CI 52-93) and 55% (95% CI 23-78), respectively. The estimated 1-year and 2-year OS were 68% (95% CI 51-85) and 53% (95% CI 34-72), respectively.

The most common grade ≥3 treatment-related adverse events were anemia (61%), febrile neutropenia (25%), and hypophosphatemia (18%). No treatment-related deaths were observed.

Conclusion: Pevonedistat in combination with cytarabine and idarubicin was well tolerated among adults with newly diagnosed, high-risk AML and induced deep remissions with promising RFS and OS.