A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy
Authors: Short Nicholas J. , Sedarati Farhad , Zhao Dan , Tsukurov Olga , Friedlander Sharon , Faller Douglas V. 
Published: November 2020

Background
Pevonedistat is the first small-molecule inhibitor of neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE). Inhibiting NAE blocks ubiquitination of select proteins upstream of the proteasome. Treatment with pevonedistat disrupts cell cycle progression and cell survival, leading to cell death in cancers, including myeloid malignancies. In a phase 1b study in patients aged ≥60 yrs with untreated AML, pevonedistat in combination with azacitidine (AZA) was tolerable and showed clinical activity (Swords et al. Blood 2018). In a randomized phase 2 study of pevonedistat + AZA vs AZA alone in patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia and low-blast AML, pevonedistat + AZA improved event-free survival (EFS) and overall survival (OS), had a similar safety profile to AZA alone, did not increase myelosuppression, and maintained AZA dose intensity (Adès et al. ASCO 2020). Venetoclax (VEN) is a small-molecule inhibitor of B-cell lymphoma 2 that is approved in the United States in combination with low-dose cytarabine or hypomethylating agents for the treatment of patients with AML. VEN + AZA has been shown to improve OS vs AZA alone, and the combination is emerging as a standard of care for older patients with newly diagnosed AML who are unfit for standard intensive chemotherapy. Despite recent advances, outcomes for these patients remain poor; novel therapies that increase duration of response (DOR) or reduce relapse rates are needed. Pevonedistat in combination with VEN has shown synergistic cytotoxic effects in AML cell lines and primary clinical AML samples (Knorr et al. Cell Death Differ 2015). This is likely mediated through pevonedistat-induced neutralization of prosurvival proteins including myeloid leukemia cell differentiation protein (MCL-1). Upregulation of MCL-1 is thought to be a primary mode of resistance to VEN. Therefore, treatment with pevonedistat + VEN may help to prevent or overcome resistance to VEN and prolong DOR. The reported clinical benefit of both pevonedistat + AZA and VEN + AZA in AML, and preclinical evidence of synergy between pevonedistat and VEN, suggest that combination treatment with all 3 therapies may result in improved outcomes compared with VEN + AZA in patients with newly diagnosed AML who are unfit for intensive chemotherapy. A phase 1/2 study of the triplet combination of pevonedistat, VEN, and AZA in secondary AML established the recommended phase 2 dose and demonstrated a high response rate in this relatively refractory population (Short et al. EHA 2020).
Methods
NCT04266795 is a randomized, open-label, controlled, phase 2 study (Figure) that is being conducted across ~85 sites globally. Eligible patients are those aged ≥18 yrs with morphologically confirmed newly diagnosed AML (World Health Organization criteria 2008) and considered unfit for treatment with cytarabine and anthracycline induction due to age and/or comorbidities. Patients are being randomized 1:1 to receive the combination of pevonedistat 20 mg/m2 intravenously (IV) on days 1, 3, and 5, VEN 400 mg by mouth on days 1-28 in cycle 1 (ramp up schedule of 100 mg on day 1, 200 mg on day 2, 400 mg on days 3-28) and then on days 1-28 (days 1-21 if remission is confirmed; can return to 28-day dosing if well tolerated) in cycle 2 onwards, and AZA 75 mg/m2 (IV or subcutaneously) on days 1-7 or 1-5, 8, and 9, or VEN + AZA, in 28-day cycles until unacceptable toxicity, relapse, or progressive disease. Randomization is stratified by age (18-&lt;75 yrs vs ≥75 yrs) and AML subtype (de novo vs secondary). The primary endpoint is EFS (time from randomization to relapse from complete remission [CR] or CR with incomplete blood count recovery [CRi], treatment failure, or death from any cause, whichever occurs first). Secondary endpoints include: OS; OS at 6 months, 1 yr, and 2 yrs; 30- and 60-day mortality; CR rate; EFS after cycle 6; DOR; time to first response; time to relapse from CR/CRi or death; health-related quality of life; pharmacokinetics; rate of red blood cell and platelet transfusion independence; and rate of hospitalization. Molecular characterization of bone marrow aspirates will be performed for measurable residual disease and mechanism of action studies. Elimination of leukemic stem cells and predictive biomarkers of response will be assessed. The study is planned to enroll ~150 patients; recruitment is ongoing.
Figure

Disclosures
Short: Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Sedarati:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Zhao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Tsukurov:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Friedlander:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Faller:Phoenicia Biosciences: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Briacell Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracta Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment.

OffLabel Disclosure:
Pevonedistat is the first small molecule inhibitor of the neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE)