Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

NCT03862157 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2018-0724NCI-2018-03465
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial studies the best dose of venetoclax when given together with azacitidine and pevonedistat and to see how well it works in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia.

Conditions

Chronic Eosinophilic Leukemia, Not Otherwise Specified; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Essential Thrombocythemia; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloproliferative Neoplasm; Myeloproliferative Neoplasm, Unclassifiable; Overt Primary Myelofibrosis; Polycythemia Vera; Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase; Prefibrotic/Early Primary Myelofibrosis; Acute Myeloid Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myeloid Neoplasm

Outcome Measures

Primary Outcomes (4)

• Incidence of dose-limiting toxicities (DLTs) (Phase I)

  Up to 28 days from treatment start date

• Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) rate (Phase II acute myeloid leukemia cohort)

  Up to 168 days (6 cycles)

• Complete response rate of the combination regimen (Phase II newly diagnosed myelodysplastic syndrome [MDS]/chronic myelomonocytic leukemia [CMML] cohort)

  Up to 168 days (6 cycles)

• CR + marrow CR (mCR) + partial remission (PR) + hematological improvement (HI) rate of the combination regimen (Phase II MDS/CMML post-hypomethylating agent failure cohort)

  Up to 168 days (6 cycles)

Secondary Outcomes (7)

• Leukemia response rate (CR + CRi + partial response [PR] + morphologic leukemia-free state [MLFS])

  Up to 5 years

• Minimal residual disease negativity rate

  Up to cycle 24, day 28

• Duration of response

  Time from response to relapse, assessed up to 5 years

• Relapse-free survival (RFS)

  Time from response to relapse, death, or last follow-up, assessed up to 5 years

• Event-free survival (EFS)

  Time from initiation of treatment to relapse, death or last follow-up, assessed up to 5 years

Study Arms (1)

Treatment (venetoclax, azacitidine, pevonedistat)

EXPERIMENTAL

Patients receive venetoclax PO QD on days 1-28, azacitidine IV or SC on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine; Drug: Pevonedistat; Drug: Venetoclax

Interventions

Pevonedistat DRUG

Given IV

Also known as: MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

Treatment (venetoclax, azacitidine, pevonedistat)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (venetoclax, azacitidine, pevonedistat)

Azacitidine DRUG

Given IV or SC

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza

Treatment (venetoclax, azacitidine, pevonedistat)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• AML COHORT ONLY: Patients must have a new diagnosis (i.e., no prior therapy for AML) of AML per World Health Organization (WHO) 2016 criteria and any one of the following (i.e. therapy-related AML or AML with myelodysplastic-related changes per WHO):
• A history of MDS
• A history of a myeloproliferative neoplasm (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF, whether primary \[pre-fibrotic or overt\] or post-polycythemia vera \[PV\]/essential \[E\]), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), MPN-unclassifiable (MPN-U) or myeloid neoplasm with a rearrangement of PDGFRA, PDGFRB or FGFR1
• A history of MDS/MPN such as chronic myelomonocytic leukemia (CMML), MDS/MPN-unclassifiable (MDS/MPN-U), MDS/MPN with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T) or atypical chronic myeloid leukemia (aCML), BCR-ABL negative
• An MDS-related cytogenetic abnormality other than del9q
• The presence of dysplasia in \>= 50% cells in \>= 2 myeloid lineages, unless accompanied by mutant NPM1 or biallelic CEBPA mutations
• Exposure to prior chemotherapy or radiation therapy for another malignancy
• NEWLY DIAGNOSED MDS/CMML COHORT ONLY: Diagnosis of MDS or CMML with intermediate-2 or high-risk disease by the International Prognostic Scoring System (IPSS)
• MDS/CMML POST-HMA FAILURE COHORT ONLY: Diagnosis of MDS or CMML with intermediate-1, intermediate-2, or high-risk disease by the IPSS who have no responded, progressed, or relapsed after treatment with at least 4 cycles of azacitidine and/or decitabine
• Eastern Cooperative Oncology Group (ECOG) performance status from 0-2
• Total bilirubin =\< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome or if elevation is attributed to underlying leukemia. Patients with Gilbert's syndrome or with elevated bilirubin attributed to underlying leukemia may enroll if direct bilirubin =\< 1.5 x ULN of the direct bilirubin (repeat if more than 3 days before the first dose)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (repeat if more than 3 days before the first dose)
• Creatinine clearance \>= 30 mL/min (repeat if more than 3 days before the first dose)
• White blood cell (WBC) count \< 50,000/uL. Note: Hydroxyurea may be used to control leukocytosis for the first 28 days of study treatment (i.e., cycle 1). Use of hydroxyurea beyond this point may be permitted as clinically indicated, on a case-by-case basis and after discussion with the principal investigator (PI). (repeat if more than 3 days before the first dose)
• Female patients who:

You may not qualify if:

• Treatment with any investigational anti-neoplastic drugs within 2 weeks before the first dose of any study drug (cycle 1 day 1 \[C1D1\])
• AML COHORT ONLY: Patients who are suitable for and agreeable to receive intensive induction chemotherapy
• NEWLY DIAGNOSED MDS/CMML COHORT ONLY: Prior treatment with hypomethylating agents
• MDS/CMML POST-HMA FAILURE COHORT ONLY: Prior treatment with venetoclax or pevonedistat
• Patients whose only site of disease is extramedullary
• Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures
• Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia
• Major surgery within 14 days before the first dose of any study drug
• Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI
• Life-threatening illness unrelated to cancer, leading to expected life expectancy (unrelated to leukemia) \< 1 year
• Patients with severe, uncontrolled coagulopathy or bleeding disorder not related to leukemia
• Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:
• CD4 count \> 350 cells/mm\^3
• Undetectable viral load

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Short NJ, Muftuoglu M, Ong F, Nasr L, Macaron W, Montalban-Bravo G, Alvarado Y, Basyal M, Daver N, Dinardo CD, Borthakur G, Jain N, Ohanian M, Jabbour E, Issa GC, Qiao W, Huang X, Kanagal-Shamanna R, Patel KP, Bose P, Ravandi F, Delumpa R, Abramova R, Garcia-Manero G, Andreeff M, Cortes J, Kantarjian H. A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents. J Hematol Oncol. 2023 Jul 8;16(1):73. doi: 10.1186/s13045-023-01476-8.

  PMID: 37422688 DERIVED

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Hypereosinophilic Syndrome; Leukemia, Myelomonocytic, Chronic; Leukemia, Neutrophilic, Chronic; Thrombocythemia, Essential; Myelodysplastic Syndromes; Thrombocytosis; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis

Interventions

Azacitidine; pevonedistat; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Eosinophilia; Leukocyte Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Hemorrhagic Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Nicholas Short

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2019
• First Posted: March 5, 2019
• Study Start: February 27, 2019
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): January 31, 2027
• Last Updated: March 11, 2026

Record last verified: 2026-03

Locations

US (1)