Pevonedistat With Azacitidine Versus Azacitidine Alone in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT03745352 | Withdrawn Phase 2 DMC FDA Drug

• 4 other identifiers: NCI-2018-02651PHII-16910247UM1CA186717
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase II trial studies how well pevonedistat works with azacitidine compared to azacitidine alone in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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. It is not yet known if pevonedistat with azacitidine or azacitidine alone may work better in treating patients with acute myeloid leukemia.

Conditions

Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Overall survival

  Analysis will be done using Cox regression, and Kaplan-Meier plots will also be provided.

  From randomization to death from any cause (or censor date), assessed up to 2 years

Secondary Outcomes (2)

• Overall response rate (ORR)

  Up to 2 years

• Duration of response (DOR) (CR/CRi response)

  Time from first documented CR/CRi response to relapse

Other Outcomes (6)

• Rate of early mortality

  At 90 days after starting treatment

• Rate of allogeneic hematopoietic cell transplantation (HCT)

  Up to 2 years

• Time to response

  From randomization to first documented CR/CRi response, assessed up to 2 years

Study Arms (2)

Arm A (pevonedistat, azacitidine)

EXPERIMENTAL

Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5 and azacitidine IV over 10-40 minutes or subcutaneously (SC) on either days 1-7, or days 1-5 and 8-9, or days 1-6 and 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine; Drug: Pevonedistat

Arm B (azacitidine)

ACTIVE COMPARATOR

Patients receive azacitidine IV or SC as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine

Interventions

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

Arm A (pevonedistat, azacitidine); Arm B (azacitidine)

Pevonedistat DRUG

Given IV

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

Arm A (pevonedistat, azacitidine)

Eligibility Criteria

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

You may qualify if:

• Patients must have an established and confirmed diagnosis of AML by World Health Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL).
• Patients must have relapsed or refractory AML, defined as:
• Relapsed: \>= 5% bone marrow blasts by morphology, reappearance of minimal residual disease (MRD) (\> 0.1%) by flow cytometry, reappearance of peripheral blood blasts, or development of extramedullary leukemia after one or more prior lines of therapy. Consolidation regimens, including autologous and allogeneic HCT, do not count as a separate prior line of therapy, (e.g., 7+3 followed by cytarabine consolidation followed by allogeneic hematopoietic cell transplantation (HCT) would be considered one prior line of therapy). Note, there is no restriction on the prior number of relapses and prior treatment of relapsed disease is allowed.
• Refractory: no complete response (CR) or complete response with incomplete bone marrow recovery (CRi) after two courses of induction therapy (e.g. therapy with the intent to induce remission). Patients 75 years or older, or patients of any age with comorbidities that prevent the use of further intensive chemotherapy, will be eligible if they did not experience CR or CRi after one course of induction therapy.
• Patients must have Karnofsky \>= 60%.
• Patients must have a white blood cell count (WBC) =\< 25 x 10\^9 cells/L. Hydroxyurea and leukapheresis are permitted to satisfy this criterion.
• Total bilirubin =\< institutional upper limit of normal (ULN) except in patients with Gilbert's syndrome or post-transfusion hemolysis. Patients with Gilbert's syndrome or post-transfusion hemolysis may enroll if direct bilirubin =\< 1.5 x ULN of the direct bilirubin.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN (unless resulting from liver infiltration with leukemia).
• Creatinine clearance \>= 30 mL/min (If serum creatinine not =\< institutional ULN).
• Hemoglobin \> 8 g/dL. Patients may be transfused to achieve this value.
• Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial if they are on effective antiretroviral regimens utilizing non-CYP-interacting agents, they have an undetectable viral load, they have a CD4 count \> 350 cells/mm\^3, and they have no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections. If there is evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated. If there is history of hepatitis C virus (HCV) infection, the patient must have been treated and have undetectable HCV viral load.
• Patients must be willing to submit blood samples for the integrated biomarker.
• Female patients of childbearing potential (i.e. who are not postmenopausal for at least 1 year before screening or are not surgically sterile) must have a negative serum pregnancy test within 72 hours prior to the first study drug administration and must agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. Male patients, even if surgically sterilized, must agree to practice effective barrier contraception during the entire study treatment period through 4 months after the last dose of study drug, or agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
• Patients may have had prior allogeneic HCT at least 3 months prior to randomization but should not have evidence of active graft versus host disease or require systemic immune suppression.
• Patients must be able to understand and be willing to sign a written informed consent document.

You may not qualify if:

• Patients must not have had prior treatment with MLN4924 (pevonedistat), azacitidine, or decitabine.
• Patients for whom, in the opinion of the treating physician, azacitidine alone is not an appropriate treatment will be excluded.
• Patients must not have documented active central nervous system (CNS) involvement by leukemia. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Patients must not have received any other investigational or commercial agents or therapies administered with the intention to treat their leukemia within 14 days or five half-lives (whichever is shorter) of first receipt of study drug, with the exception of hydroxyurea used to control WBCs.
• All non-hematologic adverse events (AEs) of prior chemotherapy, surgery, or radiotherapy, except alopecia, must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade =\< 2 prior to starting therapy.
• Patients must not have a history of other malignancies, except:
• Any malignancy that was treated with curative intent, has no known active disease present for \>= 1 year before the first dose of study drug, and is felt to be at low risk of recurrence by the treating physician;
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
• Adequately treated carcinoma in situ without evidence of disease;
• Low-risk prostate cancer after curative surgery.
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat), azacitidine, or mannitol.
• Clinically significant metabolic enzyme inducers are not permitted during this study, or within 14 days before the first dose of study drugs. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients must not have severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator, could affect their participation in the study.
• Pregnant women are ineligible because, as an Nedd8 activating enzyme (NAE) inhibitor, MLN4924 (pevonedistat) has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with MLN4924 (pevonedistat), breastfeeding must be discontinued if the mother is treated with MLN4924 (pevonedistat). These potential risks may also apply to azacitidine.
• Patients must not have had major surgery within 14 days before the first dose of any study drug or be scheduled for surgery during the study period.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine; pevonedistat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

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

• Brian A Jonas

  City of Hope Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2018
• First Posted: November 19, 2018
• Study Start: May 20, 2019
• Primary Completion: August 19, 2021
• Study Completion: August 19, 2021
• Last Updated: June 27, 2023

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share