Pevonedistat and Decitabine in Treating Patients With High Risk Acute Myeloid Leukemia

NCT03009240 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: 16270NCI-2016-02044P30CA033572
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of pevonedistat when given together with decitabine in treating patients with high risk acute myeloid leukemia. Pevonedistat and decitabine may stop the growth of cancer cells by blocking some of the enzymes need for cell growth.

Conditions

Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse effect assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

  Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

  Up to 2 years

• Dose limiting toxicities (DLT) defined as any toxicities that are at least possibly related to pevonedistat that occur during cycle 1 assessed by NCI CTCAE version 4.03

  Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

  Up to 28 days

• Maximum tolerated dose (MTD) based on assessment of DLT

  Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

  Up to 28 days

Secondary Outcomes (5)

• Complete remission (CR) rate assessed by International Working Group criteria

  Up to 2 years

• Overall response rate (ORR) (CR + incomplete CR [CRi]) assessed by International Working Group criteria

  Up to 2 years

• Overall survival (OS)

  Time from start of study therapy until death, or last contact, whichever comes first, assessed up to 2 years

• Event-free survival (EFS)

  Time from start of study therapy until death, relapse/progression, receipt of anti-leukemia therapy, or last contact, whichever comes first, assessed up to 2 years

• Duration of response

  Time interval from the date of first documented response (CR or CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years

Other Outcomes (7)

• miR-155 expression

  Up to 2 years

• miR-155 target gene (SHIP1 and PU.1) expression

  Up to 2 years

• NF-kappaB enrichment on miR-155 promoter

  Up to 2 years

Study Arms (1)

Treatment (pevonedistat, decitabine)

EXPERIMENTAL

Patients receive pevonedistat IV over 1 hour on days 1, 3, and 5 and decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unexpected toxicity.

Drug: Decitabine; Other: Laboratory Biomarker Analysis; Drug: Pevonedistat; Other: Pharmacological Study

Interventions

Decitabine DRUG

Given IV

Also known as: 5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine

Treatment (pevonedistat, decitabine)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (pevonedistat, decitabine)

Pevonedistat DRUG

Given IV

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

Treatment (pevonedistat, decitabine)

Pharmacological Study OTHER

Correlative studies

Treatment (pevonedistat, decitabine)

Eligibility Criteria

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

You may qualify if:

• Patients diagnosed with acute myeloid leukemia (AML) by World Health Organization (WHO) classification, meeting one of following criteria:
• Age 60 or older, newly diagnosed, untreated, who are unwilling to undergo or not candidates for conventional induction chemotherapy with cytarabine/anthracyclines
• Age 60 or older with relapsed or refractory disease
• Younger adult patients with previously untreated high-risk disease (complex karyotype, inv\[3\] or t\[3;3\], t\[6;9\], monosomal karyotype, therapy-related and secondary disease) that are unwilling to undergo or not candidates for conventional induction chemotherapy with cytarabine/anthracyclines and/or allogeneic stem cell transplantation
• Younger patients with refractory/relapsed AML who are otherwise not candidates for allogeneic stem cell transplantation
• Patients with extramedullary disease who meet one of the above criteria may be included
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• Patients with co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
• The effects of pevonedistat and decitabine on the developing fetus is unknown; for this reason, women of child bearing potential and men must agree to use effective contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for 4 months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
• Female patients must be:
• Postmenopausal for at least 1 year before the screening visit, OR
• Surgically sterile, OR
• If they are of childbearing potential
• Agree to practice 1 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 (female and male condoms should not be used together), OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)

You may not qualify if:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pevonedistat or decitabine
• Patients have received prior chemotherapy or radiation for AML \< two weeks before study enrollment, or those who have not recovered from the adverse events due to agents administered
• Females who are both lactating and breastfeeding or who have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of study drug
• Patients with additional (other than AML) active malignancies, other than curatively treated carcinoma in situ (CIS) of the cervix, or basal or squamous cell carcinoma of the skin; patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy and disease free from prior malignancies for \> 2 years
• Life-threatening illness unrelated to cancer
• Known cardiopulmonary disease defined as one of the following:
• Unstable angina
• Uncontrolled high blood pressure (ie, systolic blood pressure \> 180 mm Hg, diastolic blood pressure \> 95 mm Hg)
• Cardiomyopathy or history of ischemic heart disease
• Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de pointes); permanent atrial fibrillation (a fib) defined as a fib \>= 6 months; persistent a fib defined as sustained a fib lasting \> 7 days and/or requiring cardioversion in the 4 weeks before screening; however, patients with \< grade 3 atrial fibrillation (a fib) for a period of at least 6 months may enroll; grade 3 a fib is symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation; patients with paroxysmal a fib are permitted to enroll
• Implantable cardioverter defibrillator
• Congestive heart failure (New York Heart Association \[NYHA\] class III or IV; or class II with a recent decompensation requiring hospitalization or referral to a heart failure clinic within 4 weeks before screening),
• Myocardial infarction and/or revascularization (eg, coronary artery bypass graft, stent) within 6 months of first dose of study drug
• Patients who had ischemic heart disease who have had ACS, MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll
• Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Decitabine; Injections; pevonedistat

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Guido Marcucci

  City of Hope Medical 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: December 30, 2016
• First Posted: January 4, 2017
• Study Start: August 21, 2017
• Primary Completion: March 19, 2026
• Study Completion: March 19, 2026
• Last Updated: April 22, 2026

Record last verified: 2026-04

Locations

US (1)