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Clinical Trial 20883

Cancer Type: Malignant Hematology
Study Type: Treatment
NCT#: NCT03772925

Phase: Phase I
Principal Investigator: Lancet, Jeffrey

Call 813-745-6100
or 1-800-679-0775 Learn More

Overview

Study Title

A Phase 1 Study of MLN4924 (pevonedistat) and Belinostat in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Summary

his phase I trial studies side effects and best dose of pevonedistat and belinostat in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as pevonedistat and belinostat, 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.

Objective

To identify the MTD/RP2D for a regimen combining MLN4924 (pevonedistat) with belinostat in patients with refractory/relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Treatments

Therapies

Chemotherapy (NOS)

Medications

Belinostat (); MLN4924 (Pevonedistat); PXD101 (Belinostat)

Inclusion Criteria

Patients must have one of the following, histologically or cytologically confirmed:

AML (non- acute promyelocytic leukemia [APL] AML)

AML that is relapsed or refractory to at least one prior line of therapy

MDS, must meet all of the following at the time of enrollment:

Higher risk MDS (intermediate-2 or high risk by the original International Prognostic Scoring System [IPSS]), and Relapsed, refractory, or intolerant to at least one prior line of therapy containing a hypomethylating agent (deoxyribonucleic acid [DNA] methyltransferase inhibitor)

Eastern Cooperative Oncology Group (ECOG) performance status == 60%)

Total bilirubin => Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) == 60 mL/min/1.73 m^2 appropriate to race for patients with creatinine levels above institutional normal

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

Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents

No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections

If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated

If history of hepatitis C virus (HCV) infection, patients must be treated and have an undetectable HCV viral load

The effects of belinostat and/or MLN4924 (pevonedistat) on the developing human fetus are unknown. For this reason and because histone deacetylase inhibitors and NEDD8-activating enzyme (NAE) inhibitory agents are known to be teratogenic, women of child-bearing potential and men must use 1 highly effective method and 1 additional (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). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN4924 (pevonedistat) and belinostat administration

Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria

Clinical picture indicative of leukostasis or evidence of disseminated intravascular coagulopathy

Patients with uncontrolled coagulopathy or bleeding disorder

Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea

Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Ongoing toxicities >= grade 2 from prior therapy, except those related to hydroxyurea (which is permitted through the first 5 days of study treatment)

APL (M3)

Active central nervous system (CNS) leukemia

History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat) or belinostat

Stem cell transplant within previous 3 months prior to initiation of study therapy

Major surgical procedures => Uncontrolled intercurrent illness or infection

Circulating blast count > 50,000 mm^3 within 7 days preceding enrollment

Current candidacy for a potentially curative allogeneic stem cell transplant, unless declined

Left ventricular ejection fraction (LVEF) > Prolongation of the heart-rate corrected QT (QTc) interval >= 450 ms (i.e., grade 1 or higher) on electrocardiogram (ECG) prior to initiation of study treatment.

Known cardiopulmonary disease defined per protocol

Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug

Treatment with BCRP inhibitors (e.g., cyclosporine, eltrombopag [Promactal]) within 2 days before first dose of study drug

Ongoing or planned treatment with strong inhibitors of UGT1A1

Any known UGT1A polymorphism, heterozygous or homozygous

History of prior therapy with belinostat or MLN4924 (pevonedistat)

Active gastrointestinal (GI) conditions that might predispose to drug intolerance or poor drug absorption

Known hepatic cirrhosis

Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis

No other prior malignancy is allowed except for the following:

In situ cervical cancer,

Adequately treated basal cell or squamous cell skin cancer,

Adequately treated stage I or II cancer from which the patient is currently in complete remission, and

Any other cancer from which the patient has been disease-free for 1 year

Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk, interfere with the patient's participation in the study, or hinder evaluation of study results

Pregnant or nursing. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study therapy.

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