Clinical Trials /

Pevonedistat and Belinostat in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT03772925

Description:

This 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 or does not respond to treatment. 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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pevonedistat and Belinostat in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
  • Official Title: A Phase 1 Study of MLN4924 (Pevonedistat) and Belinostat in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-03227
  • SECONDARY ID: NCI-2018-03227
  • SECONDARY ID: 10246
  • SECONDARY ID: 10246
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT03772925

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
BelinostatBeleodaq, PXD 101, PXD101Treatment (belinostat, pevonedistat)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Treatment (belinostat, pevonedistat)

Purpose

This 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 or does not respond to treatment. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for a regimen
      combining MLN4924 (pevonedistat) with belinostat in patients with refractory/relapsed acute
      myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

      SECONDARY OBJECTIVES:

      I. To describe the toxicities of this regimen. II. To observe and record anti-tumor activity.
      III. If responses are observed, to determine what relationship, if any, exists between such
      responses and TP53/FLT3 mutational status.

      IV. To describe pharmacokinetic (PK) interactions, if any, between MLN4924 (pevonedistat) and
      belinostat.

      V. To test the feasibility of performing correlative studies involving nuclear RelA, p-ATR,
      p-Chk1, Cdt-1, gammaH2A.X, p-BRCA1, p-FANCD2, Ac-H3K56, Ac-H4K16, BCL-2, BIM, BCL-xL, or
      MC-1.

      OUTLINE: This is a dose-escalation study.

      Patients receive belinostat intravenously (IV) once daily (QD) over 30 minutes on days 1-5
      and pevonedistat IV QD over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days and then every 2
      months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (belinostat, pevonedistat)ExperimentalPatients receive belinostat IV QD over 30 minutes on days 1-5 and pevonedistat IV QD over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Belinostat
  • Pevonedistat

Eligibility Criteria

        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 =< 2 (Karnofsky >= 60%)

          -  Hemoglobin > 8 g/dL. Patients may be transfused to achieve level

          -  Total bilirubin =< upper limit of normal (ULN) for the laboratory except in patients
             with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct
             bilirubin =< 1.5 x ULN for the laboratory of the direct bilirubin

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Creatinine clearance within normal limits for the laboratory OR estimated glomerular
             filtration rate (GFR) >= 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

        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 =< 28 days before beginning study treatment or minor
             surgical procedures =< 7 days before beginning study treatment. No waiting required
             after placement of a vascular access device

          -  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) < 50% as assessed by echocardiogram or
             radionuclide angiography

          -  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.

               -  If baseline QTc on screening ECG is >= 450 ms (i.e., grade 1 or higher):

                    -  Check potassium and magnesium serum levels, and

                    -  Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to
                       confirm QTc interval

               -  For patients with baseline heart rate < 60 beats per minute (bpm) or > 100 bpm,
                  manual measurement of QT interval by cardiologist is required, with Fridericia
                  correction applied to that manual measurement to determine the QTc for
                  eligibility consideration

                    -  Note: For patients with a heart rate of 60-100 bpm, manual measurement of QT
                       interval and use of the Fridericia formula to determine QTc is NOT required

          -  Known cardiopulmonary disease defined as:

               -  Unstable angina

               -  Congestive heart failure (New York Heart Association [NYHA] class III or IV)

               -  Myocardial infarction (MI) within 6 months prior to first dose (patients who had
                  ischemic heart disease such as acute chest syndrome [ACS], MI, and/or
                  revascularization greater than 6 months before screening and who are without
                  cardiac symptoms may enroll)

               -  Cardiomyopathy

               -  Symptomatic pulmonary hypertension

               -  Clinically significant arrhythmia defined as any of the following:

                    -  History of polymorphic ventricular fibrillation or torsade de pointes

                    -  Permanent atrial fibrillation (a fib), defined as continuous a fib for >= 6
                       months

                    -  Persistent a fib, defined as sustaining a fib lasting > 7 days and/or
                       requiring cardioversion in the 4 weeks before screening

                    -  Grade 3 a fib defined as symptomatic and incompletely controlled medically,
                       or controlled with device (e.g., pace maker), or ablation

                    -  Patients with paroxysmal a fib or < grade 3 a fib for a period of at least 6
                       months are permitted to enroll provided that their rate is controlled on a
                       stable regimen

                    -  Known congenital long QT syndrome

                    -  Second degree atrioventricular (AV) block type II or third degree AV block

                    -  Ventricular rate < 50 bpm or > 120 bpm

          -  Treatment with clinically significant metabolic enzyme inducers within 14 days before
             the first dose of the study drug. Because the lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated medical reference.
             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 should discontinue breast cancer resistance protein (BCRP) inhibitors (e.g.,
             cyclosporine) at least 2 days before starting treatment

          -  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.

               -  Note: Pregnant women are excluded from this study because MLN4924 (pevonedistat)
                  is a NEDD8 inhibitor with the potential for teratogenic or abortifacient effects
                  and because belinostat may cause teratogenicity and/or embryo-fetal lethality by
                  virtue of targeting actively dividing cells. Because there is an unknown but
                  potential risk for adverse events (AEs) in nursing infants secondary to treatment
                  of the mother with MLN4924 (pevonedistat) or belinostat, breastfeeding should be
                  discontinued if the mother is treated with MLN4924 (pevonedistat)/belinostat
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) for the combination of MLN4924 (pevonedistat) and belinostat
Time Frame:Up to the end of cycle 1
Safety Issue:
Description:Patients' treatment dosing level, dose modification, dose-limiting toxicities (DLTs), and evaluability for DLTs will be listed and summarized by basic descriptive statistics (such as frequency and proportion). RP2D is defined as =< 1 out of 6 at highest dose level below the maximally administered dose.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs)
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. AEs and serious adverse events (SAEs), dosing levels, treatment received, best clinical response, and demographics will be listed. Basic descriptive statistics will be used to summarize toxicities related to the study drugs by grade, and all toxicities, whether related or unrelated to the study drugs.
Measure:Treatment response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Classified according to International Working Group (IWG) and European Leukemia Net (ELN) criteria for response assessment in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For the response rate calculations, all study reports will contain at least a section with all enrolled patients. Other sections of the reports may detail the response rate for evaluable patients only. All response rate analyses based on a subset of patients will be accompanied by explanations of which patients were excluded and the reasons; 95% confidence limits will be given.
Measure:Duration of response
Time Frame:From documentation of tumor response to disease progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:If there are at least 3 responses, duration of response will be summarized by the first, second, and third quantiles and illustrated by a Kaplan-Meier plot.
Measure:Time to response
Time Frame:From registration to the time of documentation of tumor response, assessed up to 2 years
Safety Issue:
Description:If there are at least 3 responses, time to response will be summarized by the first, second, and third quantiles and illustrated by a Kaplan-Meier plot.
Measure:TP53 and FLT3 mutational status
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed by next generation sequencing (NGS) and compared to best clinical response classified according to IWG and ELN criteria for response assessment in AML and MDS. A Chi-square test and a Fisher exact test will be used to determine whether there is a significant association between clinical responses and TP53/FLT3 mutational status. An ordinal regression (where best clinical responses are considered as an ordinal outcome variable) and a logistic regression (where best responses are dichotomized as yes or no responses) will be used to test the association between responses and TP53/FLT3 mutational status, with adjustment of potential factors (e.g., dose level, age, sex, etc.).
Measure:Change in MLN4924 (pevonedistat) and belinostat plasma concentrations
Time Frame:Baseline up to cycle 1 day 1
Safety Issue:
Description:Pharmacokinetic parameters in MLN4924 (pevonedistat) and in belinostat will be calculated using standard non-compartmental methods and summarized as geometric mean and geometric coefficient of variation.
Measure:Change in candidate biomarker levels in bone marrow and/or blood samples
Time Frame:Baseline up to 24 hours post-treatment with the first doses of study drugs
Safety Issue:
Description:Various paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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