Clinical Trials /

Ixazomib and Pevonedistat in Treating Patients With Multiple Myeloma That Has Come Back or Does Not Respond to Treatment

NCT03770260

Description:

This IB trial studies side effects and best dose of pevonedistat when given together with ixazomib in treating patients with multiple myeloma that has come or does not respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ixazomib and Pevonedistat in Treating Patients With Multiple Myeloma That Has Come Back or Does Not Respond to Treatment
  • Official Title: MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple Myeloma Patients: A Phase 1b Trial

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-03121
  • SECONDARY ID: NCI-2018-03121
  • SECONDARY ID: 10249
  • SECONDARY ID: 10249
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03770260

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Ixazomib CitrateMLN-9708, MLN9708, NinlaroTreatment (ixazomib citrate, pevonedistat)
PevonedistatMLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924Treatment (ixazomib citrate, pevonedistat)

Purpose

This IB trial studies side effects and best dose of pevonedistat when given together with ixazomib in treating patients with multiple myeloma that has come or does not respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of MLN4924
      (pevonedistat) in combination with MLN9708 (ixazomib citrate [ixazomib]) in relapsed and/or
      refractory multiple myeloma (RRMM) patients after more than one previous line of treatment.
      (Dose-escalation phase) II. Describe the safety profile and tolerability of the combination
      of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive
      and PI-refractory populations. (Dose-expansion phase) III. Determine the anti-tumor activity
      and overall response rates (ORR) in patients with RRMM with the use of MLN9708 (ixazomib) and
      MLN4924 (pevonedistat) in combination. (Dose-expansion phase)

      SECONDARY OBJECTIVES:

      I. Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in combination with
      MLN9708 (ixazomib) for the purpose of understanding concentration-effect relationships of
      both agents. (Dose-escalation phase) II. Define the changes in correlative pharmacodynamics
      measures, namely regulated in development and deoxyribonucleic acid (DNA) damage response 1
      (REDD1) and neural precursor cell expressed, developmentally down-regulated 8 (NEDD8).
      (Dose-escalation phase) III. Assess bone marrow-based measures of neddylation.
      (Dose-expansion phase)

      EXPLORATORY OBJECTIVES:

      I. To correlate and predict disease response using the following tests: NEDD8: evaluated on
      blood and bone marrow samples; REDD1: evaluated on blood and bone marrow samples; and NAD(P)H
      dehydrogenase (quinone) 1 (NQO1) and cystine/glutamate transporter (SLC7A11) (nuclear factor
      [erythroid-derived 2]-like 2 [NRF2] target genes): evaluated on whole blood as markers of
      MLN4924 (pevonedistat) activity.

      OUTLINE: This is a dose-escalation study of pevonedistat.

      Patients receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15, and
      pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15. Courses repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 30 days, then every 2-3
      months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ixazomib citrate, pevonedistat)ExperimentalPatients receive ixazomib citrate PO QD on days 1, 8, and 15, and pevonedistat IV over 60 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ixazomib Citrate
  • Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have RRMM with measurable disease, as defined by at least one of the
             following:

               -  Serum monoclonal protein >= 0.5 g/dL

               -  Urinary monoclonal protein excretion of >= 200 mg/24 hours

               -  Kappa or lambda light chain level >= 10 mg/dL with an abnormal free light chain
                  ratio

          -  Relapsed/refractory status and prior treatment:

               -  For dose escalation cohorts: Patients with multiple myeloma (MM) who relapsed or
                  are refractory to at least one prior therapy. Patients may have prior to exposure
                  to PIs, with the exception of prior exposure to MLN9708 (ixazomib)

               -  For proteasome-sensitive expansion cohort: Patients with MM who relapsed or are
                  refractory to at least one prior line of therapy that may not include a PI.

               -  For proteasome-relapsed/refractory expansion cohort: Patients with MM who have
                  relapsed after prior PI exposure or are PI-refractory, defined as nonresponsive
                  to treatment or progresses within 60 days of last exposure to a PI

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,000/mcL

          -  Platelets >= 75,000/mcL

          -  Bilirubin =< institutional upper limit of normal (ULN).

               -  Patients with Gilbert's syndrome may enroll if direct bilirubin =< 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN

          -  Creatinine clearance (CrCl) by Cockcroft-Gault >= 30 mL/min

          -  Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. Elevated
             indirect bilirubin due to post-transfusion hemolysis is allowed

          -  Known human immunodeficiency virus (HIV) positive patients who meet the following
             criteria will be considered eligible:

               -  CD 4 count > 350 cells/mm^3

               -  Undetectable viral load

               -  Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents
                  (e.g. excluding ritonavir)

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

          -  The effects of MLN4924 (pevonedistat) and MLN9708 (ixazomib) on the developing human
             fetus are unknown. For this reason and because NAE inhibitory agents are known to be
             teratogenic, women of child-bearing potential and men must meet the following
             criteria:

               -  Female patients who are:

                    -  Postmenopausal for at least one year before the screening visit, OR

                    -  Surgically sterile, OR

                    -  If of childbearing potential, agree to practice 1 highly effective method
                       and 1 additional (barrier) method of contraception, at the same time, from
                       the time of signing the informed consent until 4 months after the last dose
                       of the ixazomib and pevonedistat (female and male condoms should not be used
                       together), or agree to abstain from heterosexual intercourse, 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)

               -  Male patients, even if surgically sterilized, who:

                    -  Agree to practice effective barrier contraception during the entire time
                       enrolled on study through 4 months after completion of ixazomib and
                       pevonedistat administration (female and male condoms should not be used
                       together), OR

                    -  Agree to abstain from heterosexual intercourse, when this is in line with
                       the preferred and usual lifestyle of the subject. (Periodic abstinence
                       [e.g., calendar, ovulation, symptothermal, postovulation methods for the
                       female partner] withdrawal, spermicides only, and lactational amenorrhea are
                       not acceptable methods of contraception)

               -  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

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Diagnosed or treated for another malignancy within 2 years before randomization or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone resection

          -  Patients who are receiving any other investigational agents, within 30 days of the
             start of this trial and throughout the duration of this trial

          -  Patients with known central nervous system involvement 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 (AEs)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MLN4924 (pevonedistat) or MLN9708 (ixazomib) (including boron or
             boron-containing products)

          -  Patients with uncontrolled intercurrent illness

          -  Pregnant women are excluded from this study because MLN4924 (pevonedistat) is an NAE
             inhibitory agent with 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 should be
             discontinued if the mother is treated with MLN4924 (pevonedistat). These potential
             risks may also apply to the use of MLN9708 (ixazomib) in this study

          -  Major surgery within 14 days before the first dose of any study drug or a scheduled
             surgery during study period

          -  Patients with uncontrolled coagulopathy or bleeding disorder

          -  Known hepatic impairment as defined by known hepatic cirrhosis, hepatitis B surface
             antigen seropositive or known or suspected active hepatitis C infection

               -  Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the
                  setting of negative hepatitis B surface antigen and negative hepatitis B surface
                  antibody) must have an undetectable hepatitis B viral load. Patients who have
                  positive hepatitis C antibody may be included if they have an undetectable
                  hepatitis C viral load

          -  Known cardiopulmonary disease defined as:

               -  Unstable angina;

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

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

               -  Symptomatic cardiomyopathy

               -  Clinically significant arrhythmia:

                    -  History of polymorphic ventricular fibrillation or torsade de pointes,

                    -  Permanent atrial fibrillation, defined as continuous atrial fibrillation for
                       >= 6 months,

                    -  Persistent atrial fibrillation, defined as sustained atrial fibrillation
                       lasting > 7 days and/or requiring cardioversion in the 4 weeks before
                       screening,

                    -  Grade 3 atrial fibrillation defined as symptomatic and incompletely
                       controlled medically, or controlled with device (e.g., pacemaker), or
                       ablation and

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

               -  Symptomatic pulmonary hypertension

          -  Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mmHg, diastolic
             blood pressure > 95 mmHg)

          -  Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to
             institutional guidelines

          -  Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
             radionuclide angiography

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

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of MLN9708 (ixazomib), including difficulty swallowing

          -  Peripheral neuropathy that is grade >= 3, or grade 2 with pain on clinical examination
             during the screening period

          -  Patients that have previously been treated with MLN9708 (ixazomib)

          -  Systemic treatment, within 14 days before the first dose of MLN9708 (ixazomib), with
             strong CYP3A inducers (rifampin, rifapentine, rifabutin, ritonavir, carbamazepine,
             phenytoin, phenobarbital), or use of St. John's wort. Clinically significant metabolic
             enzyme inducers are not permitted during this study

          -  Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days
             will be considered a sufficient interval between treatment and administration of the
             MLN9708 (ixazomib)

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days
Safety Issue:
Description:Descriptive statistics will be provided for selected safety data by dose and time as appropriate.

Secondary Outcome Measures

Measure:Pharmacokinetics (PK) characterization of pevonedistat in combination with ixazomib citrate
Time Frame:Cycle 1, day 1 pre-dose at 0.5, 1, 2, 2.5, 5, 8, and 21 hours
Safety Issue:
Description:Descriptive statistics will be provided for selected PK data by dose and time as appropriate. Pevonedistat concentrations in these samples will be quantitatively measured using a liquid chromatography/tandem mass spectrometry (liquid Chromatography with tandem mass spectrometry [LC/MS/MS]) method in place at Covance under contract with Takeda. For pevonedistat, the individual PK parameters from a single dose will be estimated for maximum concentration (Cmax), area under the curve (AUC), half-life (t1/2), apparent CL/F, and apparent volume of distribution (V/F) using non-compartmental or compartmental PK methods with the software WinNonlin. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy.
Measure:Correlative pharmacodynamic measures (REDD1, NEDD8, NRF2 target genes) in both proteasome inhibitor (PI)-sensitive and PI-refractory patients
Time Frame:Baseline up to course 1
Safety Issue:
Description:Descriptive statistics will be provided for selected pharmacodynamic data by dose and time as appropriate. Changes in pharmacodynamic markers will be tabulated and descriptive statistics (e.g., geometric means and CV) calculated for each dose level. Exploratory correlative studies with pharmacodynamic (biological endpoints, toxicity, and efficacy) will be analyzed using Pearson or Spearman's correlation coefficient and tested with Wald's test. Significance for comparisons will be at the P<0.05 level.
Measure:Biomarker analysis of NQO1 and SLC7A11
Time Frame:Up to 2 years
Safety Issue:
Description:Descriptive statistics will first be used to summarize their gene expression in whole blood by Reverse transcription-polymerase chain reaction (RT-PCR). Biomarker data will also be displayed graphically, where appropriate. Depending on whether data is normally distributed, Person or Spearman's correlation coefficient will be used to measure the correlations of NQO1 and SLC7A11 with the dosage of pevonedistat, and then tested with Wald's test. General Linear Model (GLM) will be used to compare each of the biomarkers (NQO1 and SLC7A11) between different dose levels of pevonedistat with and without adjusting for other factors. Logistics regression model will be further employed to test the adjusted effect of each biomarkers (NQO1 and SLC7A11) on the response rate after adjusting for dosage of pevonedistat as well as other factors.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 16, 2020