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Trial record 79 of 530 for:    Neoplasms | Recruiting, Not yet recruiting, Available Studies | "Multiple Myeloma"

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

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ClinicalTrials.gov Identifier: NCT03770260
Recruitment Status : Not yet recruiting
First Posted : December 10, 2018
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Drug: Ixazomib Citrate Drug: Pevonedistat Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple Myeloma Patients: A Phase 1b Trial
Estimated Study Start Date : June 7, 2019
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021


Arm Intervention/treatment
Experimental: Treatment (ixazomib citrate, pevonedistat)
Patients 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.
Drug: Ixazomib Citrate
Given PO
Other Names:
  • MLN-9708
  • MLN9708
  • Ninlaro

Drug: Pevonedistat
Given IV
Other Names:
  • MLN4924
  • Nedd8-Activating Enzyme Inhibitor MLN4924




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 30 days ]
    Descriptive statistics will be provided for selected safety data by dose and time as appropriate.

  2. Maximum tolerated dose of pevonedistat and ixazomib citrate [ Time Frame: Up to course 1 ]
  3. Overall response rates [ Time Frame: Up to 2 years ]
    will be tabulated by dose cohort and overall for the IMWG categories of stringent complete response, complete response, very good partial response, partial response (PR), stable disease, progressive disease, and relapse and the European Group for Blood and Marrow Transplantation (EBMT) category of minimal response. A two-sided 95% exact binominal confidence intervals (CI) will be calculated for each category. The myeloma response rate (responses >= PR) will also be tabulated by dose cohort and overall. The myeloma response rate and each of the best overall response categories will be compared between dose cohorts with Chi-square test.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    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.

  3. Biomarker analysis of NQO1 and SLC7A11 [ Time Frame: Up to 2 years ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03770260


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sagar Lonial JHU Sidney Kimmel Comprehensive Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03770260     History of Changes
Other Study ID Numbers: NCI-2018-03121
NCI-2018-03121 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10249 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10249 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
First Posted: December 10, 2018    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Citric Acid
Sodium Citrate
Ixazomib
Enzyme Inhibitors
Pevonedistat
Glycine
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protease Inhibitors
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs