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

NCT03770260 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2018-0312110249UM1CA186691
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 9

Brief Summary

This phase Ib trial studies side effects and best dose of pevonedistat when given together with ixazomib in treating patients with multiple myeloma that has come back 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.

Conditions

Recurrent Multiple Myeloma; Refractory Multiple Myeloma

Outcome Measures

Primary Outcomes (3)

• Number of Participants Experiencing a Dose Limiting Toxicity (Dose Escalation)

  Number of participants experiencing a dose limiting toxicity to determine the maximum tolerated dose (MTD)

  At Day 28

• Number of Participants Experiencing a Grade 3-5 Adverse Event (Dose Expansion)

  Number of participants who experienced a grade 3-5 adverse event in the dose expansion group

  Up to 2 years after Treatment

• Overall Response Rate (Dose Expansion)

  To determine the overall responses in patients receiving pevonedistat and ixazomib

  Up to 2 Years after Treatment

Secondary Outcomes (1)

• Characterize the Pharmacokinetics (PK) of Pevonedistat and Ixazomib (Dose Escalation)

  Up to 3 months

Study Arms (1)

Treatment (ixazomib citrate, pevonedistat)

EXPERIMENTAL

Patients receive ixazomib citrate PO QD on days 1, 8, and 15 of each cycle and pevonedistat IV over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Ixazomib Citrate; Drug: Pevonedistat

Interventions

Ixazomib Citrate DRUG

Given PO

Also known as: MLN-9708, MLN9708, Ninlaro

Treatment (ixazomib citrate, pevonedistat)

Pevonedistat DRUG

Given IV

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

Treatment (ixazomib citrate, pevonedistat)

Eligibility Criteria

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

You may qualify if:

• 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
• At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.
• For proteasome-sensitive expansion cohort: Patients with MM who relapsed or are refractory to a prior line of therapy not including a proteasome inhibitor
• 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
• Age \>= 18 years
• Because no dosing or adverse event (AE) data are currently available on the use of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) in patients \< 18 years of age, and as this disease is exceptionally uncommon in this age group, children are excluded from this study
• 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

You may not qualify if:

• 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 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (9)

Smilow Cancer Center/Yale-New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Moffitt Cancer Center-International Plaza

Tampa, Florida, 33607, United States

Location

Moffitt Cancer Center - McKinley Campus

Tampa, Florida, 33612, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ixazomib; pevonedistat

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

Enrollment was stopped by the drug company during the third dose level of the Dose Escalation Phase. They discontinued clinical trials using pevonedistat. No participants were enrolled to the Dose Expansion Phase.

Results Point of Contact

• Title: Grants Administrative Manager
• Organization: Johns Hopkins University/SKCCC

jmurra33@jhmi.edu

4439273568

Study Officials

• Nisha Joseph

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2018
• First Posted: December 10, 2018
• Study Start: February 10, 2020
• Primary Completion: September 12, 2022
• Study Completion: July 6, 2023
• Last Updated: June 19, 2025
• Results First Posted: September 6, 2023

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share

Locations

US (9)