Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement

NCT02765854 | Completed Phase 2 Results DMC

• 4 other identifiers: IRB00077815NCI-2016-00043MMRC060P30CA138292
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 4

Brief Summary

This randomized phase II trial studies how well ixazomib and dexamethasone or ixazomib, dexamethasone, and lenalidomide work based on the presence of the rearrangement of a gene called nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) in treating patients with multiple myeloma that has returned after a period of improvement or does not respond to treatment. Ixazomib may stop the growth of cancer cells by blocking enzymes called proteasomes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, 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. Lenalidomide may stimulate the immune system against cancer cells and may also prevent the growth of new blood vessels that tumors need to grow. It is not yet known whether ixazomib and dexamethasone, or ixazomib, dexamethasone, and lenalidomide are more effective in treating multiple myeloma.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (1)

• The Primary Objective of the Study is to Test Whether the NFKB2 Rearrangement Can Guide the Selection of Treatment (Ixazomib Plus Dexamethasone (Id) or Ixazomib Plus Lenalidomide and Dexamethasone (IRd)) by Conducting the 3 Following Comparisons

  Comparison to a historical control: The overall response rate (ORR) of each arm at 4 cycles (112 days) is compared to the historical RR of 30%. Arm A or Arm C is designed to detect an improved RR of 60% vs. 30% using Simon's 2-stage Optimum design with a power of at least 90% and an alpha error of 5%., respectively. For Arm B will achieve a power of at least 80% at the significance level of 0.05 to claim that Arm B has equivalent RR as the historical RR of 30% assuming an equivalence tolerance of +/- 20% when the true RR of Arm B is approximately 30%. Response Rate is defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  112 days

Secondary Outcomes (4)

• Time to Treatment Failure

  Up to 30 months

• Prevalence of NFKB2 Rearrangement in Relapsed/Refractory Multiple Myeloma Patients Screened in the Study.

  At baseline and month 12

• Percentage of Patients With Response at Baseline and at 12 Months

  At baseline and at 12 months

• Incidence of Adverse Events

  30 days post-treatment, up to a total of 1 year

Study Arms (3)

Arm B (ixazomib and dexamethasone)

EXPERIMENTAL

MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A.

Drug: Dexamethasone; Drug: Ixazomib

Arm C (ixazomib, dexamethasone, lenalidomide)

EXPERIMENTAL

MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.

Drug: Dexamethasone; Drug: Ixazomib; Drug: Lenalidomide

Arm A (ixazomib and dexamethasone)

ACTIVE COMPARATOR

UNMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone.

Drug: Dexamethasone; Drug: Ixazomib

Interventions

Dexamethasone DRUG

Given PO

Also known as: Decadron, DexPak, Dexasone, Baycadron, Zema, Diodex, Hexadrol, Maxidex

Arm A (ixazomib and dexamethasone); Arm B (ixazomib and dexamethasone); Arm C (ixazomib, dexamethasone, lenalidomide)

Ixazomib DRUG

Given PO

Also known as: MLN9708, Ninlaro, Ixazomib citrate

Arm A (ixazomib and dexamethasone); Arm B (ixazomib and dexamethasone); Arm C (ixazomib, dexamethasone, lenalidomide)

Lenalidomide DRUG

Given PO

Also known as: CC-5013, Revlimid

Arm C (ixazomib, dexamethasone, lenalidomide)

Eligibility Criteria

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

You may qualify if:

• Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
• Females of childbearing potential (FCBP)\* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli-International Units (mIU)/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and ixazomib and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide through 90 days after the last dose of study drug; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy from the time of signing the informed consent form through 90 days after the last dose of study drug; in the event that the male patients choose to agree to practice true abstinence, this must follow the timelines detailed above; all patients assigned to the lenalidomide treatment group must be registered in and must comply with all requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program
• \*A female of childbearing potential is a sexually mature woman who:
• \) has not undergone a hysterectomy or bilateral oophorectomy; or
• \) has not been naturally postmenopausal for at least 24 consecutive months
• Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis
• The patient has confirmed relapsed or refractory MM
• For patients that relapse following a response to prior treatment with bortezomib or carfilzomib, six months must have elapsed since the last dose of treatment
• The patient has received 1 to 3 prior lines of therapy. By definition, a single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of steroids (ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy
• Patients must have measurable disease defined by at least 1 of the following measurements:
• Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L) for an immunoglobulin (Ig)G myeloma, ≥ 0.1 g/dL for an immunoglobulin D (IgD) myeloma or 0.5 g/dL (≥ 5g/L) for an immunoglobulin A (IgA) myeloma
• Urine light chain ≥ 200 mg/24 hours
• Serum free light chain ≥ 10 mg/dL provided the free light chain (FLC) ratio is abnormal
• Patients with oligo- or non-secretory disease must have bone marrow involvement with at least 30% plasmacytosis on aspiration
• Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2

You may not qualify if:

• The patient is refractory to carfilzomib or bortezomib; (refractory is defined as patients who never achieved a response and progressed while on carfilzomib or bortezomib or within 60 days of completing treatment)
• Prior treatment with any investigational proteasome inhibitor within 6 months of study entry
• Female patients who are breast feeding or have a positive serum pregnancy test during the screening period
• Failure to have fully recovered (ie, \> grade 1 toxicity) from the reversible effects of prior chemotherapy
• Diarrhea \> grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03
• Prior chemotherapy and/or immunotherapy within 14 days before enrollment; major surgery within 14 days before enrollment and minor surgery within 7 days prior to cycle 1 day 1
• Radiotherapy within 14 days before enrollment; if the involved field covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
• Central nervous system involvement
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment
• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
• Systemic treatment, within 14 days before the first dose of ixazomib, with strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort
• Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially compromise the patient's ability to understand the patient information, to give informed consent, to comply with the treatment according to this protocol or complete the study
• Diagnosed or treated for another malignancy within 2 years before study enrollment 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 complete resection
• Patient has ≥ grade 2 peripheral neuropathy or neuropathy with pain, regardless of grade that is seen on clinical examination during the screening period

Sponsors & Collaborators

• Emory University: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• Multiple Myeloma Research Consortium: collaborator
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (4)

Grady Memorial Hospital

Atlanta, Georgia, 30303, United States

Location

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

University of Michigan/Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Washington University/Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Dexamethasone; Calcium Dobesilate; ixazomib; Lenalidomide

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

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Leon Bernal-Mizrachi, MD
• Organization: Atrium Health Wake Forest Baptist Comprehensive Cancer Center

lbernalm@wakehealth.edu

336-716-9253

Study Officials

• Leon Bernal-Mizrachi, MD

  Emory University/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 5, 2016
• First Posted: May 9, 2016
• Study Start: September 1, 2016
• Primary Completion: May 23, 2023
• Study Completion: May 23, 2023
• Last Updated: June 26, 2025
• Results First Posted: June 26, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)