Ibrutinib and Ixazomib Citrate in Treating Newly Diagnosed, Relapsed or Refractory Waldenstrom Macroglobulinemia

May 1, 2026 updated by: Mayo Clinic

Phase II Study of Ibrutinib in Combination With Ixazomib in Patients With Waldenström Macroglobulinemia

This phase II trial studies the side effects of ibrutinib citrate when given with ixazomib, and determines how well they work in treating patients with Waldenstrom macroglobulinemia that is newly diagnosed, has come back (recurrent) or does not respond to treatment (refractory). Enzyme inhibitors, such as ibrutinib and ixazomib citrate, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the efficacy (as assessed by complete response [CR] rate) of the combination of ixazomib citrate (ixazomib) and ibrutinib in Waldenstrom macroglobulinemia (WM) patients.

SECONDARY OBJECTIVES:

I. To assess the overall response rate (ORR=partial response [PR] or better) in WM patients treated with ixazomib and ibrutinib.

II. To assess the time to progression (TTP) in WM patients treated with ixazomib and ibrutinib.

III. To further characterize the safety and toxicity of the combination of ibrutinib and ixazomib.

IV. To assess the overall survival (OS) in WM patients treated with ixazomib and ibrutinib.

CORRELATIVE RESEARCH OBJECTIVES:

I. To determine the role of members of the BTK signalosome in achievement or lack thereof of response to ibrutinib and ixazomib.

II. To explore biologic effects of ibrutinib and ixazomib on microenvironment in WM and correlate with response to treatment.

OUTLINE:

Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and ibrutinib PO daily on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
21

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Jacksonville, Florida, United States, 32224-9980
        • Mayo Clinic in Florida
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic in Rochester

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histological confirmation of WM; patients may have newly diagnosed, relapsed, or refractory disease; (definition: newly diagnosed; patients previously untreated for WM, relapse; patients who have received prior treatment for WM and now have disease recurrence; refractory; patients who have received anti-WM therapy and are noted to have progressive disease while on therapy, or those patients who demonstrated disease progression within 6 months of the last anti-WM treatment); NOTE: Ibrutinib naïve patients are allowed; if previously treated with ibrutinib, subject must have reached a response of at least stable disease (SD) and cannot have progressed while on ibrutinib; if subject stopped taking ibrutinib for reasons other than progression, they cannot have progressed for at least 6 months post last dose of ibrutinib
  • Presence of measurable disease as defined by: presence of immunoglobulin M (IgM) paraprotein, measurable lymphadenopathy on imaging studies and/or physical exam, and/or bone marrow infiltration > 10%
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to registration)
  • Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration) (NOTE: platelet transfusions in order to help patients meet eligibility criteria are not allowed)
  • Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome, in which case the direct bilirubin must be =< 1.5 x ULN (obtained =< 14 days prior to registration)
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (obtained =< 14 days prior to registration)
  • Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft Gault formula (obtained =< 14 days prior to registration)
  • Negative pregnancy test done at screening and =< 3 days (72 hours) prior to registration, for women of childbearing potential
  • Provide written informed consent
  • Willingness to provide mandatory blood specimens and bone marrow specimens for correlative research
  • Willingness to return to enrolling institution for follow-up

Exclusion Criteria:

  • Failure to have fully recovered (i.e., =< grade 1 toxicity) from the reversible effects of prior treatment for WM
  • Major surgical procedure (including open biopsy, excluding central line intravenous (IV) and port-a-cath placement) within =< 14 days prior to initiating study treatment, or anticipation of the need for major surgery during the course of the study treatment
  • Radiotherapy =< 14 days prior to registration; if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib
  • Systemic treatment, =< 14 days before registration, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or St. John's wort
  • Systemic anti-cancer therapy or participation in other clinical trials, including those with other investigational agents not included in this trial, =< 28 days of registration and throughout the duration of active treatment in this trial
  • Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not; prior bortezomib treatment is allowed as per: patients with prior exposure to bortezomib will be allowed if they do not have disease refractory to bortezomib)
  • Central nervous system involvement (Bing-Neel syndrome)
  • Infection requiring systemic antibiotic therapy or other serious infection =< 7 days prior to registration
  • Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, serious cardiac arrhythmia requiring medication (other than adequately rate-controlled atrial fibrillation), symptomatic congestive heart failure, unstable angina, stroke/transient ischemic attack (TIA) within the past 6 months or myocardial infarction within the past 6 months
  • Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
  • Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or ibrutinib, including difficulty swallowing
  • History of any other prior malignancy; (NOTE: Exception to this are adequately treated non-melanoma skin cancers, any in situ cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least two years prior to study enrollment)
  • Patient has >= grade 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination during the screening period

  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown

    • Pregnant women
    • Nursing women
    • Men or women of child bearing potential (WCBP) who are unwilling to employ effective contraception; effective contraception would be defined as utilizing 2 simultaneous methods of contraception from the time of signing consent through 90 days after the last dose of the study drugs unless they agree to participate in true abstinence when this is in line with the preferred and usual lifestyle of the subject; (WCBP: A female who is sexually mature and who: [1] has not undergone a hysterectomy or bilateral oophorectomy; or [2] has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time in the preceding 24 consecutive months])
  • Evidence of any other serious medical condition (such as psychiatric illness, infectious diseases, physical or laboratory findings) that may interfere with the planned treatment, affect compliance or place the patient at high risk from treatment-related complications or potentially interfere with the completion of the treatment as per the protocol
  • Ongoing, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
  • Liver disease with Child-Pugh class B or C liver dysfunction
  • Current treatment with a combination of ibrutinib and strong CYP3A inhibitors

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Treatment (ixazomib citrate, ibrutinib)
Patients receive ixazomib citrate PO on days 1, 8, and 15 and ibrutinib PO daily on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacokinetic Study
Correlative studies
Other Names:
  • PHARMACOKINETIC
  • PK Study
Other: Pharmacodynamic Study
Correlative studies
Other Names:
  • PHARMACODYNAMIC
Drug: Ixazomib Citrate
Given PO
Other Names:
  • Ninlaro
  • MLN-9708
  • MLN9708
Drug: Ibrutinib
Given PO
Other Names:
  • PCI-32765
  • Imbruvica
  • BTK Inhibitor PCI-32765
  • CRA-032765

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Complete Response Rate (CR)
Time Frame: 4 years
Complete response rate to be defined as an objective status of CR at any time, where confirmation of the complete response status is required on two consecutive evaluations with a second immunofixation before calling the patient a CR. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Categorized by Response Assessment Criteria as specified in Appendix III of the protocol.
4 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall Response Rate
Time Frame: Up to 5 years
Overall response rate will be estimated by the total number of patients who achieve a CR, very good partial response (VGPR), or partial response (PR) divided by the total number of evaluable patients. All evaluable patients will be used for this analysis. Exact binomial 95% confidence intervals for the true overall response rate will be calculated. Response is categorized by Response Assessment Criteria as specified in Appendix III of the protocol.
Up to 5 years
Progression-free Survival
Time Frame: From study registration to the earliest date of documentation of disease progression, assessed up to 5 years
The median time to progression will be estimated using the method of Kaplan-Meier. Categorized by Response Assessment Criteria as specified in Appendix III of the protocol.
From study registration to the earliest date of documentation of disease progression, assessed up to 5 years
Overall Survival
Time Frame: Up to 5 years
Defined as the time from study enrollment until death due to any cause. The median overall survival will be estimated using the method of Kaplan-Meier.
Up to 5 years
Number of Patients Experiencing Grade 3+ Adverse Effects (AE) Graded According to Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0
Time Frame: Up to 5 years
The maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the AE(s) to the study treatment will be taken into consideration.
Up to 5 years

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
BTK Signaling Proteins (Western Blot and Densitometric Quantification) and Gene Expression (Quantitative Real-time Polymerase Chain Reaction [PCR]) Examined in CD19/CD138+ Waldenstrom Macroglobulinemia (WM) Cells
Time Frame: Up to 5 years
15 protein/genes associated with BTK-signaling will be assessed and their levels from baseline samples will be compared with levels from samples during treatment. Changes over time will be evaluated using paired sample approaches (Wilcoxon signed rank test). Baseline levels will be correlated with response (responder versus [vs.] non-responder) using Wilcoxon rank sum tests.
Up to 5 years
Biologic Effects of Ibrutinib and Ixazomib Citrate on Microenvironment in WM
Time Frame: Up to 5 years
Blood samples & bone marrow aspirate to be taken from participants. The study will explore biologic effects of ibrutinib and ixazomib on microenvironment in WM and correlate with response to treatment. Immunophenotyping of tumor infiltrating lymphocytes (TILs) using the Multi-Omyx TILs platform. This will identify 17 different types of TILs from BM samples collected at baseline and then after one cycle of treatment. This data is represented as % and actual cell counts. Next, identification of 4 types of T-cells from the blood. This will be done from peripheral blood samples collected at Baseline and then after one cycle of treatment with ixazomib + ibrutinib (Ixa+Ibr). Next, BTK receptor occupancy: This is a competitive-binding assay essentially and will be performed in CD19+/CD138+ WM cells collected at baseline and then after one cycle of treatment with Ixa+Ibr. Readout is % occupancy. Values to be correlated with response (responder vs. non-responder) using Wilcoxon rank sum tests.
Up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Mayo Clinic

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Cancer Institute (NCI)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Asher A. Chanan-Khan, M.D., Mayo Clinic

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 14, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 6, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 3, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 11, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 18, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 24, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 5, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 1, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • MC178B (Mayo Clinic)
  • 18-000580 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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