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Mantle-Cell LymphomaPhase 1/2PrE0404NCT03323151

A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma

A Phase 1/2 study testing Ixazomib and Ibrutinib in people with Mantle-Cell Lymphoma, run by PrECOG, LLC. at 14 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory (progressed on treatment) will receive ixazomib and ibrutinib. Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for patients with mantle cell lymphoma who have received at least one prior therapy. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Mantle-Cell Lymphoma
What is being tested?
Ixazomib and Ibrutinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
43 participants
Where
14 sitesUnited States
Study dates
13 Aug 2018to 7 Sep 2023
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult
  • Relapsed or refractory, pathologically proven mantle cell lymphoma. Must have a current or prior tissue sample that is IHC positive for cyclin D 1 or that is positive by FISH or cytogenetics for t(11;14).
  • Must have been refractory to and/or relapsed/progressed after at least 1 prior therapy.
  • Prior autologous or allogeneic transplant are allowed. Patients may not have active grade II-IV acute graft-versus-host disease (GVHD) or moderate/severe chronic GVHD by NIH criteria and may not require immunosuppressive medications and/or corticosteroids for the management of acute or chronic GVHD.
  • Phase I: Prior proteasome inhibitor and/or Bruton's tyrosine kinase (BTK) inhibitors are allowed but patients may not have been exposed to the combination of proteasome inhibitor and BTK inhibitor. Patients who have progressed on ibrutinib that are felt to be at high risk for rapid progression on this study shall not be eligible for the phase I portion of the study. NOTE: Ibrutinib pre-treated patients must meet all eligibility criteria AND must have discontinued prior ibrutinib at least 3 months prior to starting study therapy. PHASE I COMPLETED NOVEMBER 25, 2019.
  • Phase II: Prior proteasome inhibitors allowed. (Please note prior to Version 3.0 of the protocol prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors were allowed but patients could not have been exposed to the combination of proteasome inhibitor and BTK inhibitor).
  • Age ≥ 18 years.
  • Eastern Oncology Oncology Group (ECOG) performance status of 0-2.
  • Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent.
  • Willing to provide archived tumor tissue, bone marrow (if sufficient bone marrow and tumor tissue are available) and blood samples for research.
  • Adequate organ function as measured by the following criteria
  • Absolute Neutrophil Count (ANC) ≥ 750/mm³
  • Platelets ˃50,000/mm³
  • Serum Creatinine ≤ 2x Upper Limit Normal (ULN)
  • ALT and AST ≤ 3x ULN
  • Total Bilirubin ≤ 1.5x ULN
  • Patients must not have received systemic treatment for MCL for at least 14 days prior to enrollment, except for steroids which may be used to manage acute symptoms related to disease up to 48 hours prior to starting study therapy. Radiation therapy must be concluded at least 14 days prior to enrollment.
  • Women must not be pregnant or breastfeeding since we do not know the effects of ixazomib and ibrutinib on the fetus or breastfeeding child. All sexually active females of childbearing potential must have a blood test to rule out pregnancy within 2 weeks prior to registration.
  • Sexually active women of child-bearing potential with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 3 months following last dose of study drugs.
  • Patients must have resolved all prior non-hematologic toxicities assessed as related to prior therapy to ≤ grade 1.
  • Patients must have measurable disease (i.e., ≥ 1.5 cm in largest diameter) by conventional imaging modalities. Patients with extranodal involvement as the only measurable site of disease must have a largest diameter ≥ 1.0 cm and must be attributable to active lymphoma in the opinion of the investigator.
  • Patients may not have current/active Central Nervous System (CNS) involvement with mantle cell lymphoma (patients with prior CNS involvement are eligible as long as they have had no evidence of active CNS disease for at least 6 months).
  • Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of this combination. Patients with a prior malignancy will be allowed without study chair approval in the following circumstances:
  • Not currently active and diagnosed at least 3 years prior to the date of enrollment.
  • Non-invasive diseases such as low risk cervical cancer or any cancer in situ
  • Localized disease in which chemotherapy would not be indicated (such as Stage I colon, lung, prostate or breast cancer). Patients with other malignancies not meeting these criteria must be discussed with PrECOG prior to enrollment.
  • Patients requiring long-term anticoagulation must be managed on an anticoagulant besides warfarin. Patients who require warfarin are not eligible.
  • Patients with a clinically significant bleeding episode as judged by the investigator within 3 months of registration are not eligible, except patients who suffer bleeding due to trauma.
  • Patients may not have had major surgery within 14 days, or minor surgery within 3 days, before registration.
  • Patients may not have any active infection requiring oral or intravenous antimicrobial therapy at the time of therapy initiation. Patients with a recent self-limited infection that has clinically resolved may complete a prescribed course of antimicrobial therapy after study initiation as long as they are asymptomatic with no clinical evidence of infection for at least 7 days prior to treatment. Patients with a recent serious (grade ≥ 3) infection requiring hospitalization must have completed all antimicrobial therapy within 14 days of therapy initiation.
  • Patients may not have evidence of uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure (New York Heart Association (NYHA) class III or higher, unstable angina, or myocardial infarction within the past 6 months. Patients with a history of any significant cardiovascular disease that has been controlled for at least 14 days before registration are allowed (except for patients who have had a myocardial infarction within 6 months).
  • No systemic treatment, within 14 days before the first dose of ibrutinib with moderate or strong inhibitors of CYP3A (Strong Inhibitors: ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, and telithromycin; Moderate Inhibitors: fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice products, and Seville oranges) or strong CYP3A inducers for ibrutinib and ixazomib (carbamazepine, rifampin, phenytoin, St. John's wort).
  • Patients with ongoing or active systemic infection, active hepatitis B or C virus infection, or known Human Immunodeficiency Virus (HIV) positive are not eligible. Testing is not required in absence of clinical suspicion.
  • Patients with a history of hepatitis B or C must have a negative peripheral blood Polymerase Chain Reaction (PCR) and may not be positive for Hepatitis B surface antigen. Patients with cirrhosis or other evidence of liver damage due to Hepatitis B or C are not eligible.
  • Patients with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the treatment according to the protocol are not eligible.
  • Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible.
  • Patients with known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of ixazomib or ibrutinib including difficulty swallowing are not eligible.
  • Patients with ≥ Grade 2 peripheral neuropathy, or Grade 1 peripheral neuropathy with pain on clinical examination during the screening period are not eligible.
  • Patients may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial throughout the duration of this study.
  • As ibrutinib will not be provided by the study, the patient must be able to obtain ibrutinib through other means (i.e., commercially or through patient assistance programs). This must be confirmed prior to registration.

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

United States14 sites

  • Winship Cancer Institute of Emory University

    Atlanta, Georgia, 30322

  • Georgia Cancer Center at Augusta University

    Augusta, Georgia, 30912

  • University of Virginia

    Charlottesville, Virginia, 22908

  • Gundersen Health System

    La Crosse, Wisconsin, 54601

  • University of Wisconsin

    Madison, Wisconsin, 53792

  • Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • West Virginia University

    Morgantown, West Virginia, 26506

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

  • Laura and Isaac Perlmutter Cancer Center at NYU

    New York, New York, 10016

  • University of Kansas

    Overland Park, Kansas, 66210

  • University of Pennsylvania Abramson Cancer Center

    Philadelphia, Pennsylvania, 19104

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Carle Cancer Center

    Urbana, Illinois, 61801

  • ProHealth Care

    Waukesha, Wisconsin, 53188

Other trials in United States

About this study

Official title: A Phase I/II Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma

Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory (progressed on treatment) will receive ixazomib and ibrutinib.

Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for patients with mantle cell lymphoma who have received at least one prior therapy.

Read more

Ixazomib is in a class of medications called proteasome inhibitors. Cancer cells depend on proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ixazomib disrupts a cancer cells' ability to survive by blocking the proteasome and disrupting protein metabolism. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether the addition of ixazomib to ibrutinib chemotherapy is effective in treating people who have relapsed or refractory MCL and to examine the side effects associated with ixazomib in combination with ibrutinib.

Read the detailed description

MCL is a rare subtype of non-Hodgkin lymphoma that is considered incurable with conventional therapy. For relapsed patients, Ibrutinib, lenalidomide, and bortezomib are all approved by the FDA but are not curative. Novel approaches are required to improve outcomes for patients with relapsed/refractory MCL.

This is an open-label study that will be done in 2 phases. Phase I will test different doses of ixazomib and ibrutinib to determine the maximum safe and tolerated dose. In Phase I, patients who have already received ibrutinib, may participate if they meet certain criteria (i.e., have not received ibrutinib for at least 3 months).

Phase II will find out the effects, good and/or bad, of ixazomib in combination with ibrutinib. In Phase II, patients will be separated into 2 groups, patients who have never received a Bruton's Tyrosine Kinase (BTK) inhibitor and patients who have received a BTK inhibitor. This study is designed to examine the effectiveness of this drug in treating patients with MCL.

Patients will be treated until progression or unacceptable toxicity.

Tumor assessments will be performed approximately every 3 months for the first year of treatment, then every 6 months until progression.

Mandatory bone marrow and tumor tissue samples (i.e., obtained during a previous procedure or biopsy) are required at baseline. Mandatory research blood samples will also be collected.

Being tested
Ixazomib, Ibrutinib
Keywords
Relapsed Mantle-Cell Lymphoma, Refractory Mantle-Cell Lymphoma, Ixazomib, Ibrutinib, Proteasome Inhibitor, Bruton's Tyrosine Kinase Inhibitor
Medical subject headings
Lymphoma, Mantle-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IxazomibDrug

    Also called Ninlaro

    Ixazomib 3 mg by mouth on days 1, 8 and 15 by mouth days 1-28 of a 28 day cycle. Dose may be escalated (Ixazomib 4 mg) dependent on dose-limiting toxicities. Note: Ixazomib dose will not be de-escalated but remain at 3 mg.

  • IxazomibDrug

    Also called Ninlaro

    Ixazomib 4 mg by mouth on days 1, 8 and 15 of a 28 day cycle until progression or unacceptable toxicity.

  • IbrutinibDrug

    Also called Imbruvica

    Ibrutinib 560 mg by mouth days 1-28 of a 28 day cycle. Dose may be de-escalated (Ibrutinib 420 mg) or escalated (Ibrutinib 560 mg) dependent on dose-limiting toxicities.

  • IbrutinibDrug

    Also called Imbruvica

    Ibrutinib 560 mg by mouth days 1-28 of a 28 day cycle until progression or unacceptable toxicity.

Study groups in NCT03323151
Study groupRoleWhat they receive
Phase I: Ixazomib & IbrutinibExperimentalIxazomib and Ibrutinib will be given by mouth until progression or unacceptable toxicity.
Receives: Drug: Ixazomib; Drug: Ibrutinib
Phase II: Ixazomib & BTK-NaiveExperimentalPatients who are BTK-Naive will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
Receives: Drug: Ixazomib; Drug: Ibrutinib
Phase II: Ixazomib & BTK Pre-Treated (Closed 8/7/2020)ExperimentalPatients previously treated with a BTK will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
Receives: Drug: Ixazomib; Drug: Ibrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase I: Dose Limiting Toxicities (DLT) Rate

    To determine the maximum tolerable dose (MTD) of ixazomib (mg) in combination with ibrutinib (mg) in patients with relapsed/refractory mantle cell lymphoma (MCL) using DLT endpoint.

    Measured: 1 month

  2. Phase II: Complete Response Rate

    CR rate will be the defined as the percentage of patients achieving CR as confirmed by bone marrow biopsy within the first 12 months of initiating treatment. Response to treatment was assessed using the Lugano classification criteria. Patients completed a PET/CT at the time of study enrollment and were restaged at cycles 3, 6, 9, and 12, and then every 6 months while on study therapy.

    All patients with suspected CR who had bone marrow involvement at screening underwent a bone marrow biopsy to confirm response.

    Measured: 12 months

Secondary outcomes (4)

  1. Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0

    Number of patients with abnormal laboratory values and/or adverse events (defined as a new untoward medical occurrence or worsening of a pre-existing medical condition) related to study treatment. Grades refer to the severity of the adverse event, where grade 1 through 5 signifies mild, moderate, severe, life-threatening, and death respectively.

    Measured: Phase I: 12 months; Phase II: 36 months

  2. Overall Response Rate (ORR)

    ORR assessed in accordance with Lugano classification

    Measured: Phase I: 12 months; Phase II: 12 months

  3. Progression-Free Survival (PFS)

    PFS assessed in accordance with Lugano classification

    Measured: Phase I & II: 48 months

  4. Overall Survival (OS)

    OS assessed during clinic visit or by reaching out to patients to confirm vital status.

    Measured: Phase I & II: 48 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Oct 2017
  2. Study start13 Aug 2018
  3. Primary completion22 Sep 2022
  4. Study completion7 Sep 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Phase I: Standard 3+3 design with the primary objective of determining the maximum tolerate dose (MTD)/recommended phase 2 dose (RP2D) of this combination in MCL. Both ibrutinib-pretreated and ibrutinib-naïve patients will be enrolled. Phase II: Dose Level 2 is the RP2D. Patients will be enrolled to two cohorts, based on prior ibrutinib treatment: BTK-naïve and BTK-pretreated (BTK pretreated closed 8/7/2020).
Masking
None (open label)
Enrolment
43 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03323151
Sponsor's protocol ID
PrE0404
Other IDs
X16077
Acronym
PrE0404
Status last verified
Jun 2026
First submitted
16 Oct 2017
Last updated
25 Jun 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Data is proprietary.

Publications

  • Cohen JB, Portell CA, Hamadani M, Jegede O, Diefenbach C, Fletcher C, Matasar M, Landsburg D, Mantha S, Kahl B. An Evaluation of Ibrutinib and Ixazomib in Patients With Relapsed/Refractory Mantle Cell Lymphoma: PrE0404. Clin Lymphoma Myeloma Leuk. 2026 Jul;26(7):465-473.e1. doi: 10.1016/j.clml.2026.04.025. Epub 2026 May 4.

    PubMed 42209393

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ixazomib and Ibrutinib in people with Mantle-Cell Lymphoma, run by PrECOG, LLC. at 14 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I: Dose Limiting Toxicities (DLT) Rate (time frame: 1 month). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03323151, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2026.

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