Ibrutinib + Venetoclax in Untreated WM

NCT ID: NCT04273139

Last Updated: 2025-07-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-09
• Study Completion Date: 2028-02-01

Brief Summary

This study evaluates the safety and efficacy of Ibrutinib combined with Venetoclax (IVEN) in the treatment of adults diagnosed with Waldenstrom's macroglobulinemia (WM) cancer with a specific MYD88 gene mutation.

This research study involves an experimental drug combination of targeted therapies.

The names of the study drugs involved in this study are:

• Venetoclax
• ibrutinib

Detailed Description

• This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
• The names of the study drugs involved in this study are:

• Venetoclax
• ibrutinib
• The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

• Participants will be on the research study for up to 2 years on combined venetoclax and ibrutinib and 4 years of follow-up .
• It is expected that about 50 people will take part in this research study.
• The U.S. Food and Drug Administration (FDA) has not approved venetoclax for your specific disease but it has been approved for other uses.

-- Venetoclax is a targeted therapy that blocks BCL-2, a protein that is important for the survival of WM cells. Laboratory studies and early clinical data have shown that the investigational new agent, venetoclax, may kill cancer cells and may cause tumors to shrink.

• The U.S. Food and Drug Administration (FDA) has approved ibrutinib as a treatment option for this disease.

--Ibrutinib is a targeted therapy that blocks BTK. It has been FDA approved in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft vs. host disease (cGVHD), and Waldenstrom's macroglobulinemia (WM). It is also used in research studies in participants with recurrent B-cell lymphoma), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated.

• The U.S. Food and Drug Administration (FDA) has not approved the combination of ibrutinib and venetoclax as a treatment for any disease.
• The U.S. Food and Drug Administration (FDA) has not approved the MYD88 test. This test is investigational.

Conditions

Waldenstrom Macroglobulinemia; MYD88 Gene Mutation

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ibrutinib and Venetoclax

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

• Ibrutinib will be administered at a predetermined dose, once daily for 28 days
• TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment)
• Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2.

Group Type: EXPERIMENTAL

IBRUTINIB

Intervention Type: DRUG

Ibrutinib Cycle 1-24 will be administered at a predetermined dose, once daily for 28 days

Venetoclax

Intervention Type: DRUG

Venetoclax Cycle 2-24 will be administered daily for 28 days. Predetermined dosage ramp up schedule during cycle 2.

Interventions

IBRUTINIB

Ibrutinib Cycle 1-24 will be administered at a predetermined dose, once daily for 28 days

Intervention Type: DRUG

Venetoclax

Venetoclax Cycle 2-24 will be administered daily for 28 days. Predetermined dosage ramp up schedule during cycle 2.

Intervention Type: DRUG

Other Intervention Names

Imbruvica; Venclexta

Eligibility Criteria

Inclusion Criteria

• Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy & aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1.
• Clinicopathological diagnosis of Waldenström macroglobulinemia [28].
• Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.
• Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia [29].
• Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation.
• Age ≥ 18 years
• ECOG performance status ≤2 (see Appendix A)
• Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum IgM level of >2 times the upper limit of normal of each institution is required
• At the time of screening, participants must have acceptable organ and marrow function as defined below:

• Absolute neutrophil count ≥500/uL (no growth factor permitted)
• Platelets ≥50,000/uL (no platelet transfusions permitted)
• Hemoglobin ≥ 7 g/dL (transfusions permitted)
• Total bilirubin < 1.5 x institutional ULN
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
• Estimated GFR ≥30 mL/min
• Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
• Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of ibrutinib or venetoclax during sexual contact with a FCBP
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
• Participants who have one or more prior systemic therapies for WM.
• Participants who are receiving any other investigational agents.
• Participants with known CNS lymphoma.
• Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note: Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate.
• Concurrent administration of medications or foods that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug.
• Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C (Appendix B).
• Concurrent administration of warfarin.
• Concurrent systemic immunosuppressant therapy within 21 days of the first dose of study drug.
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of the study drug.
• Known bleeding disorders (e.g., congenital von Willebrand's disease or hemophilia)
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Major surgery within 4 weeks of first dose of study drug.
• Malabsorption syndrome or other condition that precludes enteral route of administration.
• Female participants who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days of last dose of study drug.
• Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug
• Participants with known history of alcohol or drug abuse.
• Participants with inability to swallow pills.
• On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Participants with a history of non-compliance to medical regimens.
• Participants who are unwilling or unable to comply with the protocol.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AbbVie

INDUSTRY

Sponsor Role: collaborator

Pharmacyclics LLC.

INDUSTRY

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Jorge J. Castillo, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jorge J Castillo, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Countries

United States

References

Castillo JJ, Branagan AR, Sermer D, Flynn CA, Meid K, Little M, Stockman K, White T, Canning A, Guerrera ML, Kofides A, Liu S, Liu X, Richardson K, Tsakmaklis N, Patterson CJ, Hunter ZR, Treon SP, Sarosiek S. Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naive Waldenstrom macroglobulinemia. Blood. 2024 Feb 15;143(7):582-591. doi: 10.1182/blood.2023022420.

Reference Type: DERIVED

PMID: 37971194 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

19-651

Identifier Type: -

Identifier Source: org_study_id