Ibrutinib and Venetoclax for the Treatment of Patients with MYD88-Mutated Waldenstrom Macroglobulinemia
This phase II trial investigates how well ibrutinib and venetoclax work in treating patients with Waldenstrom macroglobulinemia that has not been treated (treatment naive) and has a specific alteration in a gene called MYD88. Ibrutinib is a targeted therapy that blocks Bruton's tyrosine kinase (BTK). Venetoclax is a targeted therapy that blocks BCL-2, a protein that is important for the survival of Waldenstrom macroglobulinemia cells. Giving ibrutinib and venetoclax in combination may kill more cancer cells compared to either drug alone, and may cause tumors to shrink.
Inclusion Criteria
- Clinicopathological diagnosis of Waldenstrom macroglobulinemia
- Known tumor expression of mutated MYD88 performed by a Clinical Laboratory Improvement Act (CLIA) certified laboratory
- Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenstrom macroglobulinemia
- Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- 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
- Absolute neutrophil count >= 500/uL (no growth factor permitted) (within 30 days prior to cycle 1 day 1)
- Platelets >= 50,000/uL (no platelet transfusions permitted) (within 30 days prior to cycle 1 day 1)
- Hemoglobin >= 7 g/dL (transfusions permitted) (within 30 days prior to cycle 1 day 1)
- Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (within 30 days prior to cycle 1 day 1)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (within 30 days prior to cycle 1 day 1)
- Estimated glomerular filtration rate (GFR) >= 30 mL/min (within 30 days prior to cycle 1 day 1)
- 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 have one or more prior systemic therapies for WM
- Participants who are receiving any other investigational agents
- Participants with known central nervous lymphoma (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., hepatitis B surface antigen negative [HBs Ag-], and anti-hepatitis B surface antibody positive [anti-HBs+] and anti-hepatitis B core antibody negative [anti-HBC-]) and positive anti-HBc from intravenous immunoglobulin (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
- 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04273139.
PRIMARY OBJECTIVE:
I. To evaluate the rate of very good partial response (VGPR) or better of the combination ibrutinib + venetoclax (IVEN) in participants with treatment naive Waldenstrom macroglobulinemia within 24 cycles of therapy.
SECONDARY OBJECTIVES:
I. To evaluate the rate of complete response (CR) with IVEN in participants with symptomatic, treatment naive Waldenstrom macroglobulinemia (WM) at 6, 12 and 24 cycles of therapy.
II. To evaluate the best overall response to IVEN in participants with symptomatic, treatment naive WM.
III. To evaluate the rate of VGPR or better at 30 months post treatment initiation.
IV. To evaluate median time to response, median time to major response and median time to VGPR to IVEN in participants with symptomatic, treatment naive WM.
V. To evaluate the 24-, 36-, 48-, 60-month progression free survival (PFS) of IVEN in participants with symptomatic treatment naive WM.
VI. To evaluate the overall survival for participants treated with IVEN.
VII. To evaluate the time to next treatment with IVEN.
VIII. To evaluate the effect of IVEN in the bone marrow burden of disease in participants with symptomatic treatment naive WM.
IX. To evaluate the impact of CXCR4 mutations on response to IVEN in participants with symptomatic treatment naive WM.
X. To evaluate the safety profile of IVEN in participants with symptomatic treatment naive WM.
XI. To evaluate the impact of IVEN in the participants’ quality of life (QOL).
OUTLINE: Study treatment for all participants terminated March 2022.
Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 2, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 12 weeks for 4 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorJorge Julio Castillo
- Primary ID19-651
- Secondary IDsNCI-2020-06641
- ClinicalTrials.gov IDNCT04273139