Ibrutinib + Venetoclax in Untreated WM

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Study on the Combination of Ibrutinib and Venetoclax in Treatment naïve Patients With Waldenström Macroglobulinemia

Conditions
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Waldenstrom Macroglobulinemia, MYD88 Gene Mutation

Intervention / Treatment
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* Drug: IBRUTINIB
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The first 12 participants will be assigned to Arm 1. All subsequent participants will be assigned to Arm 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib and Venetoclax (3 dose ramp up)<br>The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. First 12 participants 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. | Drug: IBRUTINIB<br>* Ibrutinib Cycle 1-24 will be administered at a predetermined dose, once daily for 28 days<br>* Other names: Imbruvica;Drug: Venetoclax<br>* Venetoclax Cycle 2-24 will be administered daily for 28 days. Predetermined dosage ramp up schedule during cycle 2.<br>* Other names: Venclexta;|
| Experimental: Ibrutinib and Venetoclax (2 dose ramp up)<br>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 schedule during cycle 2. | Drug: IBRUTINIB<br>* Ibrutinib Cycle 1-24 will be administered at a predetermined dose, once daily for 28 days<br>* Other names: Imbruvica;Drug: Venetoclax<br>* Venetoclax Cycle 2-24 will be administered daily for 28 days. Predetermined dosage ramp up schedule during cycle 2.<br>* Other names: Venclexta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Very Good Partial Response (VGPR) | Proportion of patients with VGPR to therapy. (VGPR is >90% reduction in serum IgM from baseline) | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Response (CR) 6 Cycles | Proportion of patients with a complete response after 6 cycles of therapy | 6 Cycles (28 day cycle) | 
| Rate of Complete Response (CR) 12 Cycles | Proportion of patients with a complete response after 12 cycles of therapy | 12 Cycles (28 day cycle) | 
| Rate of Complete Response (CR) 24 Cycles | Proportion of patients with a complete response after 24 cycles of therapy | 24 Cycles (28 day cycle) | 
| Overall Response 24 Cycles | Proportion of patients with minor response (MR) , partial response (PR), very good partial response (VGPR), or complete response (CR) to therapy. | 24 Cycles (28 day cycle) | 
| Rate of VGPR at 30 months | Proportion of patients with a VGPR at 30 months from beginning therapy. | 30 Months | 
| Median time to response | Time from treatment initiation until first response | 12 Months | 
| Median time to major response | Time from treatment initiation until partial response or better (>50% reduction in serum IgM) | 12 Months | 
| median time to VGPR | Time from treatment initiation until very good partial response (>90% reduction in serum IgM) | 12 Months | 
| Progression Free Survival (PFS) | Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase). | 24 Months | 
| Progression Free Survival (PFS) | Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase). | 36 Months | 
| Progression Free Survival (PFS) | Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase). | 48 Months | 
| Progression Free Survival (PFS) | Time from initiation of therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase). | 60 Months | 
| Overall survival | Time from initiation of therapy until death | duration of time from start of treatment to time of death or last follow-up up to 72 months | 
| Time to next treatment | Time from initiation of IVEN protocol therapy until initiation of new line of therapy. | 24 Months | 
| Impact of IVEN in the participants' quality of life | Quality of life questionnaire European Organisation for Research and Treatment of Cancer. Scores range from 0-100 with high scores indicating a better outcome. | 24 Months | 
| Number of participants with Treatment Related Adverse Events as Assessed (CTCAE) version 5.0 | CTCAE version 5.0 | 6 Months | 
| Impact ofCXCR4 mutations on overall response | Comparison of response rates between participants with CXCR4 mutations and without CXCR4 mutations | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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venetoclax, Waldenstrom Macroglobulinemia, ibrutinib