Testing the Addition of a New Drug, Venetoclax, to the Usual Treatment (Ibrutinib and Rituximab) for Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma

Study Overview
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Brief Summary
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This phase II trial studies the effects of ibrutinib and rituximab with or without venetoclax in treating patients with previously untreated Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving venetoclax with ibrutinib and rituximab with may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib and rituximab alone.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare the rate of complete response (CR) in previously untreated participants with Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) who are treated upfront with ibrutinib, rituximab and venetoclax (IRV) versus (vs.) ibrutinib and rituximab (IR) regimen. SECONDARY OBJECTIVES: I. To compare overall response rates (ORR) in WM participants treated upfront with IRV vs. those treated with IR. II. To compare progression free survival (PFS), time to next treatment, duration of response in WM participants treated upfront with IRV vs. those treated with IR. III. To compare the rate of very good partial response (VGPR) or better in WM participants treated upfront with IRV vs. those treated with IR. IV. To evaluate the safety of the IRV regimen as compared to IR regimen in participants with WM. V. To evaluate the time to CR in WM participants treated upfront with IRV and those treated with IR. VI. To evaluate the ORR in participants who progress on treatment with IR and are crossed over to treatment with IRV. VII. To compare overall survival (OS) in WM participants treated upfront with IRV vs. those treated with IR. BANK OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 of cycles 1-24 and rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycles 1 and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm I may receive ibrutinib, rituximab, and venetoclax as in Arm II for up to an additional 24 cycles. ARM II: Patients receive ibrutinib PO QD on days 1-28 of cycles 1-24, rituximab IV on days 1, 8, 15, and 22 of cycles 1 and 5, and venetoclax PO QD on days 1-28 of cycles 2-24. 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 2 years and then every 6 months for up to 5 years.

Official Title
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A Phase II Randomized Study of Ibrutinib and Rituximab With or Without Venetoclax in Previously Untreated Waldenström's Macroglobulinemia (WM) / Lymphoplasmacytic Lymphoma (LPL)

Conditions
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Lymphoplasmacytic Lymphoma, Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: Ibrutinib
* Biological: Rituximab
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have had a confirmed diagnosis of Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL). Participants must have measurable disease as determined by IgM protein quantification. Testing to establish baseline disease status must be performed within 28 days prior to registration Participants must have at least one of the criteria to require therapy for WM including anemia, thrombocytopenia, neuropathy related to WM, symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises, WM associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms. Constitutional symptoms can be described as unintentional weight loss >= 10% within the previous 6 months prior to screening; Fevers higher than 100.5 degrees Fahrenheit (F) or 38.0 degrees Celsius (C) for 2 or more weeks prior to screening without evidence of infection; Night sweats for more than 1 month prior to screening without evidence of infection; Clinically relevant fatigue which is not relieved by rest due to WM Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inhibitor within 7 days prior to the first dose of study drug will be excluded from the study. If such participants can be safely switched to an alternative agent, then the participants will be eligible to enroll Participants must be >= 18 years of age Participants must have history and physical exam within 28 days prior to registration Participants must have Zubrod performance status =< 2 Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min. Values must be obtained within 14 days prior to registration Total bilirubin =< 1.5 x IULN (institutional upper limit of the norm) (within 14 days prior to registration) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x IULN (within 14 days prior to registration) Alkaline phosphatase =< 3 x IULN (within 14 days prior to registration) Platelet count >= 50,000 cells/mm^3 (without transfusion or growth factor support within 14 days prior to registration) Hemoglobin >= 8.0 g/dL (without transfusion or growth factor support within 14 days prior to registration) Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (without transfusion or growth factor support within 14 days prior to registration) Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration Participants must be able to take and swallow oral medication (capsules) whole. Participants may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for two years or watchful waiting is appropriate in the opinion of the treating physician. Also, malignancy that in the opinion of the investigator, is considered cured with minimal risk of recurrence within 5 years, is permissible consideration of eligibility for this trial Participants must be offered the opportunity to participate in specimen banking Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system CROSSOVER CRITERIA: Participants must have been registered and received treatment in the IR arm, and must show progression of disease at any time during cycles 3-24 CROSSOVER CRITERIA: In case of transformation to intermediate or high-grade lymphoma or development of Bing-Neel syndrome the participants will not undergo registration step 2 crossover and will be taken off the study CROSSOVER CRITERIA: Participants must have Zubrod performance status =< 2 CROSSOVER CRITERIA: Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min. Values must be obtained within 14 days prior to registration CROSSOVER CRITERIA: Participants must have no evidence of marked hepatic dysfunction on any recent liver function tests within 14 days prior to registration CROSSOVER CRITERIA: Platelet count >= 50,000 cells/mm^3 (without transfusion or growth factor support within 14 days prior to registration) CROSSOVER CRITERIA: Hemoglobin >= 8.0 g/dL (without transfusion or growth factor support within 14 days prior to registration) CROSSOVER CRITERIA: Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (without transfusion or growth factor support within 14 days prior to registration) Exclusion Criteria: Participants must not have had prior systemic therapy. Prior therapy with rituximab will be allowed as long as the last rituximab dose was at least 12 months prior to registration Participants must not be intolerant to rituximab Participants must not have known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) 4 weeks prior to registration Participants must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). Hepatitis C virus (HCV) testing is only required if clinically indicated or if the participant has a history of HCV Participants must not consume grapefruit, Seville oranges or starfruit within 3 days prior to the first dose of venetoclax Participants must not be pregnant or nursing because venetoclax has not been studied in pregnant or nursing women and the mechanism of action is expected to cause fetal harm. A woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, effective contraception e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condom, cervical ring, sponge, etc.). This also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures throughout the study and for at least 30 days after competition of therapy

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: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (ibrutinib, rituximab)<br>Patients receive ibrutinib PO QD on days 1-28 of cycles 1-24 and rituximab IV on days 1, 8, 15, and 22 of cycles 1 and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm I may receive ibrutinib, rituximab, and venetoclax as in Arm II for up to an additional 24 cycles. | Drug: Ibrutinib<br>* Given PO<br>* Other names: PCI-32765;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Arm II (ibrutinib, rituximab, venetoclax)<br>Patients receive ibrutinib PO QD on days 1-28 of cycles 1-24, rituximab IV on days 1, 8, 15, and 22 of cycles 1 and 5, and venetoclax PO QD on days 1-28 of cycles 2-24. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Given PO<br>* Other names: PCI-32765;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate | A Cochran-Mantel-Haenszel test will be performed to compare the complete response rates in Arm 1 and Arm 2 accounting for the stratification factor of prior rituximab, and complete response rate will be reported in each study arm with a binomial confidence interval. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Will be analyzed using the Kaplan-Meier method, and a stratified log-rank test will be performed to compare survival outcomes in the ibrutinib rituximab (IR) and ibrutinib rituximab venetoclax (IRV) arms while controlling for the effects from the stratification factor of prior rituximab treatment. | From the date of registration to the date of first documentation of progressive disease or symptomatic deterioration, or death due to any cause, assessed up to 5 years | 
| Overall survival | Will be analyzed using the Kaplan-Meier method, and a stratified log-rank test will be performed to compare survival outcomes in the IR and IRV arms while controlling for the effects from the stratification factor of prior rituximab treatment. | From the date of registration to the date of death due to any cause, assessed up to 5 years | 
| Time to complete response | Will be analyzed using the cumulative incidence competing risks method. | From the date of registration to the date of complete response, assessed up to 5 years | 
| Overall response rate | Defined as the percentage of participants achieving a best response of complete response, very good partial response, or partial response while on study. Will be reported with a binomial confidence interval. | Up to 5 years | 
| Rate of very good partial response | Defined as the percentage of participants achieving a best response of complete response or very good partial response while on study. Will be reported with a binomial confidence interval. | Up to 5 years | 
| Incidence of adverse events | As assessed by Common Terminology Criteria for Adverse Events Version 5.0. | Up to 5 years |