Testing the Combination of Venetoclax and Rituximab, in Comparison to the Usual Treatment (Ibrutinib and Rituximab) for Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma

Waldenstrom Macroglobulinemia Clinical Trial

Official title:

A Phase II Randomized Study Comparing Ibrutinib and Rituximab vs. Venetoclax and Rituximab in Previously Untreated Waldenström's Macroglobulinemia (WM) / Lymphoplasmacytic Lymphoma (LPL)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04840602
• Other study ID #: NCI-2021-02851
• Secondary ID: NCI-2021-02851S2
• Status: Recruiting
• Phase: Phase 2
• Start date: January 5, 2022
• Est. completion date: March 31, 2028

Study information

• Verified date: June 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies the effects of venetoclax and rituximab in comparison to ibrutinib and rituximab 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 and rituximab may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib and rituximab alone.

Description:

PRIMARY OBJECTIVE:

I. To compare the rate of very good partial response or better (VGPR or better) in previously untreated participants with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) who are treated upfront with ibrutinib plus rituximab (IR) versus (vs.) venetoclax plus rituximab (VR) regimen.

SECONDARY OBJECTIVES:

I. To compare overall response rates (ORR) in WM participants treated upfront with IR vs. those treated with VR.

II. To compare progression-free survival (PFS), time to next treatment, duration of response in WM participants treated upfront with IR vs. those treated with VR.

III. To compare the rate of complete response (CR) in WM participants treated upfront with IR vs. those treated with VR.

IV. To evaluate the safety of the IR regimen as compared to VR regimen in participants with WM.

V. To evaluate the time to VGPR in WM participants treated upfront with IR and those treated with VR.

VI. To evaluate the ORR in participants who progress on treatment with IR and VR and are crossed over to the other respective arm.

VII. To compare overall survival (OS) in WM participants treated upfront with IR vs. those treated with VR.

BANKING 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 rituximab and venetoclax as in Arm II for up to an additional 24 cycles. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT and bone marrow biopsy and aspiration as well as blood sample collection during screening and on the trial.

ARM II: Patients receive venetoclax PO QD on days 1-28 of each cycle 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 II may receive ibrutinib and rituximab as in Arm I for up to an additional 24 cycles. Patients undergo CT or PET/CT and bone marrow biopsy and aspiration as well as blood sample collection during screening and on the trial.

After completion of study treatment, patients removed from protocol prior to progression are followed every 3 months until progression, death or 5 years after initial registration, whichever occurs first. Patients followed after progression of disease are followed every 6 months until death or 5 years after initial registration.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 92
• Est. completion date: March 31, 2028
• Est. primary completion date: March 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

• IgM Spike: = 500 mg/dL (= 5 g/L)

• Extramedullary disease: The manifestation of a lymphoid mass outside of the bone marrow, resulting in enlargement in extramedullary organs such as the lymph nodes or spleen. Note: all participants must have measurable IgM spike, but are not required to have extramedullary disease

• 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 not have had prior systemic therapy. Prior therapy with rituximab will be allowed as long as the last rituximab dose was at least 6 months prior to registration

• 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)

• 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

• 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 or VR 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)

Related Conditions & MeSH terms

• Lymphoma
• Lymphoplasmacytic Lymphoma
• Waldenstrom Macroglobulinemia

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Bone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
• Bone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
• Computed Tomography
Undergo CT or PET/CT

Drug:
• Ibrutinib
Given PO

Procedure:
• Positron Emission Tomography
Undergo PET/CT

Biological:
• Rituximab
Given IV

Drug:
• Venetoclax
Given PO

Locations

Country	Name	City	State
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel East Hospital	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Dublin Methodist Hospital	Dublin	Ohio
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Central Ohio Breast and Endocrine Surgery	Gahanna	Ohio
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Mount Carmel Grove City Hospital	Grove City	Ohio
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Fairfield Medical Center	Lancaster	Ohio
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Saint Rita's Medical Center	Lima	Ohio
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	OhioHealth Mansfield Hospital	Mansfield	Ohio
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	OhioHealth Marion General Hospital	Marion	Ohio
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Licking Memorial Hospital	Newark	Ohio
United States	Newark Radiation Oncology	Newark	Ohio
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Mercy Health Perrysburg Cancer Center	Perrysburg	Ohio
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Mercy Health - Saint Anne Hospital	Toledo	Ohio
United States	Mercy Health - Saint Vincent Hospital	Toledo	Ohio
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Very good partial response or better (VGPR or better) rate	A Cochran-Mantel-Haenszel test will be performed to compare the VGPR or better rates in Arm 1 and Arm 2 accounting for the stratification factor of prior rituximab, and VGPR or better rate will be reported in each study arm with a binomial confidence interval.	Up to 5 years
Secondary	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 venetoclax rituximab (VR) 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
Secondary	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 VR 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
Secondary	Rate of 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
Secondary	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
Secondary	Time to VGPR or better	Defined as the percentage of participants achieving a best response of very good partial response or better while on study. Will be reported with a binomial confidence interval.	Up to 5 years
Secondary	Incidence of adverse events	As assessed by Common Terminology Criteria for Adverse Events Version 5.0.	Up to 5 years