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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Suspended
CT.gov ID
NCT04840602
Collaborator
(none)
71
74
2
22.2
1
0

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

PRIMARY OBJECTIVE:
  1. 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:
  1. To compare overall response rates (ORR) in WM participants treated upfront with IRV vs. those treated with IR.

  2. 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.

  3. To compare the rate of very good partial response (VGPR) or better in WM participants treated upfront with IRV vs. those treated with IR.

  4. To evaluate the safety of the IRV regimen as compared to IR regimen in participants with WM.

  5. To evaluate the time to CR in WM participants treated upfront with IRV and those treated with IR.

  6. To evaluate the ORR in participants who progress on treatment with IR and are crossed over to treatment with IRV.

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

BANK OBJECTIVE:
  1. 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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
71 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Randomized Study of Ibrutinib and Rituximab With or Without Venetoclax in Previously Untreated Waldenström's Macroglobulinemia (WM) / Lymphoplasmacytic Lymphoma (LPL)
Actual Study Start Date :
Jun 24, 2021
Anticipated Primary Completion Date :
Apr 30, 2023
Anticipated Study Completion Date :
Apr 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Arm I (ibrutinib, rituximab)

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
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765
  • Biological: Rituximab
    Given IV
    Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Riabni
  • Rituxan
  • Rituximab ABBS
  • Rituximab ARRX
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar JHL1101
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • Rituximab Biosimilar SIBP-02
  • rituximab biosimilar TQB2303
  • Rituximab PVVR
  • rituximab-abbs
  • Rituximab-arrx
  • Rituximab-pvvr
  • RTXM83
  • Ruxience
  • Truxima
  • Experimental: Arm II (ibrutinib, rituximab, venetoclax)

    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
    Given PO
    Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765
  • Biological: Rituximab
    Given IV
    Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Riabni
  • Rituxan
  • Rituximab ABBS
  • Rituximab ARRX
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar JHL1101
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • Rituximab Biosimilar SIBP-02
  • rituximab biosimilar TQB2303
  • Rituximab PVVR
  • rituximab-abbs
  • Rituximab-arrx
  • Rituximab-pvvr
  • RTXM83
  • Ruxience
  • Truxima
  • Drug: Venetoclax
    Given PO
    Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto
  • Outcome Measures

    Primary Outcome Measures

    1. Complete response rate [Up to 5 years]

      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.

    Secondary Outcome Measures

    1. Progression-free survival [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]

      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.

    2. Overall survival [From the date of registration to the date of death due to any cause, assessed up to 5 years]

      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.

    3. Time to complete response [From the date of registration to the date of complete response, assessed up to 5 years]

      Will be analyzed using the cumulative incidence competing risks method.

    4. Overall response rate [Up to 5 years]

      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.

    5. Rate of very good partial response [Up to 5 years]

      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.

    6. Incidence of adverse events [Up to 5 years]

      As assessed by Common Terminology Criteria for Adverse Events Version 5.0.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Centralia Oncology Clinic Centralia Illinois United States 62801
    2 Carle on Vermilion Danville Illinois United States 61832
    3 Cancer Care Specialists of Illinois - Decatur Decatur Illinois United States 62526
    4 Carle Physician Group-Effingham Effingham Illinois United States 62401
    5 Crossroads Cancer Center Effingham Illinois United States 62401
    6 Carle Physician Group-Mattoon/Charleston Mattoon Illinois United States 61938
    7 Carle Cancer Center Urbana Illinois United States 61801
    8 Mary Greeley Medical Center Ames Iowa United States 50010
    9 McFarland Clinic PC - Ames Ames Iowa United States 50010
    10 McFarland Clinic PC-Boone Boone Iowa United States 50036
    11 McFarland Clinic PC-Trinity Cancer Center Fort Dodge Iowa United States 50501
    12 McFarland Clinic PC-Jefferson Jefferson Iowa United States 50129
    13 McFarland Clinic PC-Marshalltown Marshalltown Iowa United States 50158
    14 Saint Joseph Mercy Hospital Ann Arbor Michigan United States 48106
    15 Saint Joseph Mercy Brighton Brighton Michigan United States 48114
    16 Trinity Health IHA Medical Group Hematology Oncology - Brighton Brighton Michigan United States 48114
    17 Saint Joseph Mercy Canton Canton Michigan United States 48188
    18 Trinity Health IHA Medical Group Hematology Oncology - Canton Canton Michigan United States 48188
    19 Saint Joseph Mercy Chelsea Chelsea Michigan United States 48118
    20 Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital Chelsea Michigan United States 48118
    21 Henry Ford Hospital Detroit Michigan United States 48202
    22 Genesee Cancer and Blood Disease Treatment Center Flint Michigan United States 48503
    23 Genesee Hematology Oncology PC Flint Michigan United States 48503
    24 Genesys Hurley Cancer Institute Flint Michigan United States 48503
    25 Hurley Medical Center Flint Michigan United States 48503
    26 Trinity Health Saint Mary Mercy Livonia Hospital Livonia Michigan United States 48154
    27 Ascension Saint Mary's Hospital Saginaw Michigan United States 48601
    28 Oncology Hematology Associates of Saginaw Valley PC Saginaw Michigan United States 48604
    29 Ascension Saint Joseph Hospital Tawas City Michigan United States 48764
    30 Huron Gastroenterology PC Ypsilanti Michigan United States 48106
    31 Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus Ypsilanti Michigan United States 48197
    32 Saint Francis Medical Center Cape Girardeau Missouri United States 63703
    33 Siteman Cancer Center at West County Hospital Creve Coeur Missouri United States 63141
    34 Washington University School of Medicine Saint Louis Missouri United States 63110
    35 Siteman Cancer Center-South County Saint Louis Missouri United States 63129
    36 Siteman Cancer Center at Christian Hospital Saint Louis Missouri United States 63136
    37 Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri United States 63376
    38 Memorial Sloan Kettering Basking Ridge Basking Ridge New Jersey United States 07920
    39 Memorial Sloan Kettering Monmouth Middletown New Jersey United States 07748
    40 Memorial Sloan Kettering Bergen Montvale New Jersey United States 07645
    41 Memorial Sloan Kettering Commack Commack New York United States 11725
    42 Memorial Sloan Kettering Westchester Harrison New York United States 10604
    43 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    44 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    45 University of Rochester Rochester New York United States 14642
    46 Memorial Sloan Kettering Nassau Uniondale New York United States 11553
    47 Strecker Cancer Center-Belpre Belpre Ohio United States 45714
    48 Adena Regional Medical Center Chillicothe Ohio United States 45601
    49 Mount Carmel East Hospital Columbus Ohio United States 43213
    50 Columbus Oncology and Hematology Associates Inc Columbus Ohio United States 43214
    51 Riverside Methodist Hospital Columbus Ohio United States 43214
    52 Grant Medical Center Columbus Ohio United States 43215
    53 The Mark H Zangmeister Center Columbus Ohio United States 43219
    54 Mount Carmel Health Center West Columbus Ohio United States 43222
    55 Doctors Hospital Columbus Ohio United States 43228
    56 Delaware Health Center-Grady Cancer Center Delaware Ohio United States 43015
    57 Grady Memorial Hospital Delaware Ohio United States 43015
    58 Dublin Methodist Hospital Dublin Ohio United States 43016
    59 Central Ohio Breast and Endocrine Surgery Gahanna Ohio United States 43230
    60 Mount Carmel Grove City Hospital Grove City Ohio United States 43123
    61 Fairfield Medical Center Lancaster Ohio United States 43130
    62 Saint Rita's Medical Center Lima Ohio United States 45801
    63 OhioHealth Mansfield Hospital Mansfield Ohio United States 44903
    64 Marietta Memorial Hospital Marietta Ohio United States 45750
    65 OhioHealth Marion General Hospital Marion Ohio United States 43302
    66 Knox Community Hospital Mount Vernon Ohio United States 43050
    67 Licking Memorial Hospital Newark Ohio United States 43055
    68 Newark Radiation Oncology Newark Ohio United States 43055
    69 Mercy Health Perrysburg Cancer Center Perrysburg Ohio United States 43551
    70 Southern Ohio Medical Center Portsmouth Ohio United States 45662
    71 Saint Vincent Mercy Medical Center Toledo Ohio United States 43608
    72 Mercy Health - Saint Anne Hospital Toledo Ohio United States 43623
    73 Saint Ann's Hospital Westerville Ohio United States 43081
    74 Genesis Healthcare System Cancer Care Center Zanesville Ohio United States 43701

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Sikander Ailawadhi, Southwest Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT04840602
    Other Study ID Numbers:
    • NCI-2021-02851
    • NCI-2021-02851
    • S2005
    • S2005
    • U10CA180888
    First Posted:
    Apr 12, 2021
    Last Update Posted:
    Jul 28, 2022
    Last Verified:
    Apr 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 28, 2022