Testing the Effectiveness of a Combination Targeted Therapy (ViPOR) for Patients With Relapsed and/or Refractory Aggressive B-cell Lymphoma

Phase 2

Not yet recruiting

• Conditions: High Grade B-Cell Lymphoma With MYC and BCL6 Rearrangements; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type; Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements; Recurrent High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements; Recurrent High Grade B-Cell Lymphoma, Not Otherwise Specified; Recurrent T-Cell/Histiocyte-Rich Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type
• Interventions: Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Drug: Ibrutinib; Drug: Lenalidomide; Procedure: Magnetic Resonance Imaging; Biological: Obinutuzumab; Procedure: Positron Emission Tomography; Drug: Prednisone; Drug: Venetoclax

• Registration Number: NCT06649812
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II trial tests how well venetoclax, ibrutinib, prednisone, obinutuzumab, and Revlimid® (ViPOR) works in treating patients with CD10 negative diffuse large B-cell lymphoma (DLBCL) and high-grade lymphoma with MYC and BCL2 rearrangements that has come back after a period of improvement (relapsed) and/or that has not responded to previous treatment (...

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the complete response (CR) rate of ViPOR in relapsed/refractory (R/R):

Ia. CD10-negative DLBCL; and Ib. CD10-positive or negative high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 (with or without BCL6) translocations (HGBCL-double hit \[DH\]-BCL2).

SECONDARY OBJECTIVES:
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Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Status Verified: 2024-10
• Study First Submitted: 2024-10-18
• Study First Submitted QC: 2024-10-18
• Last Update Submitted: 2024-10-18
• Study First Posted: 2024-10-21
• Last Update Posted: 2024-10-21
• Study Start: 2025-01-17
• Primary Completion: 2027-09-01
• Study Completion: 2027-09-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

• Patient must be ≥ 18 years of age

• Patient must have histologically or cytologically confirmed aggressive B-cell lymphoma as follows:

  • CD10-negative DLBCL, which includes:

    • CD10-negative non-GCB DLBCL, not otherwise specified (NOS) (i.e., CD10-/BCL6- or CD10-/BCL6+/MUM1+ DLBCL)
    • CD10-negative GCB DLBCL, NOS (i.e., CD10-/BCL6+/MUM1- DLBCL)
    • CD10-negative HGBCL with MYC and BCL6 (without BCL2) translocations (HGBCL-DH-BCL6)
    • CD10-negative HGBCL, NOS (without MYC and BCL2 translocations)
    • CD10-negative T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) OR

  • CD10-positive or negative HGBCL with MYC and BCL2 rearrangements (with or without BCL6 rearrangement) (HGBCL-DH-BCL2)

  • NOTE: The site principal investigator must review and verify the pathology report findings to ensure the patient is eligible and is assigned to the respective cohort at the time of registration

• Patient must have relapsed and/or refractory disease after at least 1 prior anthracycline and anti-CD20 antibody-containing regimen

• Patient must not have confirmed or suspected primary mediastinal large B-cell lymphoma (PMBL)

• Patient must not be pregnant due to the potential harm to an unborn fetus with the treatment regimens being used.

  • All patients of childbearing potential must have a serum or urine study with a sensitivity of at least 25 mIU/mL within 14 days prior to registration to rule out pregnancy and again within 24 hours prior to starting cycle 1 day 1 of treatment.
  • A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Patients of childbearing potential must not expect to conceive children by abstaining from sexual intercourse or by using accepted and effective methods of contraception throughout the entire duration of protocol treatment, including during dose interruptions, and for 6 months after the last dose of protocol treatment. Male patients must not father children by abstaining from sexual intercourse or by using a condom during sexual contact with pregnant partners or partners of childbearing potential throughout the entire duration of protocol treatment, including dose interruptions, and for 6 months after the last dose of protocol treatment even if they have had a successful vasectomy

• Male patients must agree to not donate semen or sperm during the entire duration of protocol treatment or for at least 28 days after the last dose of lenalidomide even if they have had a successful vasectomy

• Patient must agree to abstain from breastfeeding during the entire duration of protocol treatment and for at least 6 months after the last dose of protocol treatment

• Patient must agree to abstain from donating blood during the entire duration of protocol treatment and for at least 28 days after the last dose of lenalidomide

• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

• Absolute neutrophil count (ANC) ≥ 1,000/mcL without requirement for granulocyte colony stimulating factor (G-CSF) support (obtained ≤ 7 days prior to registration)

• Hemoglobin ≥ 8 g/dL (obtained ≤ 7 days prior to registration)

• Platelets ≥ 75,000/mcL without requirement for platelet transfusion support (obtained ≤ 7 days prior to registration)

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (or ≤ 3.0 x institutional ULN for patients with documented Gilberts syndrome) (obtained ≤ 7 days prior to registration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 x institutional ULN (obtained ≤ 7 days prior to registration)

• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m^2 (estimated by Cockcroft-Gault method or measured) (obtained ≤ 7 days prior to registration)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patient must not have active central nervous system (CNS) lymphoma requiring treatment

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patient must not have taken or require warfarin or other strong CYP3A inhibitors or inducers within 7 days prior to registration.

  • NOTE: Antiplatelet agents, other anticoagulants aside from warfarin, as well as mild or moderate CYP3A inhibitors or inducers are permitted on study but should be used with caution

• Patient must not have an uncontrolled intercurrent illness that would interfere with the safety or efficacy assessment of this protocol

• Patient must not have evidence of an active infection at the time of registration

• Patient must not have the following current or prior anti-cancer treatment:

  • Any chemotherapy, targeted therapy, or anti-cancer antibodies received within 2 weeks prior to registration

    • NOTE: Short courses of corticosteroids or palliative external beam radiation therapy (XRT) prior to registration are permitted

  • More than 3 prior lines of cytotoxic chemotherapy, excluding targeted therapy, anti-cancer antibodies, antibody-drug conjugates, and bi-specific antibodies

    • NOTE: Cytoreductive chemotherapy followed by autologous stem cell transplant (ASCT) counts as 1 line of cytotoxic therapy. Similarly, cytoreductive chemotherapy (either pre-T-cell collection or as bridging therapy) followed by pre-conditioning therapy/chimeric antigen receptor T-cell (CAR-T) counts as 1 line of therapy, as long as no disease progression occurs between interventions. For both therapies, if progressive disease is documented between 2 distinct regimens, then they should be counted as 2 lines of cytotoxic chemotherapy

  • Radio- or toxin-immunoconjugates within 10 weeks prior to registration

  • Previous treatment with more than one of the following study agents: venetoclax, ibrutinib, or lenalidomide

  • Prior autologous stem cell transplant (ASCT), chimeric antigen receptor T-cell (CAR-T) therapy, or allogeneic stem cell (or other organ) transplant within 3 months prior to registration

  • Any evidence of active graft-versus-host disease or requirement for immunosuppressants within 28 days prior to registration

    • NOTE: In addition, patient must have recovered (i.e., ≤ grade 1 or baseline) from all adverse events due to previously administered anti-cancer treatment, surgery, or procedure
    • NOTE: Exceptions to this include events not considered to place the patient at unacceptable risk of participation in the opinion of the treating investigator (i.e., alopecia)

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• Patient must have adequate formalin fixed paraffin embedded (FFPE) tumor tissue specimen from the initial diagnostic biopsy or on-study repeat tumor tissue biopsy for molecular analysis

  • NOTE: Excisional tumor biopsy is preferred. Core needle biopsies will be considered adequate if there is enough tissue for the mandatory molecular analysis. Submission of an entire FFPE tumor block is preferred, but if unavailable 10 x 10um FFPE scrolls may be submitted as an alternative. If adequate archived FFPE tumor tissue is unavailable, the patient must be willing to undergo research biopsy for molecular analysis

• Patient must have measurable disease

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ViPOR)	Biopsy	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Bone Marrow Aspiration	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Biospecimen Collection	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Bone Marrow Biopsy	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Computed Tomography	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Ibrutinib	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Lenalidomide	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Magnetic Resonance Imaging	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Obinutuzumab	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Positron Emission Tomography	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Prednisone	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.
Treatment (ViPOR)	Venetoclax	Patients receive venetoclax PO QD on days 2-14, ibrutinib PO QD on days 1-14, prednisone PO QD on days 1-7, obinutuzumab IV on days 1 and 2, and Revlimid PO QD on days 1-14 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, PET, CT and/or MRI and optional tumor biopsy and bone marrow aspiration and biopsy throughout the study.

Primary Outcome Measures

Name	Time	Method
Complete response (CR) rate	Up to 5 years	Will be assessed using the Lugano Classification and will be defined as the complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.

Secondary Outcome Measures

Name	Time	Method
CR rate	Up to 5 years	Estimates will be presented with 90% confidence intervals. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Logistic/linear regression will be performed for binary/continuous endpoints variables.
Overall response rate	Up to 5 years	Estimates will be presented with 90% confidence intervals. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Logistic/linear regression will be performed for binary/continuous endpoints variables.
Duration of response (DOR)	From the documented beginning of response to the time of relapse up to 10 years	Estimates will be presented with 90% confidence intervals. Kaplan-Meier method will be used to visualize DOR. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Logistic/linear regression will be performed for binary/continuous endpoints variables.
Event-free survival (EFS)	From study entry to any treatment failure including discontinuation of treatment for any reason, such as disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death up to 10 years	Estimates will be presented with 90% confidence intervals. Kaplan-Meier method will be used to visualize EFS. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Multivariable analysis will be performed with Cox PH model and logistic/linear regression will be perfo...
Time to progression (TTP)	From study entry until lymphoma progression or death due to lymphoma up to 10 years	Estimates will be presented with 90% confidence intervals. Kaplan-Meier method will be used to visualize TTP. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Multivariable analysis will be performed with Cox PH model and logistic/linear regression will be perfo...
Progression-free survival (PFS)	From entry onto study until lymphoma progression or death from any cause up to 10 years	Estimates will be presented with 90% confidence intervals. Kaplan-Meier method will be used to visualize PFS. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Logistic/linear regression will be performed for binary/continuous endpoints variables.
Overall survival (OS)	From date of study entry to date of death up to 10 years	Estimates will be presented with 90% confidence intervals. Kaplan-Meier method will be used to visualize OS. Frequency and proportion will be used to describe variables on the nominal/ordinal scale, and measures of dispersion for interval/ratio variables. Logistic/linear regression will be performed for binary/continuous endpoints variables.
Incidence of adverse events	Up to 30 days after last dose of study treatment	Toxicity data will be pooled for tabulation and analysis.