Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (VIPOR) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System

Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (VIPOR) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System

Background:

People with primary diffuse large B-cell lymphoma of the central nervous system (CNS) and aggressive B-cell lymphomas with secondary CNS involvement have a poor prognosis. Researchers want to learn if a combination of drugs can help.

Objective:

To learn if it is safe to give people with these cancers Nivolumab (VIPOR-Nivo).

Eligibility:

People aged 18 and older with B-cell lymphoma in the CNS that does not respond to treatment, response to treatment does not last long, or there is no standard treatment.

Design:

Participants will be screened with:

Health history

Physical exam

Blood, urine, and heart tests

Computed tomography (CT), fludeoxyglucose F18 (FDG) positron emission tomography (PET), and magnetic resonance imaging (MRI) scans. Participants will lie in scanners that take pictures of the body. For some scans, a contrast or chemical agent will be injected into a vein.

Lumbar puncture or Ommaya tap. Participants will have a small needle inserted into their lower back or scalp to obtain fluid.

Possible tumor biopsy. Participants will have a needle inserted into a tumor to take a sample.

Participants will get the study drugs in 21-day cycles. They may have up to 6 treatment cycles. They will take some drugs by infusion into a vein and some drugs by mouth.

Participants will get counseling at least every 28 days on the risks of lenalidomide.

Participants will have visits throughout the study. Visits may include repeats of the screening tests. They may also include:

Bone marrow biopsy. Participants will have a needle inserted into their hipbone to remove marrow.

Saliva samples and cheek swabs

Participants will have periodic follow-up visits for about 10 years.

Study Overview

• Status: Active, not recruiting
• Conditions: Primary Diffuse Large B-cell Lymphoma of the Central Nervous System (CNS); Aggressive B-cell Lymphoma With Secondary Involvement of the CNS
• Intervention / Treatment: Drug: Obinutuzumab; Drug: Prednisone; Drug: Lenalidomide; Drug: Venetoclax; Drug: Ibrutinib; Drug: Acetaminophen; Drug: Diphenhydramine; Other: Peg-filgrastim; Diagnostic test: CT Scan (chest, abdomen, and pelvis); Diagnostic test: MRI; Diagnostic test: 18f-FDG-PET; Diagnostic test: PET; Diagnostic test: Lumbar puncture/Ommaya tap; Diagnostic test: Bone marrow aspiration/biopsy; Combination product: EKG

Detailed Description

Background:

• Primary diffuse large B-cell lymphoma of the central nervous system (CNS) primary central nervous system lymphoma (PCNSL) and aggressive B-cell lymphomas with secondary CNS involvement (SCNSL) have a poor prognosis
• Most CNS lymphomas (CNSL) exhibit molecular biology features of activated B cell diffuse large B-cell lymphoma (ABC DLBCL)
• We developed VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide [Revlimid (Registered Trademark)]) treatment in systemic lymphomas as a platform most effective for ABC DLBCL
• All agents in the VIPOR combination achieve meaningful CNS penetration and clinical activity for lymphomas involving the CNS

Objective:

-To determine the safety and tolerability of VIPOR in participants with PCNSL and SCNSL

Eligibility:

• Primary diffuse large B-cell lymphoma of the CNS (PCNSL) or non-germinal center B-cell (non-GCB) diffuse large B-cell lymphoma with secondary involvement of the CNS (SCNSL)
• Relapsed/refractory after prior therapy or ineligible for standard frontline therapy
• Age >= 18 years
• No pregnant women
• Adequate organ function

Study Design:

• A safety study of 10 evaluable participants with PCNSL or SCNSL treated with VIPOR (the original study protocol enrolled 4 participants to Cohort 1, Arm 1 consisting of VIPOR plus nivolumab which is now closed).
• Participants will receive VIPOR in 21-day cycles for a maximum of 6 cycles to collect data on safety and efficacy.
• Accrual ceiling will be set at 16 participants to allow for a few inevaluable participants or screen failures.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Participants must have histologically or cytologically confirmed primary diffuse large B-cell lymphoma of the central nervous system (CNS) primary central nervous system lymphoma (PCNSL) or non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma with secondary involvement of the CNS (SCNSL). NOTE: Participants with B-cell lymphomas that were previously indolent but now involve the CNS (i.e., transformed from previous follicular lymphoma, chronic lymphocytic leukemia, marginal zone lymphoma, and mantle cell lymphoma) are eligible.

• Participants must have a disease that is relapsed or refractory after initial systemic treatment or be considered ineligible for standard frontline therapy with high-dose methotrexate due to one of the following criteria:

  • Age>= 70 years
  • Estimated glomerular filtration rate < 60 ml/min/1.73m^2
  • Presence of ascites or pleural effusion
• Participants must have evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.) and/or imaging (measurable lymph nodes or masses on computed tomography (CT) or magnetic resonance imaging (MRI) and/or evaluable fluorodeoxyglucose (FDG)-avid lesions on positron emission tomography (PET).
• Participants with second malignancies not requiring active systemic therapy or premalignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonal gammopathy of undetermined significance (MGUS) are eligible.
• Participants that are positive for hepatitis B core antibody (HBcAb), hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative hepatitis B and/or C viral load by polymerase chain reaction (PCR).
• Age >=18 years
• Eastern Cooperative Oncology Group (ECOG) performance status <=2. NOTE: In participants with neurologic deficits caused by CNS lymphoma any ECOG status is acceptable to be eligible.

• Participants must have adequate organ and marrow function as defined below:

  • absolute neutrophil count >= 1000 cells/mcL (1 X 10^9/L)
  • platelet count >= 50,000 cells/mcL (50 X 10^9/L)
  • hemoglobin > 8.0 g/dL (transfusions permitted)
  • total bilirubin <= 1.5 X upper limit of normal (ULN) (unless Gilbert's syndrome or disease infiltration of the liver is present)
  • Aspartate Aminotransferase or serum glutamic oxaloacetic transaminase/ Alanine Aminotransferase or serum glutamic pyruvic transaminase AST(SGOT)/ALT(SGPT) <= 3.0 X institutional ULN for those without lymphoma involvement OR <= 5.0 X institutional ULN for those with lymphoma involvement
  • Serum Creatinine OR creatinine clearance (Cr Cl) <= 1.5 mg/dL OR > 40 ml/min/1.73m^2

NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine clearance or estimated glomerular filtration rate (eGRF) in the clinical lab

Laboratory assessments to determine eligibility may be performed at Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) certified laboratories outside the National Institutes of Health (NIH) and results forwarded to the study team for review and management. Given that the methodologies utilized are similar across all laboratories, no significant variability is expected and there is no anticipation that study data will be affected. However, as different laboratories use slightly different kinds of equipment, each laboratory must determine/validate its own reference ranges. Therefore, on this protocol, normal ranges from each lab will be used in reference to terms such as upper limit of normal (ULN), except in cases where absolute values are appropriate and are specified as such

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be < 1.5 x the ULN; except if, the aPTT is prolonged because of a positive Lupus Anticoagulant.

• Male and female participants must agree to use certain methods of birth control. A highly effective method of birth control for female participants is defined as a method that has a low failure rate (i.e., less than 1% per year) when used consistently and correctly and includes implants, injectables, birth control pills with two hormones, some intrauterine devices (IUDs). Male participant cannot use highly effective methods and are required to use barrier. The specific guidelines are as follows:

  • Women: Females of childbearing potential (FOCBP), defined as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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), must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking Revlimid (R), as well as for the duration after the last dose of study drug as listed below.
  • Men: Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures to prevent pregnancy of their partner and should also agree to not donate sperm while taking the study treatment and for the durations as listed below.
• Contraception Requirements
• Time frame/Study Drug/Women/Men
• Pre-Treatment/During Treatment: Time frame prior to/during dosing:
• All drugs: Begins 28 days prior to treatment/Begins on day 1
• Post-Treatment: Time frame after the last dose:
• Venetoclax: 90 days/90 days
• Ibrutinib: 3 months/3 months
• Obinutuzumab: 18 months/6 months
• Revlimid (R): 28 days/28 days
• All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS)(TM) program and be willing and able to comply with the requirements of Revlimid REMS(TM).
• Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through designated time points after study drugs discontinuation (as required for women contraception in the table above)

EXCLUSION CRITERIA:

• Participants with plasmablastic lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma are not eligible.
• Chemotherapy (excluding corticosteroids), radiation therapy, and/or monoclonal antibody <=7 days prior to first administration of study treatment. Rationale for a short 7-day window is that participants with relapsed CNS lymphomas often have existing neurologic conditions that mandate urgent therapy.
• Previous treatment with more than one of the following classes of medications: (1) Bruton's tyrosine kinase (BTK) inhibitors, (2) B-cell lymphoma 2 (Bcl-2) inhibitors, (3) immunomodulatory imide drugs (IMIDs) (including lenalidomide and pomalidomide).

• Participants who require continuous treatment with a strong cytochrome P450 family 3, subfamily A (CYP3A) inhibitor/inducer (i.e., with the exception of any medication to be specifically studied in this protocol).

  --NOTE: A comprehensive list of inhibitors, inducers, and substrates may be found at: https://drug-interactions.medicine.iu.edu/MainTable.aspx

• Human immunodeficiency virus (HIV)-positive participants
• Pregnant women- a pregnancy test (urine or serum) with a sensitivity of 25 mIU/mL must be done at screening.
• Participants with second malignancies requiring active systemic therapy are excluded.
• Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification
• History of any ventricular arrhythmia
• Unable to swallow capsules, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
• Uncontrolled ongoing or active infection
• Concomitant use of warfarin or other vitamin K antagonists
• Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.
• Currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the National Cancer Institute (NCI)/Child Pugh classification)
• Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide); VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles

Drug: Obinutuzumab; Obinutuzumab 1000 mg IV (intravenous) days 1 and 2 for a maximum of 6 cycles every 21 days (each cycle is 21 days); Other Names: Gazyva; Drug: Prednisone; Prednisone 100 mg PO (by mouth) daily days 1-7 for a maximum of 6 cycles every 21 days (each cycle is 21 days); Other Names: Deltasone; Prednisone Intensol; Rayos; Drug: Lenalidomide; Lenalidomide 10 or 15 mg PO (by mouth) on days 1-14 for 1 cycle (21 days); followed by Lenalidomide 10 or 15 mg PO daily days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days); Other Names: REVLIMID; Drug: Venetoclax; Venetoclax 800 mg PO (by mouth) on days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days); Other Names: Venclexta; Venclyxto; Drug: Ibrutinib; Ibrutinib 560 mg PO (by mouth) daily days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days); Other Names: Imbruvica; Drug: Acetaminophen; 650 mg by mouth (PO) daily on days 1 and 2 approximately 30-60 minutes prior to Obinutuzumab infusion.; Other Names: Tylenol; Ofirmev; FeverAll; Drug: Diphenhydramine; 50mg by mouth (PO) daily on days 1 and 2 approximately 30-60 minutes prior to Obinutuzumab infusion.; Other Names: Benadryl; Banophen; Nytol; Other: Peg-filgrastim; 6 mg subcutaneous once on day 8 only.; Other Names: Neulasta; Diagnostic test: CT Scan (chest, abdomen, and pelvis); To assess sites of disease.; Other Names: Computed tomography scan; Diagnostic test: MRI; If clinically indicated.; Other Names: Magnetic resonance imaging; Diagnostic test: 18f-FDG-PET; If clinically indicated.; Other Names: F18-fluorodeoxyglucose-positron emission tomography; Diagnostic test: PET; If clinically indicated.; Diagnostic test: Lumbar puncture/Ommaya tap; If clinically indicated.; Diagnostic test: Bone marrow aspiration/biopsy; If clinically indicated.; Combination product: EKG; To determine eligibility.; Other Names: Electrocardiogram

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Who Completed at Least 2 Cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Therapy Without Stopping Due to Toxicity	The proportion of participants who complete at least 2 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) therapy without stopping due to toxicity will be determined and reported along with a 95% confidence interval. Success is defined as completing at least 2 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) therapy without the need to discontinue treatment due to toxicity (i.e., serious adverse event). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	After 2 Cycles (each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR)	Complete response is disappearance of all detectable evidence of disease and disease-related symptoms measured by the Lugano criteria. The complete response rate of up to 6 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be reported along with a 95% confidence interval.	After cycles 3 and 6
Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	The overall response rate of up to 6 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be reported along with a 95% confidence interval. Complete response (CR) + Partial response (PR) was measured by the Lugano criteria. Complete response is disappearance of all detectable evidence of disease and disease-related symptoms. Partial response is a ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses.	After cycles 3 and 6
Overall Survival (OS)	Overall survival (OS) is defined as the duration of time from the date of study enrollment until time of death from any cause, or 10 years post-treatment whichever occurs first. Overall survival (OS) after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be determined using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval.	Up to 2.6 years
Progression Free Survival (PFS)	Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, death, or 10 years post-treatment, whichever occurs first. The progression-free survival (PFS) after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be estimated using progression or death without progression as events, using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval. Progression was measured by the Lugano criteria and is appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size.	Up to 2.6 years
Duration of Response (DOR)	The duration of response after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be determined starting at the date a response is identified and will be estimated using a Kaplan-Meier curve along with a median DOR, and its associated 95% confidence interval. The duration of response (DOR) is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, death, or, in the absence of progressive disease (PD), date of last assessment. CR is disappearance of all detectable evidence of disease and disease-related symptoms. PR is a ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progression is appearance of any new nodal lesion.	From date of first response until the date of recurrent or progressive disease is objectively documented, up to a max 2.6 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Adverse events were monitored/assessed from the date of first dose of any study drug, through 30 days after the last dose of any study drug after the last dose of any study drug. Participants were followed for a maximum duration of 2.6 years.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rahul Lakhotia, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2022
• Primary Completion (Actual): June 1, 2024
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: January 26, 2022
• First Submitted That Met QC Criteria: January 26, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Estimated): January 8, 2026
• Last Update Submitted That Met QC Criteria: December 23, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: CNS; PCNSL; SCNSL; Systemic Lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Polycyclic Compounds; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Piperidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Benzene Derivatives; Diagnostic Techniques, Surgical; Tomography; Diagnostic Imaging; Pregnadienediols; Ethylamines; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Isoindoles; Diagnostic Techniques, Neurological; Radiography; Image Interpretation, Computer-Assisted; Radiographic Image Enhancement; Image Enhancement; Photography; Tomography, X-Ray; Benzhydryl Compounds; Lenalidomide; Acetaminophen; Prednisone; Diphenhydramine; Biopsy; Magnetic Resonance Imaging; venetoclax; obinutuzumab; Spinal Puncture; ibrutinib; pegfilgrastim; Tomography, X-Ray Computed
• Other Study ID Numbers: 10000516; 000516-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD recorded in the medical record will be shared with intramural investigators upon request. All large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No