Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (VIPOR) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System
Phase: PHASE1
Conditions: Primary Diffuse Large B-cell Lymphoma of the Central Nervous System (CNS), Aggressive B-cell Lymphoma With Secondary Involvement of the CNS
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: VIPOR in CNSL 
Version Date: 12/01/2025 
 
 
 
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Abbreviated Title: VIPOR in CNSL 
NIH Protocol #: 000516 
Version Date: 12/01/2025 
NCT Number: NCT05211336 
 
Title: Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid 
(VIPOR) for Diffuse Large B-cell lymphoma involving the Central Nervous System 
 
 
        NCI Principal Investigator:    Rahul Lakhotia, M.B.B.S. 
Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
Building 10, Room 4N115 
National Institutes of Health (NIH) 
Bethesda, MD 20892 
 
Email:  rahul.lakhotia@nih.gov  
 
 
 
Drug Name: 
Venetoclax 
(Venclexta) 
Obinutuzumab 
(Gazyva) 
Lenalidomide 
(Revlimid) 
Ibrutinib 
(Imbruvica) Prednisone 
IND Number: 134937 
Sponsor: 
CCR 
 
Manufacturer: 
 
AbbVie, Inc. 
 
Genentech, Inc. Celgene Corporation/ 
Bristol Myers Squibb AbbVie, Inc. 
Generic 
Supplier: 
CC Pharmacy 

Abbreviated Title: VIPOR in CNSL 
Version Date: 12/01/2025 
 
 
 
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PRÉCIS 
Background: 
• Primary diffuse large B-cell lymphoma of the CNS (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]) 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 individuals 
• 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. 

Abbreviated Title: VIPOR in CNSL 
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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
1 
INTRODUCTION .................................................................................................................. 7 
1.1 
Study Objectives ........................................................................................................... 7 
1.2 
BACKGROUND AND RATIONALE ........................................................................ 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 13 
2.1 
Eligibility Criteria ....................................................................................................... 13 
2.2 
Screening Evaluation .................................................................................................. 17 
2.3 
Participant Registration and Status Update Procedures ............................................. 19 
2.4 
Baseline Evaluation .................................................................................................... 20 
3 
STUDY IMPLEMENTATION ............................................................................................ 20 
3.1 
Study Design............................................................................................................... 20 
3.2 
Drug Administration ................................................................................................... 21 
3.3 
Dose Modifications and Dose Delays ........................................................................ 22 
3.4 
On Study Assessments/Evaluations............................................................................ 27 
3.5 
Post-Treatment Evaluations ........................................................................................ 30 
3.6 
Study Calendar ........................................................................................................... 31 
3.7 
Cost and Compensation .............................................................................................. 32 
3.8 
Criteria for Removal from Protocol Therapy and Off-Study Criteria ........................ 32 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 33 
4.1 
Permitted Concomitant Medications .......................................................................... 33 
4.2 
Medications to be used with Caution ......................................................................... 35 
4.3 
Prohibited Concomitant Medications ......................................................................... 37 
5 
CORRELATIVE STUDIES FOR RESEACH ..................................................................... 38 
5.1 
Biospecimen Collection .............................................................................................. 38 
5.2 
Sample Collection and Processing ............................................................................. 39 
5.3 
Sample Storage, Tracking and Disposition ................................................................ 41 
5.4 
Samples for Genetic/Genomic Analysis ..................................................................... 43 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 44 
6.1 
Data Collection ........................................................................................................... 44 

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6.2 
Data Sharing Plans...................................................................................................... 45 
6.3 
Response Criteria ........................................................................................................ 46 
6.4 
Toxicity Criteria ......................................................................................................... 49 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 49 
7.1 
Definitions .................................................................................................................. 49 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ................................... 50 
7.3 
NCI Clinical Director Reporting ................................................................................ 50 
7.4 
NIH Required Data and Safety Monitoring Plan........................................................ 50 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 50 
8.1 
Definitions .................................................................................................................. 50 
8.2 
Assessment of Safety Events ...................................................................................... 52 
8.3 
Reporting of Serious Adverse Events ......................................................................... 53 
8.4 
Waiver of expedited reporting to CCR ....................................................................... 53 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ................................. 53 
8.6 
Reporting Pregnancy .................................................................................................. 53 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .............. 54 
8.8 
Sponsor Protocol Deviation Reporting ....................................................................... 54 
9 
CLINICAL MONITORING ................................................................................................. 54 
10 STATISTICAL CONSIDERATIONS.................................................................................. 55 
10.1 
Objectives and Endpoints ........................................................................................... 55 
10.2 
Sample Size Determination ........................................................................................ 57 
10.3 
Populations for Analyses ............................................................................................ 57 
10.4 
Statistical Analyses ..................................................................................................... 57 
11 COLLABORATIVE AGREEMENTS ................................................................................. 59 
12 HUMAN PARTICIPANTS PROTECTIONS ...................................................................... 59 
12.1 
Rationale For Participant Selection ............................................................................ 59 
12.2 
Participation of Children ............................................................................................ 59 
12.3 
Participation of Participants Unable to Give Consent ................................................ 59 
12.4 
Risk/Benefit Assessment ............................................................................................ 60 
12.5 
Consent Process and Documentation ......................................................................... 62 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 63 
13.1 
Study Discontinuation And Closure ........................................................................... 63 

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13.2 
Quality Assurance And Quality Control .................................................................... 63 
13.3 
Conflict of Interest Policy........................................................................................... 64 
13.4 
Confidentiality and Privacy ........................................................................................ 64 
14 PHARMACEUTICAL INFORMATION ............................................................................. 65 
14.1 
Venetoclax .................................................................................................................. 65 
14.2 
Ibrutinib ...................................................................................................................... 65 
14.3 
Prednisone .................................................................................................................. 66 
14.4 
Obinutuzumab ............................................................................................................ 66 
14.5 
Lenalidomide .............................................................................................................. 67 
15 REFERENCES ..................................................................................................................... 69 
16 LIST OF ABBREVIATIONS ............................................................................................... 72 
17 APPENDICES ...................................................................................................................... 75 
17.1 
Appendix A: Performance Status Criteria .................................................................. 75 
17.2 
Appendix B: Child-Pugh Score .................................................................................. 76 
17.3 
Appendix C: Risk of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods for Lenalidomide ................................................................................. 77 
17.4 
Appendix D: Study Calendar ...................................................................................... 80 
 
 
 

Abbreviated Title: VIPOR in CNSL 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

Abbreviated Title: VIPOR in CNSL 
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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES  
1.1.1 Primary Objective 
• 
To determine the safety and tolerability of VIPOR in primary DLBCL of the CNS 
(PCNSL) and secondary CNS lymphoma (SCNSL) 
1.1.2 Secondary Objectives 
• To determine the overall response rate (CR + PR) of up to 6 cycles of VIPOR in CNSL 
• To determine the complete response (CR) rate of up to 6 cycles of VIPOR in CNSL 
• To determine the duration of response (DOR) after VIPOR in CNSL 
• To estimate the 10-year progression-free survival (PFS) after VIPOR in CNSL  
• To assess 10-year overall survival (OS) after VIPOR in CNSL  
1.1.3 Exploratory Objectives 
• 
To perform comprehensive molecular profiling of CNSL tumors and explore correlations 
with clinical response 
• To genotype circulating-tumor DNA (ctDNA) from plasma and cerebrospinal fluid (CSF) 
and correlate to tissue genotyping 
• To assess the pharmacokinetics (PK) of venetoclax and ibrutinib in the plasma and CSF 
• To study cytokine changes across VIPOR therapy 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Primary CNS Lymphoma 
Primary diffuse large B-cell lymphoma of the CNS is a rare disease representing less than 3% of 
all non-Hodgkin lymphoma. It refers to lymphomas that arise exclusively within the brain 
parenchyma, spinal cord, eyes, cranial nerves, and meninges without systemic involvement.[1] 
Epidemiological studies show an increased incidence of PCNSL over recent years particularly in 
those with advanced ages.[2] PCNSL occurs in both human immunodeficiency virus (HIV) 
negative and positive participants, but HIV-associated PCNSL is virtually always associated with 
Epstein Barr Virus (EBV) and is biologically distinct from EBV-negative PCNSL.  
1.2.2 Treatment of Primary Diffuse Large B-cell Lymphoma (DLBCL) of the CNS 
Compared to participants with systemic DLBCL, the outcome for subjects with PCNSL is worse. 
Treatment of PCNSL differs significantly from systemic DLBCL because many chemotherapy 
agents do not adequately penetrate the blood-brain barrier. Historically, whole brain radiation 
(WBRT) has been a mainstay of treatment because it is effective, and side stepped the limitations 
of chemotherapy in penetrating the CNS. However, when used alone, responses are typically short-
lived and virtually all subjects relapse.[3] The development of the chemotherapy-based treatments 
relied heavily on strategies used for solid brain tumors and was not optimized for the treatment of 
DLBCL. High dose methotrexate (HD-MTX), an agent with good CNS penetration, has been the 
centerpiece of PCNSL treatment for years; however, when used alone it produces a progression-

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free survival of only 7 months.[4] When HD-MTX was followed by whole brain radiotherapy, it 
produced a high complete remission rate, but no evidence of cure.[4-6] Further, combined 
modality treatment that includes WBRT is associated with severe long-term neurotoxicity.[4-7] 
For this reason, there has been much interest in developing regimens that obviate the need for 
radiation. Most promising in this regard are combinations of high dose methotrexate with systemic 
agents that cross the blood brain barrier, such as cytarabine and ifosfamide, particularly in subjects 
under 60 years of age.[8] The Bonn group and others have adopted such an approach and have 
reported promising results with chemotherapy and deferred radiation in younger subjects.[8, 9] In 
their trial, 9% died of treatment related toxicity. Overall, the median time to treatment failure was 
21 months with a median follow-up of 26 months; for those over 60 years of age, the time to 
treatment failure (TTF) was 15 months and for those under 60 years old, 60% were free from 
progression at 4 years. These results show that current strategies have a poor outcome with an 
unacceptably high treatment related mortality, and low rates of cure. Thus, there is an important 
need to develop more effective and less toxic strategies based on the molecular biology of 
PCNSL.[10, 11] We have developed a novel chemotherapy regimen for subjects with relapsed and 
refractory PCNSL that combines ibrutinib with temozolomide, etoposide, liposomal doxorubicin, 
dexamethasone, and rituximab (TEDDI-R).[12] Although this regimen is highly effective for 
subjects with relapsed and refractory PCNSL, it can be associated with hematologic toxicities and 
may not be tolerated by all subjects. Further, some subjects relapse after TEDDI-R, and effective 
salvage therapies are needed. 
1.2.3 Molecular Biology of Primary Diffuse Large B-cell Lymphoma of the CNS 
PCNSL has a high load of somatic mutations. Approximately, 30-40% have mutations of BCL6. 
In addition, aberrant hypermutation in the following proto-oncogenes and tumor suppressor genes 
are found: PIM1 (50%), c-MYC (60%), TTF (70%), PAX5 (60%), and Fas (CD95) (20%).[13] 
Interestingly, PCNSL almost never leaves the CNS and though many theories have been 
hypothesized, the reason for this neuro-tropism is not well understood. Theories that may explain 
this phenomenon include the following: 1) the brain is an immune sanctuary and the malignant B-
cells are eliminated in the periphery by a specific antitumor immune response; 2) the malignant B-
cells are dependent on a chemokine that is present in high concentrations within the brain such as 
BCA-1 – B-cell attracting chemokine encoded by CXCL13; 3) the malignant B-cells are dependent 
on specific adhesion signals; 4) the malignant B-cells are dependent on an antigen that is only 
found in the CNS.  
Accessing tissue to better understand the biology of PCNSL has been very challenging due to the 
rarity of the disease and the technical challenges of obtaining tissue from the CNS. In addition, 
interpretation and analysis of CNS tissue have been impeded by the architecture of the CNS – 
characteristically there is variable cell density, neovascularization, and many infiltrating immune 
cells. However, four molecular profiling studies have been performed and they all revealed 
different messages about the biology of PCNSL. In the first of these, Rubenstein et al. looked at 
23 cases of PCNSL and contrasted PCNSL with systemic DLBCL.[14] They showed that the 
oncogenes PIM1 and MYC were highly expressed in PCNSL relative to systemic DLBCL and 
there was also evidence of high expression of IL4 genes. They also demonstrated high expression 
of STAT 6 – which is important in interleukin-4 (IL4) signaling - and high levels of this were 
associated with poor survival, albeit in a small series. In the second of these studies, Tun et al., 
evaluated 13 cases of PCNSL.[15] They described a characteristic signature that was composed of 

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extracellular matrix and adhesion-related genes. A third study, by Montesinos-Rongen et al. looked 
at 21 cases and demonstrated a signature of a late germinal center B-cell and finally Booman et al 
looked at 9 cases and described a signature that was enriched in genes that were involved in 
apoptosis and the immune response.[16]  
Most PCNSLs that arise in immunocompetent hosts originate from an activated B-cell (ABC) 
based on molecular biology analyses. In a limited series, PCNSL was shown to have deregulation 
of the NF-kappa B pathway, which is a defining molecular feature of ABC DLBCL.[17] Other 
studies have found coiled mutations of the signaling cascade protein – CARD11 – in 16% of 
PCNSL, activating L265 mutations of MYD88 in 36% of PCNSL, and mutations of CD79B (L. 
Staudt personal communication), all mutations that are almost exclusively found in ABC 
DLBCL.[17, 18] 
1.2.4 Secondary CNS lymphoma 
Secondary involvement of the CNS is an infrequent but often fatal complication of diffuse large 
B-cell lymphomas (DLBCL) and other aggressive B-cell lymphomas[19]. The term secondary 
CNS lymphoma (SCNSL) needs to be distinguished from PCNSL. SCNSL involves the brain, 
eyes, or CSF but either has concurrent systemic involvement of non-Hodgkin lymphoma (NHL) 
or has relapsed in the CNS after treatment for systemic NHL (isolated CNS relapse). Involvement 
of the CNS at the time of diagnosis for DLBCL occurs in ~5% of subjects and usually presents as 
leptomeningeal disease with involvement of the CSF[20]. Risk factors for the development of 
SCNSL after therapy have been identified and include a high International Prognostic Index (IPI), 
age > 60 years, elevated serum lactate dehydrogenase (LDH), advanced disease stage, ECOG 
performance status > 1, extensive extranodal involvement, and involvement of specific extranodal 
sites (kidney, testes and possibly uterus or breast).[21] A specific clinical predictor algorithm 
known as the CNS-IPI has been developed and validated based on these risk factors to identify 
subjects at greater risk of SCNSL after therapy for DLBCL. In a landmark retrospective study, 
subjects with all 6 of the risk factors (N=13) included in the CNS-IPI had a 32.5% risk of 
developing SCNSL, while those without any risk factor (N=235) had a 0.0% risk. The CNS-IPI 
tool is used in routine practice to identify subjects with newly diagnosed DLBCL who should be 
treated with CNS prophylaxis to prevent late recurrences in the CNS. Furthermore, the occult 
leptomeningeal disease can be detected by flow cytometry and identifies subjects with low volume 
involvement who should receive active treatment. However, CNS prophylaxis and/or active initial 
treatment of CNS disease does not eliminate the risk of developing SCNSL at a later time, as either 
a component of the systemic relapse or an isolated CNS relapse. 
Compared to subjects with systemic DLBCL, the outcome for subjects with SCNSL is worse. The 
treatment of SCNSL differs significantly from systemic DLBCL because many chemotherapy 
agents do not adequately penetrate the blood-brain barrier and have been modeled on studies from 
PCNSL. In a large, international study of 291 subjects with SCNSL, the majority of subjects (87%) 
developed SCNSL as part of their first relapse, and 39% had a concurrent systemic relapse.[20] 
These subjects often developed debilitating symptoms and the post-relapse survival was only 3.9 
months for the entire cohort. On multivariable analysis of the subjects who were deemed eligible 
for second-line therapy with curative intent (59% of cohort), subjects aged < 60, with an ECOG 
PS 0-1, and without parenchymal involvement had a 2-year OS of 62% (95% confidence interval 
(CI) 36-80). Overall, however, there are few effective treatments for most subjects and SCNSL, 
and this complication represents a major unmet clinical need. Prospective phase II and III studies 

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have established the role of high-dose antimetabolites and consolidative therapy, including WBRT 
or with autologous stem cell transplantation (ASCT), in subjects with PCNSL, but similar data in 
SCNSL is lacking with only a few small phase II studies suggesting a role for autologous 
transplantation.[22, 23] Indeed, this strategy is limited in population-based settings due to limited 
generalizability to most subjects, failure of salvage treatment, toxicity and unsuccessful stem 
cell harvest. 
The molecular biology that confers CNS tropism for aggressive B-cell lymphomas is largely 
understudied, but recent studies have suggested that certain subsets of DLBCL have a greater risk 
of CNS spread, and that these tumors may be reliant on chronic active B-cell receptor signaling. 
Subjects with DLBCL who express both MYC and BCL2 by immunohistochemistry (i.e. ‘dual 
expressors’) have a greater risk of CNS relapse than a patient without (9.4% vs. 2.4% 
p=0.001)[24]. Although “dual expressor” DLBCL is not a specific biologic entity recognized by 
the World Health Organization (WHO) Classification of Lymphoid Malignancies, these subjects 
most commonly are ABC DLBCL. Subjects with ABC DLBCL are most commonly associated 
with chronic active BCR signaling and the likeliest to respond to inhibitors of Bruton tyrosine 
kinase (BTK) such as ibrutinib and acalabrutinib.[25, 26] Additional evidence of the underlying 
biology of SCNSL tumors comes from a recent paper from the Staudt lab who studied 574 DLBCL 
biopsies and comprehensively analyzed them using exome and transcriptome sequencing, DNA 
copy-number analyses and targeted amplicon resequencing. In this study, they identified four 
prominent genetic subtypes of DLBCL based on the underlying genetic aberrations.[27] One 
genetic subtype was termed MCD based on this striking co-occurrence of both MYD88L265P 
mutations and CD79B mutations. Importantly, these mutations frequently co-occur in PCNSL, and 
the MCD subtype was associated with extensive extranodal involvement and had additional 
acquired mutations that are recurrently mutated in primary extranodal lymphomas. These 
observations suggest a biologic link between nodal MCD and extranodal lymphomas, including 
PCNSL. A recent study of SCNSL tumors confirmed that most cases of DLBCL that secondarily 
involve the CNS are of the MCD genetic subtype.[28] 
1.2.5 Scientific Rationale and Clinical Activity of VIPOR in systemic ABC DLBCL 
Insights into the molecular pathogenesis of lymphoid tumors have identified abnormalities in key 
survival pathways. Regulation of apoptosis by BCL-2 family proteins is a central regulator of 
normal B and T cells and lymphoid tumors have acquired multiple mechanisms of deregulation 
including translocation, amplification, and elevated gene expression from loss of endogenous 
MiRs that repress BCL-2 expression and gene hypomethylation. More recently, pathogenic B-cell 
receptor signaling has been identified in B-cell lymphomas and targeting BTK has shown clinical 
activity across B-cell lymphomas. In particular, mutations affecting the BCR receptor and 
downstream signaling molecules have been identified in ABC DLBCL where they lead to 
enhanced NFκB activation. Lenalidomide inhibits NFκB through its effect on IRF4. Furthermore, 
lenalidomide affects expression of multiple other proteins through its effect on cereblon E3 
ubiquitin ligase and has immune-modulatory properties.  
In the development of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide 
(Revlimid), we hypothesized that inhibiting multiple pathogenic survival pathways would leverage 
the efficacy of targeted agents in systemic lymphomas. To help address this hypothesis, we first 
assessed if combinations of these agents were synergistic in vitro and in murine tumor models and 
showed synergy between BTK and BCL-2 inhibitors and lenalidomide. Further, in vitro studies 

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indicated that venetoclax inhibits the development of ibrutinib resistance in ABC DLBCL 
(unpublished data from the Staudt lab).  
A major limiting factor for targeted therapy in lymphomas is the need for continuous dosing, which 
precludes the ability to give multiple agents. Hence, we developed VIPOR  (NCT03223610) in 
relapsed/refractory B-cell lymphomas with a fixed-duration schedule [29]. The regimen was found 
to be safe with no unexpected toxicities and no maximum tolerated dose identified. The main 
toxicities are hematologic with grade 3/4 neutropenia, thrombocytopenia, and anemia occurring in 
50%, 38%, and 15% of subjects and 27%, 16%, and 3% of cycles, respectively. Importantly, this 
study excluded subjects with CNS involvement.    
1.2.6 Scientific Rationale for VIPOR in CNS lymphomas 
The CNS penetrance and pharmacokinetics of the individual components of VIPOR have been 
evaluated in several clinical trials. A phase 1 study (NCT01542918) of lenalidomide with or 
without intraventricular rituximab for relapsed/refractory CNSL included time-matched plasma-
CSF sample pairs to determine CSF penetrance. Among 14 subjects treated with doses of 10, 15, 
or 20 mg of lenalidomide, the 16-hour (trough) plasma concentration was 0-220 ng/mL, and the 
intraventricular CSF concentration was 0-16.68 ng/mL, with a mean CSF trough concentration of 
4.9 ng/mL. The CSF/plasma ratio, calculated on time-matched pairs where the CSF lenalidomide 
concentration was >0, was 0-49%. Further, this group found that there is a dose-dependent increase 
in CSF concentration with lenalidomide, with higher CSF/plasma partition coefficients at the 15 
or 20 mg lenalidomide dose.[30]   
For ibrutinib CNS penetrance, in a phase 1b trial (NCT02315326) by Grommes et al., 15 subjects 
with recurrent/refractory CNS lymphoma including PCNSL and SCNSL were given ibrutinib at 
doses from 560-840 mg orally daily and had CSF samples drawn at 2 hours post the cycle 2, day 
28 dose. Mean CSF ibrutinib concentration was 3.105 ng/mL (equivalent to 7.05 nM; range, 0.305-
9.22). In subjects receiving 560 mg of ibrutinib, the mean CSF concentration was 1.553 ng/mL 
(range 0.991-2.62). The mean CSF levels in subjects receiving 840 mg of ibrutinib was 3.992 
ng/mL (range 0.305-9.22).[31] In our TEDDI-R study (NCT03964090) for PCNSL, subjects were 
treated at ibrutinib dose levels of 560 mg (6), 700 mg (4), and 840 mg (8). In these 18 subjects, the 
time to max concentration in the CSF was approximately 2 hours and the T1/2 was 18.1 (4.1-31.2) 
hours. In the 560 mg, 700 mg, and 840 mg ibrutinib cohorts, the median max CNS concentration 
was 1.4, 1.98, and 1.33 nM, respectively, and the median corrected area under the curve (AUC) 
AUCcsf/AUCplasma was 43.4%, 35.1%, and 28.7%, respectively. These cohorts showed that there 
was not a proportional dose dependent increase in max CSF concentration or the areas under the 
curve at the 700 mg or 840 mg ibrutinib doses.[12] In relapsed/refractory CNSL, 2-hour-post mean 
CSF concentrations of ibrutinib monotherapy at doses of 560 to 840 mg daily was 0.77ng/ml 
(1.7nM) and 1.95ng/ml (4.4nM), respectively, and higher when checked at 2-hour-post at day 28 
of therapy, 1.65ng/ml and 3.18ng/ml, respectively.[32]  
In a case report of a patient with CLL with CNS involvement treated with venetoclax, time-
matched plasma and CSF concentrations of venetoclax were obtained. The max and minimum 
concentrations at 2 hours and 23 hours post venetoclax were 1.2 and 0.52 μg/mL in plasma, 
respectively, and 2.8 and 1.5 ng/mL in CSF, respectively. The plasma to CSF concentration ratio 
was 0.1%.[33] In unpublished data collected at the NCI on two subjects treated with off-label use 
of VIPOR for relapsed/refractory PCNSL using 800 mg venetoclax daily, the mean 2-hour post 

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dose CSF concentration was 2.35 ng/mL (2 samples) and the 24-hour post-dose CSF mean was 
1.83 ng/mL (3 samples).  
Given that most CNSL share biologic features with ABC DLBCL and that VIPOR demonstrates 
the most clinical activity in ABC DLBCL, a formal study including the VIPOR platform for CNSL 
is highly rational.  
1.2.7 Clinical experience with VIPOR in refractory PCNSL 
At the time of this writing, we have had 5 subjects with PCNSL who relapsed after treatment with 
TEDDI-R that we have treated off-label with the VIPOR regimen due to their limited treatment 
options, and all 4 achieved at least a partial response.  
The first patient was a 48-year-old man with primary refractory PCNSL who was treated on our 
TEDDI-R study (14-C-0157, NCT03964090). After 6 cycles, he was in complete remission, but 
he relapsed only 3 months later. Given that these subjects have a dismal prognosis, we offered him 
off-label use of VIPOR as a potential bridge to CAR-19. After only 1 cycle of VIPOR, he had an 
80% decrease in his brain lesion. He was given a second cycle of VIPOR and successfully 
transitioned to CAR T-cell therapy on clinical trial at Massachusetts General Hospital. 
Interestingly, he achieved a complete response to CAR-19 that lasted 13 months before another 
clinical relapse. We then re-challenged him with VIPOR and after 1 cycle, he is again in complete 
remission. He continues on VIPOR with a plan to bridge to transplant. 
The second patient was a 34-year-old woman with primary PCNSL who progressed on a high-
dose methotrexate regimen and was referred for our clinical trial of TEDDI-R. The study was on 
administrative hold at the time of referral, so we treated her with off-label TEDDI-R. She was one 
of the few subjects who only achieved a partial response to TEDDI-R. She was also offered off-
label use of VIPOR and achieved a partial response after 2 cycles. She was also successfully 
transitioned to CAR T-cell therapy on clinical trial at Massachusetts General Hospital and remains 
in remission 13 months after infusion. 
The third patient was a 67-year-old man with relapsed PCNSL who was treated on our TEDDI-R 
study (14-C-0157) and achieved a complete response. He relapsed a few months after remission 
and was treated with off-label VIPOR for 2 cycles. He achieved a partial response to VIPOR and 
was a 3rd patient who was successfully transitioned to CAR T-cell therapy on clinical trial at 
Massachusetts General Hospital after the use of VIPOR. Unfortunately, this patient did not respond 
to CAR-19 and died of disease progression. 
A fourth patient was a 67-year-old woman with primary refractory PCNSL who was treated on 
our TEDDI-R study (14-C-0157) and achieved a complete response. She relapsed a few months 
after remission and was treated with off-label VIPOR for 2 cycles and achieved a partial response. 
She was offered a referral to the CAR-19 clinical trial but did not want to be referred. She currently 
continues therapy with VIPOR with a plan for 6 cycles. 
A fifth patient was a 78-year-old man with primary refractory PCNSL who was also treated on our 
TEDDI-R study (14-C-0157) but did not achieve a clinical response. This patient was treated with 
1 cycle of VIPOR off-label but did not achieve a response. He did not have any adverse effects of 
the VIPOR treatment.  

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13 
1.2.8 Safety Summary of VIPOR-based therapy in B-cell lymphoma 
This study will utilize a novel combination of targeted agents and two important safety aspects 
will apply as part of the primary objective. First, the safety of VIPOR in patients with lymphoma 
involving the CNS. The safety of the combination has been established in over 58 patients with 
relapsed aggressive and indolent B-cell lymphomas without CNS involvement who were treated 
on an ongoing study at the NCI [NCT03223610]. The preliminary results have been presented at 
the 2020 Annual Meeting of the American Society of Hematology [34]. In these patients, most 
toxicity was hematologic and 16% and 7% of cycles were associated with G3 or G4 
thrombocytopenia, respectively. Further, 15% and 7% of cycles were associated with G3 or G4 
neutropenia which resulted in an amendment to ensure that all patients receive growth factor 
support. The most common G3/G4 non-hematologic toxicities were hypokalemia (17%), increased 
LFTs (9%), diarrhea (7%), and atrial fibrillation (5%). Other serious but rare toxicities that 
occurred included intracranial hemorrhage (N=1), tumor lysis syndrome (N=1), and 
pneumoperitoneum (N=1). Dose reductions were required on only 7% of cycles. We hypothesize 
that the toxicity of VIPOR will not be different in the participants included on this study. 
1.2.9 Preliminary Safety of VIPOR-Nivo in CNSL 
The original study design of this protocol added the PD-1 inhibitor nivolumab to VIPOR therapy. 
There were 4 participants enrolled to this treatment arm before the study was stopped for safety 
reasons and that treatment arm was closed to accrual.  The safety concern was a participant who 
developed grade 4 hepatotoxicity during the nivolumab/lenalidomide window alone.  Also, a 
multicenter study of nivolumab in PCNSL demonstrated an overall response rate of only 6% and 
these data became available after we initiated our original study design.   
Regarding the toxicity, an older male participant with relapsed/refractory PCNSL enrolled 
following front-line treatment with high-dose methotrexate-based combination therapy with 
rituximab as well as ibrutinib monotherapy. On day 5 of window therapy with nivolumab and 
lenalidomide alone, he presented with a low-grade fever and increased confusion.  Laboratory 
evaluations revealed ALT and AST elevations in the 2000 range and a slightly elevated bilirubin. 
Study treatment was held and the participant was treated with high-dose corticosteroid therapy 
which rapidly improved the hepatitis.  Liver biopsy revealed acute hepatitis with zone 3 necrosis 
most consistent with drug-induced toxicity from PD-1 inhibition.  The study was suspended from 
further enrollment and amended to remove nivolumab from the treatment regimen. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Participants must have histologically or cytologically confirmed primary diffuse large B-
cell lymphoma of the CNS (PCNSL) or non-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 

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14 
from previous follicular lymphoma, chronic lymphocytic leukemia, marginal zone 
lymphoma, and mantle cell lymphoma) are eligible.  
2.1.1.2 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/1.73m2 
• 
Presence of ascites or pleural effusion 
2.1.1.3 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 CT or MRI and/or evaluable FDG-avid lesions on PET). 
2.1.1.4 Participants with second malignancies not requiring active systemic therapy or pre-
malignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonal 
gammopathy of undetermined significance (MGUS) are eligible. 
2.1.1.5 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). See Section 4.1.2. 
2.1.1.6 Age ≥18 years  
2.1.1.7 ECOG performance status ≤2 (see Appendix A). NOTE: In participants with neurologic 
deficits caused by CNS lymphoma any ECOG status is acceptable to be eligible. 
2.1.1.8 Participants must have adequate organ and marrow function as defined below: 
absolute neutrophil count 
≥ 1000 cells/mcL (1 × 109/L) 
platelet count  
≥ 50,000 cells/mcL (50 × 109/L) 
hemoglobin 
> 8.0 g/dL (transfusions permitted) 
total bilirubin  
 
≤ 1.5 × 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 × institutional ULN for those without lymphoma 
involvement  
OR 
≤ 5.0 × institutional ULN for those with lymphoma 
involvement  
 
Serum Creatinine  
OR 
creatinine clearance (Cr Cl) 
≤ 1.5 mg/dL  
OR 
> 40 ml/min/1.73m2  
NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine clearance or eGRF in the 
clinical lab 

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15 
Laboratory assessments to determine eligibility may be performed at CLIA (or equivalent) 
certified laboratories outside the 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 ULN, except in cases where absolute 
values are appropriate and are specified as such 
2.1.1.9 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. 
2.1.1.10 Participants must agree to use certain methods of birth control. A “highly effective 
method of birth control” for  participants of childbearing potential  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). Participant who can father children are required to use 
barrier. The specific guidelines are as follows:  
• Individuals of childbearing potential (IOCBP), defined as a sexually mature 
individual 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 starting Revlimid, as well as 
for the duration after the last dose of study drug as listed below. For more details see 
Appendix C. 
• Individuals who can father children must agree to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures as outlined in Appendix C 
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. 

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2.1.2.9 History of any ventricular arrhythmia 
2.1.2.10 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.  
2.1.2.11 Uncontrolled ongoing or active infection 
2.1.2.12 Concomitant use of warfarin or other vitamin K antagonists  
2.1.2.13 Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia. 
2.1.2.14 Currently active, clinically significant hepatic impairment (≥ moderate hepatic impairment 
according to the NCI/Child Pugh classification (Appendix B)) 
2.1.2.15 Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit 
compliance with study requirements. 
2.1.3 Recruitment strategies 
Study participants will be recruited from the population of participants screened in the lymphoid 
malignancies clinic of the National Institutes of Health. These will include both referrals from 
outside physicians as well as participant self-referrals. This protocol may be abstracted into a plain 
language announcement posted on NIH websites, including clinicaltrials.gov and the CCR 
website, and on NIH social media platforms. 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the participant has signed a consent include 
the following: 
• Email, written, in person or telephone communications with prospective participants  
• Review of existing medical records to include H&P, laboratory studies, etc.  
• Review of existing MRI or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the participant has signed this study consent 
. Assessments performed at outside facilities or on another NIH protocol within the timeframes 
below may also be used to determine eligibility once a participant has signed the consent.  
Assessments and procedures to confirm study eligibility should be completed within 28 days prior 
to treatment initiation (unless otherwise noted).  
2.2.2.1 Clinical Assessments 
• Medical history, including diagnosis, treatment (e.g., systemic treatments, radiation, 
and surgeries), status, and significant prior/ongoing side effects and symptoms 

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• Physical examination, including weight, vital signs (i.e., temperature, pulse, respiratory 
rate, and blood pressure); and, assessment of performance status using the ECOG scale  
• Review of concomitant medications 
2.2.2.2 Laboratory Evaluations  
• CBC with differential 
• Chemistry panels including: Acute Care Panel (Sodium (NA), Potassium (K), Chloride 
(CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR); Mineral 
Panel (Albumin, Calcium, Magnesium, Phosphorus); Hepatic Panel (Alkaline 
Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin); and, 24-hour 
urine creatinine clearance (if needed to measure CrCl in cases where serum creatinine 
>1.5 mg/dl) 
• Coagulation panel, including PT and aPTT 
• HIV 1 /2 antibody, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody 
(HBsAb), Hepatitis B core antibody (HBcAb), and Hepatitis C antibody (HCV Ab) 
o Participants who are HBsAg negative and HBcAb positive or HBsAg positive 
will have viral load testing by HBV PCR. 
o Participants who are HCV Ab positive will have viral load testing by HCV 
PCR.  
• Urine and/or serum HCG in IOCBP (within 14 days prior to initiation of study 
treatment) 
o A pregnancy test (urine or serum) with a sensitivity of 25 mIU/mL must be 
done in accordance with Celgene Revlimid REMSTM guidelines for individuals 
of childbearing potential (IOCBP) only. 
2.2.2.3 Imaging Studies  
• CT chest, abdomen, and pelvis (C/A/P) (with IV and PO contrast unless 
contraindicated)  
• MRI brain 
• 
18F FDG-PET brain and body (must be performed at NIH) 
2.2.2.4 Other Assessments and Procedures (within 14 days prior to treatment unless otherwise 
stated) 
• Pathologic review of archival sample for confirmation of B-cell lymphoma by 
Laboratory of Pathology, NCI (no time limit). If the sample is not available, and there 
is an accessible tumor, a biopsy will be done to confirm the diagnosis.  
• Lumbar puncture/Ommaya tap for CSF studies including protein, glucose, cell 
count/differential, cytology, and flow cytometry for confirmation of CNS involvement  
• Electrocardiogram (EKG) 
• 
Confirmation of registration to Revlimid REMSTM program 

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20 
2.4 
BASELINE EVALUATION 
The baseline evaluations should be performed within 14 days prior to the first dose of the study 
treatment unless otherwise noted; tests performed as part of screening do not need to be repeated 
if they were performed within the specified window prior to initiation of study therapy. See the 
Study Calendar (Appendix D) for details.          
3 
STUDY IMPLEMENTATION 
NOTE:  The original study design included nivolumab, i.e., VIPOR-Nivo, for up to 6 cycles 
with an initial treatment window of lenalidomide with nivolumab alone.  Due to safety concerns, 
study enrollment was suspended after enrollment of 4 participants, and re-designed as is reflected 
below.   
3.1 
STUDY DESIGN 
This is a non-randomized, open-label, single institution study evaluating the combination of 
VIPOR regimen in up to 16 participants with CNSL (PCNSL and SCNSL). Participants may 
undergo optional fresh tumor research biopsies prior to treatment and at the time of progression 
wherever feasible. In patients without an Ommaya catheter, this may be placed prior to the start of 
therapy but is not required for treatment. The study treatment will assess the safety, tolerability, 
and efficacy of VIPOR in CNSL which may continue for up to 6 cycles, or until one of the criteria 
in Section 3.8.1 applies. 
Treatment should be delivered on an outpatient basis in most situations. Treatment can be delivered 
on an inpatient basis for other reasons clearly documented in the medical record (preplanned 
decision for increased monitoring, convenience, or collection of correlative samples). 
Participants will be restaged regularly as explained in the Study Calendar  
(Appendix D) and followed for up to 10 years. 

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21 
3.1.1 Study Schema 
 
3.2 
DRUG ADMINISTRATION 
After enrollment participants will proceed to induction therapy. A maximum of 6 cycles of 
induction therapy will be given every 21 days with the following dosing schedule: 
• Obinutuzumab 1000 mg IV rate escalated infusiona on days 1 and 2 
• Prednisone 100 mg PO daily days 1-7 (approximately 30-60 minutes prior to obinutuzumab 
infusion on days 1 and 2) 
• Ibrutinib 560 mg PO daily days 1-14 
• Lenalidomide 15 mg PO daily days 1-14 (if CrCl > 60 mL/min) or 10 mg PO daily days 1-
14 (if CrCl <60 mL/min but >40 mL/min) 
• Venetoclax 800 mg PO daily on days 1-14 
• Acetaminophen 650 mg PO daily on days 1 and 2 (approximately 30-60 minutes prior to 
Obinutuzumab infusion) 
• Diphenhydramine 50 mg PO daily on days 1 and 2 (approximately 30-60 minutes prior to 
Obinutuzumab infusion) 
• Peg-filgrastim 6 mg subcutaneous once on day 8 only 
 
a Obinutuzumab infusion starting at 50 mg/hr with rate increase by 50 mg/hr every 30 minutes as 
tolerated to a maximum rate of 400 mg/hr. If tolerated, subsequent infusions may start at 100 mg/hr 
with rate increase by 100 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Monitor 
participants closely for signs/symptoms of the infusion reaction and interrupt/discontinue infusion 
for any signs of a reaction and contact the investigator. 

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For more details see Section 14 
3.3 
DOSE MODIFICATIONS AND DOSE DELAYS 
The following sections detail dose modifications guidelines for each individual drug of the VIPOR 
regimen based on documented toxicity. Dose reductions for multiple study agents based on the 
same toxicity is not necessary and dosing should be modified only for the most likely offending 
agent identified. 
3.3.1 Criteria for Starting a New Cycle of Study Therapy 
A new course of study treatment may begin on Day 1 of a new cycle if: 
• ANC ≥ 1000/μL and 
• Platelet count ≥ 50,000/μL and 
• CrCl > 40 ml/min 
• No drug-related ≥ Grade 3 toxicity  
If the criteria are not met, assessments may be repeated after 1 week. The initiation of a new cycle 
of study therapy should be delayed until participant meets criteria to receive study drug as planned.  
A dose delay of up to 6 weeks from the planned start of an induction cycle is permitted to allow 
recovery of toxicities. Actions for recurrent hematologic adverse events are described in the tables 
for each drug in the sections below (lymphopenia is not considered a hematologic toxicity, as it is 
an expected outcome of therapy). If treatment is delayed for more than 6 weeks, the participant 
should be withdrawn from the study treatment.  
If one of the study drugs is discontinued because of toxicity as addressed below, participant will 
continue treatment with other drugs. If two or more drugs are discontinued, participants will be 
taken off study treatment.  
3.3.2 Dose Modifications for Venetoclax and Obinutuzumab 
Sample guidelines for dose delay and modification of venetoclax when paired with obinutuzumab 
are shown in Table 1 . These guidelines pertain to dose delays and modifications based on physical 
examination findings, observed toxicities, and laboratory results obtained within 72 hours before 
study treatment administration.  
No dose modifications of obinutuzumab are allowed. Venetoclax dose may be re-escalated (even 
to the full dose) at the discretion of the investigator. See Table 2 for the dose levels for venetoclax 
dose reduction. 
For non-hematologic toxicities, dosing of study therapy may be resumed upon resolution to Grade 
 1 or baseline status.  

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23 
Table 1: Sample Guidelines for Dose Delay or Modification of Venetoclax when given with 
Obinutuzumab and Combination Targeted Therapy 
Event(s) 
Dose Delay or Modification 
Neutropenia:  
• Grade 3 (ANC <1,000/μL) 
for > 7 days, OR 
• Grade 4 (ANC <500/μL) 
for any duration 
• 
Hold venetoclax. 
• 
Administer growth factors (e.g., G-CSF for neutropenia as 
indicated). 
-If ANC < 1000/L for < 7 days, administer full dose of study 
treatment for the next cycle. 
-If ANC < 1000/L for > 7 days, reduce the dose of venetoclax by 1 
dose level. 
• 
For subsequent episodes, dose reduction 2 of venetoclax and drug 
discontinuation will be considered. 
• 
If the primary cause of neutropenia is thought to be lymphoma 
infiltration into the bone marrow, the Principal investigator may 
elect not to reduce the dose of venetoclax . 
Febrile neutropenia or 
neutropenia with infection 
• 
Hold venetoclax and obinutuzumab until resolution. 
Thrombocytopenia:  
• Grade 3 (decrease to 
<50,000/ μL) associated 
with > Grade 2 bleeding, 
OR 
• Grade 4 (decrease to 
<25,000/ μL) with or 
without bleeding 
• 
Hold venetoclax. 
-If platelet count < 50,000/L for < 7 days, administer full dose of 
study treatment for the next cycle. 
-If platelet count < 50,000/L for > 7 days, reduce the dose of 
venetoclax by 1 dose level. 
• 
For subsequent episodes, dose reduction 2 of venetoclax and drug 
discontinuation will be considered. 
Severe thrombocytopenia 
(platelets  10,000/L) 
and/or symptomatic 
bleeding in participants who 
are not receiving 
concomitant anticoagulants 
or platelet inhibitors 
• 
Hold obinutuzumab in case of severe thrombocytopenia (platelets 
 10,000/L) or symptomatic bleeding (irrespective of platelet 
count) until it resolves. 
Thrombocytopenia with 
platelets  20,000/L and/or 
symptomatic bleeding in 
participants who are 
receiving concomitant 
anticoagulants or platelet 
inhibitorsa,b 
• 
Hold obinutuzumab in case of platelets  20,000/L or symptomatic 
bleeding (irrespective of platelet count) until it resolves. 
-For participants who are receiving concomitant anticoagulant 
when thrombocytopenia with platelets  20,000/L develops, 
adjust the dose or hold the drug per investigator discretion.a 
-For participants who are on platelet inhibitors when 
thrombocytopenia with platelets  20,000/L develops, consider 
temporarily holding their use.b 
Grade 1 or 2 neutropenia 
and/or thrombocytopenia 
• 
No dose reduction or delay. 

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• Pre-Subsequent Cycles (D1 C2-C6) of Induction Therapy: After Cycle 1, pre-dose 
assessments may be performed up to 3 days prior to Day 1 of a cycle except where 
otherwise noted.  
Response Assessments: Response assessments will be done per Section 3.4.3.1 below. Once 
treatment is complete, participants will be restaged per Section 3.5. 
• Unscheduled Visits: In the event of an unscheduled/unplanned visit (e.g., additional 
clinical assessment(s) due to toxicity), the investigator should use best clinical judgement 
as to the necessary assessments. In the event that the decision is made to continue treatment, 
all tests/assessments as required by the next visit on the Study Calendar (Appendix D) 
should still be conducted (or repeated) within the applicable windows. If a decision is made 
to discontinue treatment, the participant should have an End of Treatment Visit followed 
by post-therapy follow-up with tests/assessments completed (or repeated) within the 
applicable windows. 
• Post Treatment Evaluations: See Section 3.5 
3.4.2 Description of Procedures 
• Medical history: a review of treatment history, any ongoing medical conditions and 
medical history pertaining to eligibility on study and involvement during study. 
• Physical exam: review of organ systems, weight, and vital signs (i.e., temperature, pulse, 
respirations, blood pressure).  
• Performance status (ECOG): an assessment of activities of daily living; see Appendix A 
• Ophthalmologic evaluation and VTE risk assessment at baseline and during treatment as 
clinically indicated 
• Laboratory assessments: the following comprises the required tests/analytes per panel. 
These may be performed at CLIA (or equivalent) certified laboratories outside 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. 
o CBC with differential: includes Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils, WBC, RBC, Hemoglobin, Hematocrit, RBC Indices, 
MCV, RDW, and Platelets.  
o Panels: 
▪ Acute care panel: includes Sodium (NA), Potassium (K), Chloride (CL) 
Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, and eGFR. 
▪ Hepatic panel: includes Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, and Direct Bilirubin. 
▪ Mineral panel: includes Albumin, Calcium, Magnesium, and Phosphorus. 
o Other: LDH, Uric Acid 
o TSH and T3 and/or T4 if needed 
o PT/ PTT 
o Lymphocyte phenotyping TBNK  

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29 
o HIV 1/2 antibody, Hepatitis B surface antigen (HBsAg), Hepatitis B surface 
antibody (HBsAb), Hepatitis B core antibody (HBcAb), and Hepatitis C antibody 
(HCV Ab) to determine eligibility 
o HBV and HCV viral load in positive participants to determine eligibility and to 
monitor for reactivation (see Section 4.1.2)  
o CMV and EBV PCR 
o Pregnancy test: Urine or serum HCG with a minimum sensitivity of 25 mIU/mL 
for individuals of child-bearing potential: 
➢ Individuals of childbearing potential (IOCBP) with regular or no 
menstruation must have a pregnancy test weekly for the first 21 days and 
then every 21 days while on lenalidomide therapy (including breaks in 
therapy); at discontinuation of lenalidomide and at 30 Day safety visit.  
➢ A FCBP with irregular menstruation must have a pregnancy test weekly for 
the first 21 days and then every 14 days while on lenalidomide therapy 
(including breaks in therapy), at discontinuation of lenalidomide and at Day 
14 (+/-1 day) and at 30 Day safety visit. 
o 24-hour urine creatinine clearance (if needed to measure CrCl in cases where serum 
creatinine >1.5 mg/dl) 
o Urinalysis 
o Quantitative Immunoglobulin Panel 
• EKG to determine eligibility 
• Imaging evaluations: 
o CT scans (chest, abdomen, and pelvis); may be adjusted to assess additional known 
sites of disease  
o Brain MRI 
o 
18F-FDG-PET Scan brain and body (must be performed at NIH only). Additional 
PET/MRI may be performed as clinically indicated. 
These scans (with the exception of 18F-FDG-PET) may be performed outside of the NIH 
and the result forwarded to the study team for review at screening or any time during the 
study. Given that the methodologies utilized are similar across all facilities, no significant 
variability is expected and there is no anticipation that study data will be affected. 
• Lumbar puncture/Ommaya tap for CSF studies including protein, glucose, cell 
count/differential, cytology, and flow cytometry to determine eligibility and during the 
study if clinically indicated.  
• Bone marrow aspiration/biopsy should be performed within 3 months prior to starting 
protocol treatment. May be repeated after Cycle 6 if the previous test result was positive or 
if otherwise clinically indicated. 
• Study drug administration schedule- see Section 3.2 
• Adverse events and concomitant medication review: Adverse events and concomitant 
medication will be continuously monitored throughout the study until disease progression 

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30 
or end of treatment visit. Adverse events that occur beyond 30 days after the last 
administration will be recorded per 6.1.  
• 
Correlative studies: Refer to section 5 
3.4.3 Additional Information 
3.4.3.1 Response Assessments 
Participants will be restaged at the following time points. Response assessments will be done by 
investigators. For additional details on response criteria, see Section 6.3 . 
• After cycle 1 (within 7 days prior to treatment on day 1 of cycle 2) 
• After cycle 3 (within 7 days prior to treatment on day 1 of cycle 4) 
• After cycle 6 (cycle 6 day 21 +/- 7 days) 
NOTE:  If a participant stops treatment for any reason other than disease progression before 
completion of 6 cycles, response assessments should continue as listed in Study Calendar  
(Appendix D).  
NOTE:  Restaging scans should only be performed based on involved sites of disease at baseline 
(e.g., patients with CNS disease only should undergo restaging MRI brain and PET brain while 
those with systemic disease should also undergo CT C/A/P and PET torso).  
3.4.3.2 Disease Progression 
At the time of suspected or confirmed disease progression, the following are required: 
• Imaging by MRI brain, CT scan, and FDG-PET (only if can be performed at NIH)  
• Lumbar puncture/Ommaya tap for CSF studies including protein, glucose, cell 
count/differential, cytology, and flow cytometry  
• Ophthalmologic evaluation (only if ocular involvement was noted at baseline evaluation) 
• Symptom-guided clinical assessment with physical exam 
• Lymphocyte phenotyping TBNK 
NOTE: In the event that disease progression is not confirmed, yet a decision is made to initiate 
a new anti-cancer treatment for any reason, all of these assessments should be done prior to 
start of the new therapy.  
3.5 
POST-TREATMENT EVALUATIONS 
All post-treatment visit(s) may be completed by remote visit with a member of the study team 
(e.g., if the participant is not able to return to the NIH CC). Remote visits will be conducted in by 
phone, email or other NIH approved remote platform used in compliance with local policy, 
including M20-1. Required labs/scans can be obtained by a local provider, with results sent for 
review and any suggested management by the study team. A participant may be referred to their 
local provider or asked to come to the NIH CC for an in-person assessment, if clinically indicated, 
and at the discretion of the investigator; otherwise, physical exams are not required at these time 
points. In the case of any visits with participants’ local providers, records will be obtained for the 
research records. Remote contact not necessary if participant seen at study site. 

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3.5.1 End of Treatment/Disease Progression Visit 
When a participant completes all 6 cycles of treatment or discontinues early, all applicable 
activities scheduled for the End of Treatment Visit/PD should be performed at the time of 
discontinuation (Appendix D).  
Some procedures indicated in Study Calendar should be done only in case of PD. This visit should 
take place as soon as possible after the last administration of study drug (no more than 30 [+/-7] 
days). If a new anti-neoplastic therapy is to be initiated, this visit should occur before starting the 
new therapy. In cases where treatment was on hold, the visit should occur no more than 30 (+/-7) 
days after the date participant is taken off treatment, and if needed may coincide with the 30-day 
safety follow up visit (as needed). 
3.5.2 30-Day Safety Follow-Up Visit 
The safety follow-up visit should occur approximately 30 days after the end of the last cycle; or 
before the initiation of a new anti-cancer treatment, whichever comes first. Participants with an 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first.  
3.5.3 Follow-Up Visits – Prior to Disease Progression 
Participants who complete trial therapy or discontinue trial treatment for a reason other than 
disease progression will move into the Follow-Up Phase and should be assessed as below by 
clinical evaluation and radiologic imaging to monitor status. Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, or withdrawal/end of the study.  
In follow-up post-treatment prior to disease progression, participants will be seen at the following 
time points:  
• Every 3 months during post treatment year 1 (+/- 14 days) 
• Every 4 months during post treatment year 2 (+/- 14 days) 
• Every 6 months during post treatment year 3 (+/- 21 days) 
• Every 1 year during post treatment years 4-10 (+/- 28 days)  
All required testing is as noted in the Study Calendar (Appendix D). 
NOTE:  Restaging scans should only be performed based on involved sites of disease at baseline 
(e.g., patients with CNS disease only should undergo restaging MRI brain while those with 
systemic disease should also undergo CT C/A/P. Patients who achieve CR by post-treatment PET 
only need repeat PET imaging as clinically indicated).  
3.5.4 Follow-Up Visits – Survival/Post-Disease Progression 
Once participants progress or start use of alternative antineoplastic therapy, they will be contacted, 
approximately every 3 months (+/- 14 days), for a maximum of 10 years to assess survival and the 
use of alternative antineoplastic therapy and stem cell transplant until withdrawal/end of the study 
(Section 3.8.2).  
3.6 
STUDY CALENDAR 
See Appendix D. Appendix D: Study Calendar 

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3.7 
COST AND COMPENSATION 
3.7.1 Cost 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs. 
3.7.2 Compensation 
Participants will not be compensated on this study. 
3.7.3 Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.8 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA 
Prior to removal from study, every effort must be made to have all participants complete a safety 
visit approximately 30 (+7) days following the last dose of study therapy. Additional safety visits 
and follow-up will continue as per Section 3.5.  
3.8.1 Criteria for removal from protocol therapy 
• Disease progression 
• Unacceptable adverse event(s) as explained in Section 3.3 
• Delay of treatment for more than 6 weeks, unless it is felt by the Principal Investigator 
to be in the participant’s best interests to remain on study in exceptional circumstances. 
• Participant requests to be withdrawn from the treatment 
• Participant requires a prohibited concomitant medication as explained in Section 4.3 
• Participant HBV DNA level exceeds 100 IU/mL while on antiviral medication as 
explained in Section 4.1.2 
• Pregnancy 
• Investigator’s discretion 
• Study is cancelled for any reason 
3.8.2 Off-Study Criteria 
• Screen failure and/or failure to maintain eligibility (i.e., between enrollment and day 1 
of study treatment) 
• Completion of 10 years follow-up period 
• Participant requests to be withdrawn from the study 
• Lost to follow-up 
• Death  
• Study is cancelled for any reason 

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3.8.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to report for two (2) scheduled 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The team will attempt to contact the participant and reschedule the missed visit within 5 
business days and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB-approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
PERMITTED CONCOMITANT MEDICATIONS 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim) is permitted per 
institutional policy and in accordance with the ASCO guidelines. Transfusions may be given in 
accordance with institutional policy. 
4.1.1 For Participants on pre-treatment corticosteroids 
Pretreatment dexamethasone (or other corticosteroid) is part of the standard treatment for 
participants with CNS mass lesions. Dexamethasone or other steroid doses will be reduced and/or 
terminated as early as possible according to safe medical practice. 
4.1.2 Prophylaxis of Hepatitis B reactivation  
Participants who are positive for either Hepatitis B core antibody (HBcAb) or Hepatitis B surface 
antigen (HBsAg) and not acutely infected are at varying risk for reactivation of Hepatitis B 
especially when combined with novel agents like ibrutinib and rituximab. Participants may be 
included in the study provided that they have HBV DNA levels below the World Health 
Organization’s cutoff of 100 IU/mL prior to starting therapy. These participants will be treated 
with entecavir (or equivalent) to prevent hepatitis B reactivation and should have HBV DNA levels 
obtained monthly during treatment, and at: End of Treatment, 30 Day Post-Treatment Safety Visit; 
and every 3 months for 12 months after the last cycle of therapy by means of real-time PCR with 
the use of an assay that has a sensitivity of at least 10 IU/mL.  
If the HBV DNA assay becomes positive during combination therapy, study treatment should be 
held, and the participant should be immediately referred to a gastroenterologist or hepatologist 
for management recommendations.  

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If a participant’s HBV DNA level exceeds 100 IU/mL while the participant is receiving antiviral 
medication, study treatment must be permanently discontinued 
4.1.3 Prophylaxis of Pneumocystis jiroveci (previously Pneumocystis carinii) 
All participants will receive prophylaxis for Pneumocystis Jiroveci during VIPOR therapy. 
Trimethoprim/sulfamethoxazole 1 double strength (DS) tablet by mouth for three days each week. 
Monday, Wednesday, Friday is the preferred schedule. Participants allergic to either component 
may receive inhaled pentamidine 300 mg once a month or other standard treatments. 
4.1.4 Nausea 
Medications to prevent nausea and vomiting are permitted as clinically indicated. 
4.1.5 Febrile Neutropenia 
This is a life-threatening complication requiring urgent broad-spectrum antibiotics. Management 
may be as an inpatient or outpatient depending on the clinical situation. 
4.1.6 Symptomatic anemia  
This should be treated with appropriate red blood cell support. Only irradiated leukodepleted blood 
products should be used.  
4.1.7 Thrombocytopenia  
In the absence of bleeding or planned invasive procedures, platelet transfusions should be given 
for platelets < 10,000/mm3. If invasive procedures are planned or the participant develops 
bleeding, platelet transfusions should be administered in accordance with standard of practice, 
usually maintaining a platelet count > 50,000/mm3. 
4.1.8 Central Venous Access 
Central Venous Access may be used for administration of intravenous medications and for drawing 
blood samples. Possible lines include:  
• Temporary internal jugular line;  
• PICC lines via the brachial vein;  
• semi-permanent HICKMAN,  
• GROSHONG catheters; or 
• medi-port implanted devices.  
All devices will have nursing supervision to include participant self-care and cleaning/flushing of 
the devices. 
4.1.9 Venous Thromboembolism Prophylaxis 
The use of lenalidomide has been associated with the development of venous thromboembolism, 
including deep venous thrombosis and pulmonary embolism. Ibrutinib has been associated with 
increased risk of bleeding, including serious intracranial hemorrhage. VTE risk assessment will be 
performed in all participants at baseline and the risks and benefits of anticoagulation with aspirin 
or low molecular weight heparin will be assessed by the investigators and discussed with the 
participant. General risk factors for participants with cancer include, but are not limited to 
underlying disease, family history, age, obesity, immobilization, hormonal therapy, central venous 

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catheter, recent DVT, sex, renal dysfunction, and certain chemotherapy-based regimens. It is not 
known whether prophylactic anticoagulation or anti-platelet therapy prescribed in conjunction 
with Revlimid may lessen the potential for venous thromboembolism. It is up to the discretion of 
the Investigator after consideration of the participant’s individual risk/benefit profile whether to 
institute VTE prophylaxis.  
4.2 
MEDICATIONS TO BE USED WITH CAUTION 
Concomitant medications that fall into the categories below could potentially lead to adverse 
reactions and should be considered cautionary (except where noted). If a potential study participant 
is taking any of the medications in the categories described below, the investigator must assess 
and document the use of medications known or suspected to fall in the following medication 
categories: 
• Moderate/weak CYP3A inducers such as efavirenz and oxcarbazepine 
• CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins (because of 
expected inhibition of the metabolism of CYP2C8 substrates by venetoclax) 
• CYP2C9 substrates such as tolbutamide (because of expected inhibition of the metabolism of 
CYP2C9 substrates by venetoclax). It is recommended to exclude CYP2C9 substrates with a 
narrow therapeutic index such as phenytoin. 
For participants taking digoxin, periodic monitoring of digoxin plasma levels is recommended due 
to increased Cmax and AUC with concomitant lenalidomide therapy (please see lenalidomide 
product insert).  
Participants taking concomitant therapies such as erythropoietin stimulating agents or estrogen 
containing therapies, may have an increased risk of venous thromboembolism with lenalidomide 
(please see lenalidomide product insert). 
4.2.1 CYP3A Inhibitors/Inducers 
Venetoclax and ibrutinib are metabolized primarily by CYP3A4. Avoid co-administration with 
strong CYP3A4 inhibitors or moderate CYP3A inhibitors and consider alternative agents with less 
CYP3A inhibition. If a strong CYP3A inhibitor must be used, reduce ibrutinib dose to 280 mg or 
withhold treatment temporarily. Participants should be monitored for signs of ibrutinib toxicity. 
No dose adjustment is required in combination with mild or moderate inhibitors. Avoid grapefruit 
and Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of CYP3A. 
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction. 
A list of inhibitors, inducers, and substrates may be found at: https://drug-
interactions.medicine.iu.edu/MainTable.aspx  
Although the ibrutinib Package Insert (dated May 2022) indicates to dose reduce ibrutinib to 280 
mg daily in participants with B-Cell malignancies if it is co-administered with a moderate 
CYP3A inhibitor and results in toxicity, in this protocol dose modifications are different because 
ibrutinib is being used indefinitely where dose interruptions are more clinically feasible.  In our 
study of combination therapy, we use time-limited therapy and holding doses even for just a few 
days can have a detrimental effect on efficacy.  Furthermore, this study is testing the agent in 
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suggests that higher doses to achieve CNS penetration are critical to efficacy.  In other scenarios 
(such as CLL and MCL), one gets full BTK occupancy at lower doses, so it is less of an 
issue.  We do not think that we should make any changes to our dose modification tables for 
these scientific reasons and do not anticipate additional toxicity based on this decision. 
4.2.2 QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with electrocardiograms and electrolytes should be considered.  
4.2.3 Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp) or other 
transporters, except OCT2. Ibrutinib is a mild inhibitor of P-gp and breast cancer  resistance protein 
(BCRP). Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a 
therapeutic dose. There is no clinical data available; therefore, to avoid a potential interaction in 
the GI tract, narrow therapeutic range P-gp or BCRP substrates such as digoxin or methotrexate 
should be taken at least 6 hours before or after ibrutinib. Inhibition of the BCRP pathway may 
increase exposure to drugs that undergo BCRP mediated hepatic efflux, such as rosuvastatin. 
4.2.4 Antifungal Agents 
Given the overlapping toxicity of these targeted agents as well as other immunosuppressive 
therapies, such as steroids, there is an increased risk of infectious complications, including 
potential invasive fungal infections. Participants on this study will be undergoing frequent imaging 
for response evaluation and the investigators will also evaluate these imaging studies for potential 
infectious complications, including possible invasive fungal infection. Further clinical work-up 
may include, but is not limited to, peripheral blood analysis for fungal blood markers and/or 
bronchoscopy with bronchoalveolar lavage (BAL) testing for fungal markers/cultures and other 
infectious pathogens.  
Antifungal therapy with echinocandins, such as micafungin or caspofungin, as well as treatment 
with ambisome are permitted on study if deemed clinically appropriate. Due to the strong 
inhibition of CYP3A with certain azoles (e.g., voriconazole, posaconazole, itraconazole or 
ketoconazole), treatment with any of these agents will require dose reduction of ibrutinib as per 
Section 4.2.1. Prophylactic antifungals will not be routinely used given the low estimated risk of 
fungal infections with cyclic, non-continuous dosing of targeted agents 
4.2.5 Antiplatelet Agents and Anticoagulants 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in participants requiring other anticoagulants or medications that inhibit platelet function. 
Participants with congenital bleeding diathesis have not been studied.  
For participants requiring the initiation of therapeutic anticoagulation therapy (e.g., atrial 
fibrillation), consider the risks and benefits of continuing ibrutinib treatment. If therapeutic 
anticoagulation is clinically indicated, treatment with ibrutinib should be held and not be restarted 
until the participant is clinically stable and has no signs of bleeding. Participants should be 
observed closely for signs and symptoms of bleeding. No dose reduction is required when study 

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drug is restarted. 
4.2.6 Surgery 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib during the perioperative period for participants 
who require surgical intervention or an invasive procedure while receiving ibrutinib: 
• For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 3 days prior to the intervention when feasible and should be held at 
least 3 days after the procedure and restarted at the discretion of the investigator when the 
surgical site is reasonably healed without serosanguinous drainage or the need for drainage 
tubes. 
• For minor procedures (such as a central line placement, needle biopsy, lumbar puncture 
[other than shunt reservoir access], thoracentesis, or paracentesis), ibrutinib should be held 
for at least 1 days prior to the procedure when feasible and should not be restarted for at 
least 1 day after the procedure. For bone marrow biopsies that are performed while the 
participant is on ibrutinib, it is not necessary to hold ibrutinib for these procedures. 
4.3 
PROHIBITED CONCOMITANT MEDICATIONS 
4.3.1 Prohibited Therapy 
Participants who require the use of any of the excluded therapies listed below will be discontinued 
from study treatment.  
Use of the following therapies is prohibited during the study: 
• Immunotherapy 
• Hormone therapy (other than contraceptives, hormone replacement therapy, or megestrol 
acetate) 
• Any therapies intended for the treatment of lymphoma whether FDA approved or 
experimental (outside of this study) 
• Warfarin or warfarin derivatives 
The following concomitant medications are not allowed from 7 days prior to the first dose of study 
drugs and during study drug administration: 
• Strong CYP3A4 inhibitors such as voriconazole, ketoconazole, and clarithromycin 
• Strong CYP3A4 inducers such as rifampin and carbamazepine 
A comprehensive list of inhibitors, inducers, and substrates may be found at: https://drug-
interactions.medicine.iu.edu/MainTable.aspx. Pretreatment corticosteroids for CNS disease is 
permitted before entering this study as explained in Section 2.1.2.4. 
4.3.2 Vaccines 
Live-virus vaccines should not be given at any time during study therapy and are not recommended 
until B-cell recovery post completion of study therapy.  

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Tissue samples will be sent to the Hematopathology Section of Laboratory of Pathology until 
they are retrieved by staff in the lab of Lou Staudt, MD, PhD, Lymphoid Malignancies Branch, 
CCR, NCI. 
5.2.2 Lymph node excision or core needle biopsy procedure 
Participants with accessible tumor tissue who agree to have an optional biopsy performed will be 
biopsied as outlined in the table in Section 5.1. These samples will be processed as per the standard 
operating procedures of the Hematopathology Section of the Laboratory of Pathology, NCI, 
including fresh, frozen and/or formalin-fixed, paraffin-embedded (FFPE) tissue.  
If participant has a biopsy during screening to confirm eligibility, baseline biopsy will not be 
repeated. 
Optional tumor biopsies will be obtained by core needle biopsy or surgery. If core biopsies are 
collected, it is preferable that the interventional radiologist will collect 4-6 core needle biopsies. 
Biopsies for research will be performed only if there is minimal risk of morbidity. Deep-seated 
organs such as lung will be excluded from biopsy for research purposes. General anesthesia will 
not be performed to obtain biopsies for research purposes but when necessary, conscious sedation 
may be used. If a biopsy is being performed for medical or diagnostic purposes, with or without 
general anesthesia, a sample may be obtained for research purposes, if adequate tissue is available 
to meet medical or diagnostic purposes, upon participant consent. 
5.2.3 Gene expression profiling  
Gene expression profiling using Affymetrix U133plus 2.0 arrays will be performed for all cases. 
For those cases with available fresh frozen pre-treatment biopsy samples, gene expression profiling 
will be performed as described by the Staudt laboratory, with assignment to ABC or GCB 
subgroups based on a Bayesian predictor. For participants with only an FFPE biopsy sample, we 
will use a newly described method that can use RNA from FFPE biopsies to accurately predict 
ABC vs. GCB DLBCL subtypes. Briefly, RNA is extracted from FFPE samples with a Qiagen 
FFPE extraction kit followed by amplification using uniform and state of the art assay kits, prior 
to standard Affymetrix U133Plus2.0 array analysis.  
5.2.4 Mutational analysis  
Most primary CNS lymphomas appear to be of non-GCB origin and studies that have looked at 
mutational analysis of tumors have found a high rate of mutations of the B-cell receptor as well as 
MYD88 mutations and CARD11 mutations. Therefore, mutational analysis will include but is not 
restricted to CD79B, CD79A, CARD11 and MYD88, ITAM and A20. This is an evolving field so 
there may be other mutations and signaling pathways related to NF-kappa B that may also be 
evaluated. For collection timepoints see table above. 
5.2.5 Blood and Cerebrospinal Fluid (CSF) Samples  
5.2.5.1 Cytokine analysis and circulating tumor DNA (ctDNA) 
Cytokine analysis may include but is not limited to the following: IL-6, IL-10, interferon beta, 
and TNF alpha. Analysis of ctDNA will be performed using blood and CSF samples as described 
above. CSF studies will only be performed in participants with Ommaya Reservoirs. 

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5.2.5.2 PBMCs for Mutational Analysis 
Peripheral blood samples will be sent to Biospecimen Processing Core (BPC)where the samples 
will be processed to separate out mononuclear cells (PBMC) by Ficoll gradient. The PBMC will 
be viably frozen and stored in the BPC. Mutational analysis will include but is not restricted to 
CD79B, CD79A, CARD11 and MYD88, ITAM and A20. 
5.2.5.3 Pharmacokinetic Analyses of Oral Targeted Therapy (OTT- ibrutinib and venetoclax) 
This study provides the opportunity to study the peripheral blood and CSF PK of several anticancer 
agents. The goal is to have samples of plasma/serum, peripheral blood and CSF PK; CSF PK 
studies will only be performed in participants with Ommaya Reservoirs. 
NOTE: Timing of PK sample collection: Every effort will be made to collect samples for PK 
analysis as prescribed in the table above.  
5.2.6 Future use of blood, serum, CSF, and tissue specimens  
Specimens (blood, serum, CSF, and tissue) collected in the course of this research project will be 
banked and used in the future to investigate new scientific questions. Future investigations will be 
conducted on blood, serum, CSF, and tissue specimens and may include analysis of cellular, 
molecular, genetic and genomic biology and RNA analysis. These studies may involve sequencing 
of tumor DNA. Samples derived from biopsies may be utilized for procedures such as electron 
microscopy, immunofluorescence, immunohistochemistry, other histopathologic special stains, 
establishment of cell cultures, and as a source of material for laboratory studies of nucleic acids 
and proteins. 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.3.1 General 
All specimens obtained in the protocol are used as defined in the protocol. Samples from 
consenting participants will be stored until they are no longer of scientific value or if a participant 
withdraws consent for their continued use, at which time they will be destroyed.  
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.  
5.3.2 Hematopathology Section of Laboratory of Pathology (Tissue samples) 
Archival and/or freshly collected and processed tumor tissue may be stored in the 
Hematopathology Section of Laboratory of Pathology until ready for planned and/or future 
research assays if the participant has agreed to allowing specimens to be used in future research 
studies. IRB approval will be obtained before using any samples to conduct studies that are not 
described within this protocol. Samples will be stored under conditions appropriate to the type of 
sample and processing (e.g., ambient or frozen).  
Tissue that is given to the technician will be assigned an accession number (HP#) in the HP Case 
Logbook; sample tracking also takes place with a FileMaker Pro data base called HP Patient 
Information and Specimen Inventory.  A participant background sheet may be filled out and filed 
with any accompanying paperwork, with final reports and any supplemental reports that follow 
added as completed. 

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Archival and/or freshly collected and processed tumor tissue as well as germline DNA samples 
will be transferred upon request to the Staudt lab for sequencing and molecular analysis. These 
analyses may include, but are not limited to, whole-genome sequencing (WGS), whole-exome 
sequencing (WES), copy-number alterations (CNA), RNA-sequencing as well as single-cell RNA-
sequencing. 
5.3.3 Biospecimen Processing Core /Clinical Pharmacology Program  
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).  
For sample pickup, page 102-11964.  
For immediate help, call 240-760-6180 (main biospecimen processing core number) or, if no 
answer, 240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov 
In addition to performing analyses, samples will be processed, barcoded, and stored in the BPC 
until requested by the investigator. 
5.3.3.1 Sample Data Collection 
All samples sent to the Biospecimen Processing Core (BPC) will be barcoded, with data entered 
and stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined BPC personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by the BPC. These computers all have a password 
restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the ID, 
name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as 
box and freezer location. Participant demographics associated with the clinical center participant 
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.). 
5.3.3.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C according 
to stability requirements. These freezers are located onsite in the BPC and offsite.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval. 
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 

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5.3.4 Staudt Lab 
5.3.4.1 Sample Data Collection 
Participant samples, collected for research under this IRB approved protocol, may be archived in 
the Staudt laboratory. All data associated with archived clinical research samples is entered into 
the web-based NCI Labmatrix database, a centralized system with access controlled via centralized 
login. Access to this database for samples collected from this study is limited to Dr. Staudt and his 
research staff, each requiring individual login and password. All staff in the laboratory receive 
annually updated NIH/CITI or other training, as appropriate, and maintain standards of computer 
security.  
The data recorded for each sample may include the participant ID, trial name/protocol number, 
date drawn/collected, treatment cycle/time point, sample source (e.g., peripheral blood, marrow, 
tissue, etc.) as well as box and freezer location. All received samples will be given a unique bar 
code number, which will be added to the sample NCI Labmatrix database. Only this bar code will 
be recorded on the sample vial and the vials will not be traceable back to Participants without 
authorized access to the NCI Labmatrix database. 
5.3.4.2 Sample Storage 
Samples are stored in freezers at -80°C (e.g., sera, plasma, tissue samples) or under liquid nitrogen 
(e.g., cells), according to established stability requirements. These freezers are located onsite under 
the direction of Dr. Staudt. Access to samples from this protocol for research purposes will be as 
outlined in this protocol or by permission of the Principal Investigator only.  
5.3.5 Study Completion, Future Use and Sample Destruction 
The study will remain open so long as sample or data analysis continues. Following completion of 
the planned analyses, samples will remain in storage as detailed above. Tissue specimens and 
derived tissue lysates, RNA and DNA collected in the course of this research project may be 
banked and used in the future to investigate new scientific questions related to this study that are 
not expressly stated in the present protocol. However, this research may only be done if the 
proposed research has undergone prospective IRB review and approval, including 
consent/reconsent if required. 
If the participant withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be able 
to be retrieved.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. 
5.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.4.1 Description of the scope of genetic/genomic analysis 
The research correlates for this study are expected to include DNA/RNA sequencing of tumors 
and circulating-tumor DNA (ctDNA). In addition, whole exome sequencing of blood, buccal swab, 
or saliva may include evaluation for known lymphoma mutations. 

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5.4.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
As stated in section 5.4, unique identifiers are attached to samples and are linked through the secure 
database to medical record information, with the key provided only to researchers on the study. 
Therefore, potential identification would only occur in the event of a data breach – an unlikely 
event given the security standards of the databases utilized. A certificate of confidentiality has 
been obtained (section 13.4). Unlinked genomic data will be deposited in public genomic databases 
such as dbGaP in compliance with the NIH Genomic Data Sharing Policy (6.2.2). The pedigree 
analysis will not be performed. 
5.4.3 Management of Results 
Participants will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis 
5.4.4 Genetic Counseling 
Participants will be contacted with a request to provide a sample to be sent to a CLIA certified 
laboratory. If the research findings are verified in the CLIA certified lab, the participant will be 
offered the opportunity to come to NIH to have genetic education and counseling to explain this 
result; at the time of any such event(s), these activities will be funded by the NCI/CCR in 
consideration of the specific circumstances. If the participant does not want to come to NIH, a 
referral to a local genetic healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
6.1.1 Summary 
The PI will be responsible for overseeing entry of data into a data capture system provided by the 
NCI CCR and ensuring data accuracy, consistency, and timeliness. The principal investigator, 
associate investigators/research nurses and/or a contracted data manager will assist with the data 
management efforts. Primary and final analyzed data will have identifiers so that research data can 
be attributed to an individual human participant. 
All adverse events (AEs), including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event.  
Document AEs from the date of first dose of any study drug, through 30 days after the last dose of 
any study drug. Beyond 30 days after the last intervention, only adverse events which are serious 
and related to the study intervention need to be recorded 
All grade 3, grade 4 and grade 5 abnormal laboratory values will be recorded in the database.  
Grade 1 and grade 2 abnormal laboratory values will be recorded in the database as an AE only if 

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the laboratory abnormality is characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
participant’s outcome. 
The PI (or designee) evaluation of each AE not captured in the clinical database determining that 
it meets the criteria above will be documented in the source documents. 
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the participant’s outcome. 
Adverse Events of grade 1 will not be collected. 
Information on all concomitant medications, administered blood products, as well as interventions 
occurring during the study must be recorded on the participant’s eCRF in C3D 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
I will share human data generated in this research for future research as follows: 
 X  Coded, linked data in an NIH-funded or approved public repository.  
 X  Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
 X  Coded, linked or identified data with approved outside collaborators under appropriate 
agreements. 
 
How and where will the data be shared?  
Data will be shared through: 
 X  An NIH-funded or approved public repository. Insert name or names: ClinicalTrials.gov, 
dbGaP. 
 X  BTRIS (automatic for activities in the Clinical Center) 
 X  Publications and/or public presentations. 
 
When will the data be shared? 
 X  At the time of publication or shortly thereafter. 

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6.3.2 Complete Response (CR) 
For CR determination, all the following criteria must be met: 
1. Complete disappearance of all detectable evidence of disease and disease-related 
symptoms, if present before therapy 
2. All lymph nodes and nodal masses must have regressed on CT to normal size (1.5 cm 
in the greatest transverse diameter [GTD] for nodes >1.5 cm before therapy, regardless 
of the short axis). Previously involved nodes that were between 1.1 cm and 1.5 cm in 
the long axis and more than 1.0 cm in the short axis before treatment must have 
decreased to 1.0 cm in the short axis after treatment. All splenic and hepatic nodules 
and other extranodal disease must have disappeared. 
3. FDG-PET scan must be negative (for the combined CT+PET assessment of CR). A 
posttreatment residual mass of any size is permitted as long as it is PET-negative. The 
Five-Point Scale (5-PS) Deauville criteria will be used to interpret PET scans with a 
score of 1-3 being considered PET negative and 4-5 considered PET positive [37] 
(Section 6.3.6). 
4. The spleen and/or liver, if enlarged before therapy on the basis of physical examination 
or CT scan, should not be palpable on physical examination and should be considered 
normal size by imaging studies. 
5. If the bone marrow was involved before treatment, the infiltrate must have cleared on 
repeated bone marrow biopsy. The biopsy sample on which this determination is made 
must be adequate (with a goal of >20 mm unilateral core). If a sample is indeterminate 
by morphology, it should be negative by IHC (if bone marrow was involved before 
therapy and a radiological CR was achieved, but with no bone marrow assessment after 
treatment, the response should be classified as a PR). 
6. No new sites of disease are detected during assessment. 
6.3.3 Partial Response (PR) 
For PR determination in participants with measurable disease, all the following criteria must be 
met: 
1. 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. 
2. No increase should be observed in the size of other nodes, liver, or spleen, meeting the 
criteria for PD. 
3. Splenic and hepatic nodules must regress by ≥50% in the SPD or, for single nodules, 
in the GTD. 
4. With the exception of splenic and hepatic nodules, other organs should not have any 
measurable disease. 
5. Bone marrow assessment is not required for PR determination. 
6. No new sites of disease should be observed. 
7. At least 1 PET-positive site of disease (required for the CT+PET assessment of PR). 
For PR determination in participants with evaluable disease that is not measurable, all the 
following criteria must be met: 

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1. A ≥50% decrease in the SUVmax from baseline PET scan. 
2. Bone marrow assessment is not required for PR determination. 
3. No new sites of disease should be observed. 
4. At least 1 PET-positive site of disease (required for the CT+PET assessment of PR). 
6.3.4 Stable Disease (SD)  
Stable disease (SD) is defined as: 
1. A participant is considered to have stable disease when he or she fails to attain the 
criteria needed for a CR, PR, or MR but does not fulfill those for PD. 
2. The PET should be positive at, at least 1 previously involved site of disease, with no 
new areas of lymphoma involvement on the posttreatment CT or PET (for the combined 
CT+PET assessment of stable disease). 
6.3.5 Progressive Disease (PD) or Relapsed Disease  
Progressive disease or relapsed disease (after CR) is defined as: 
1. 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. 
2. Appearance of any new unequivocal extra-nodal lesion measuring >1.0 cm, not thought 
to be benign by the reviewer, even if other lesions are decreasing in size 
3. At least a 50% increase from the nadir in the sum of the product of diameters of any 
previously involved nodes, or in a single involved node, or in the size of other lesions 
(e.g., splenic or hepatic nodules). To be considered PD, a lymph node with a diameter 
of the short axis of <1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or 
more than 1.5 cm in the long axis. 
4. At least a 50% increase from the nadir in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. 
5. Cytology confirmation of DLBCL is required when there is an appearance on CT of a 
new lesion ≥1.5 cm in its long axis and is PET-negative. 
6.3.6 The Five-Point Deauville Scale (5-PS) for SCNSL 
In addition to the CNS lymphoma working group criteria, the five-point Deauville scale (5-PS) 
has been validated for use at interim staging and at the end of treatment for systemic lymphomas 

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and was adopted as the preferred reporting method at the First International Workshop on PET in 
Lymphoma in Deauville, France (i.e., Deauville criteria), and in several international trials.  
The 5-PS scores the most intense uptake in a site of initial disease: 
1. if present, as follows:no uptake or no residual uptake (when used at interim) 
2. slight uptake, but below blood pool (mediastinum) 
3. uptake above mediastinal, but below or equal to uptake in the liver 
4. uptake slightly to moderately higher than liver 
5. markedly increased uptake or any new lesion (on response evaluation) 
6.3.7 Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The participant's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
6.3.8 Duration of Response 
The duration of response (DOR) is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started), death, or, in the absence of PD, date of last assessment. 
 
6.3.9 Progression-Free Survival 
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. 
6.3.10 Overall Survival 
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. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/  

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7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at:  
https://irbo.nih.gov/hrpp-policy-guidelines/.  
Note: Only IND Safety Reports that meet the definition of an unanticipated problem or present 
new information that might affect the willingness of participants to enroll or remain on the study 
will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (approximately weekly) when participants 
are being actively treated on the trial to discuss each participant.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 

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medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms: related or not 
related.  
• Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 

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• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.1.6 Adverse Events of Special Interest (AESI) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is required. Such an event might require further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the trial Sponsor to 
other parties (e.g., Regulatory Authorities) may also be warranted. 
AESIs for this study include the following: 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
○ Treatment-emergent ALT or AST > 3x ULN in combination with total bilirubin > 
2x ULN 
○ Treatment-emergent ALT or AST > 3x ULN in combination with clinical jaundice 
• Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product. This term applies 
only when a contamination of the study drug is suspected. 
These AESI will be reported to the sponsor through expedited reporting on the SAE report form 
(see Section 8.3). 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution (return to baseline or stabilization) of the event, seriousness, and outcome. The 
assessment of severity and relationship to the study product will be done only by those with the 
training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator. AEs occurring during the collection and reporting period will be 
documented appropriately regardless of relationship. AEs will be followed through resolution 
(return to baseline or stabilization). 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 

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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Reported to sponsor from the first study intervention, Study Day 1 through the safety follow up 
visit. Beyond the safety follow-up visit, only adverse events which are serious and related to the 
study intervention will be reported. Exceptions are listed in section 8.4.  
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) via an electronic SAE 
reporting system (e.g. HiLIT). In the event of system downtime or issues, SAE reports will be 
submitted using the CCR SAE Report form to the sponsor at: OSROSafety@mail.nih.gov . CCR 
SAE report form and instructions can be found at:  
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-Communications/SitePages/Forms-and-
Instructions.aspx?csf=1&web=1&e=uWBXtI  
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR  
As death due to disease progression are part of the study objectives, and captured as an endpoint 
in this study, they will not be reported in expedited manner to the sponsor. However, if there is 
evidence suggesting a causal relationship between the study drug and the event, report the event 
in an expedited manner according to section 8.4. 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
N/A.  
8.6 
REPORTING PREGNANCY  
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions 
can be found here:  https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI   
8.6.1 Maternal exposure 
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known. 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs.  
The outcome of all pregnancies should be followed up and documented. 

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8.6.2 Paternal exposure 
Participants should refrain from fathering a child or donating sperm during the study and for 6 
months after the last dose of obinutuzumab. 
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 6 months after the last dose of 
obinutuzumab should, if possible, be followed up and documented. Pregnant partners may be 
offered the opportunity to participate in an institutional pregnancy registry protocol (e.g., the 
NIH IRP pregnancy registry study) to provide data about the outcome of the pregnancy for safety 
reporting purposes. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
8.8 
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
 
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements. 
 
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure: 
• that the rights of the participants are protected;  
• that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and  
• the quality and integrity of study data and data collection methods are maintained. 

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10.2 SAMPLE SIZE DETERMINATION 
In participants with CNS lymphoma, it would be desirable if the success rate were consistent with 
80% or better as opposed to 50%. To do so, the following design will be used. In this small pilot 
trial, 10 evaluable participants who receive VIPOR will be evaluated for the feasibility of 
achieving success. If there are 7 or more who exhibited a success, the probability of this occurring 
is no more than 17.2% if the true probability of success is 50% or less and is at least 87.9% if the 
true probability of success is 80% or more. Thus, attaining success in 7 or more treated participants 
would be considered enough to demonstrate an adequate level of safety and feasibility for the 
treatment based on the specified criterion. 
As of 6/6/2022, four total participants were enrolled and treated on Cohort 1, Arm 1 (i.e., 
VIPOR-Nivo). These participants will not be included in the analysis of the primary endpoint but 
will be evaluated for toxicity and survival outcomes. 
10.2.1 Accrual Ceiling 
It is expected that 10 evaluable participants can be accrued within 1 year.  
The accrual ceiling will be set at 16 participants to account for the 4 participants treated in 
Cohort 1, Arm 1 (VIPOR-Nivo; closed) in addition to the 10 participants required to assess 
success in Cohort 1, Arm 2 (VIPOR), and to also allow for 2 inevaluable participants. 
10.3 POPULATIONS FOR ANALYSES 
Any participants who received at least one dose of any study drugs will be evaluated for success.  
10.3.1 Evaluable for toxicity:  
All participants will be evaluable for toxicity from the time of their first treatment with any of the 
VIPOR study drugs. 
10.3.2 Evaluable for objective response:  
Only those participants who have measurable or evaluable disease present at baseline, have 
received at least one cycle of VIPOR, and have had their disease re-evaluated will be considered 
evaluable for response. These participants will have their response classified according to the 
definitions in Section 6.3. (NOTE: Participants who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
10.3.3 Evaluable Non-Target Disease Response:  
Participants who have lesions present at baseline that are evaluable but do not meet the definitions 
of measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
Participants will be evaluated to see if they are successful with respect to feasibility and safety.  

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10.4.2 Analysis of the Primary Endpoints 
Success is defined as completing at least 2 cycles of VIPOR therapy without the need to 
discontinue treatment due to toxicity. The fraction of participants who achieve a success will be 
determined and reported along with a 95% confidence interval. 
10.4.3 Analysis of the Secondary Endpoints 
The following secondary endpoints will be analyzed as described: 
• The overall response rate (ORR) of up to 6 cycles of VIPOR in PCNSL and SCNSL will 
be reported along with a 95% confidence interval. 
• The complete response (CR) rate of up to 6 cycles of VIPOR in PCNSL and SCNSL will 
be reported along with a 95% confidence interval. 
• 
The duration of response (DOR) after VIPOR in PCNSL and 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 progression-free survival (PFS) after VIPOR in PCNSL and 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. 
• Overall survival (OS) after VIPOR in PCNSL and SCNSL will be determined using a 
Kaplan-Meier curve. The median will be determined and presented with its associated 
95% confidence interval. 
10.4.4 Safety Analyses 
The safety of the agents will be reported by tabulating the number of participants who experience 
toxicity, by grade and type of toxicity. 
10.4.5 Baseline Descriptive Statistics 
The on-study demographic and clinical characteristics of participants will be summarized in a 
table. 
10.4.6 Planned Interim Analyses 
None  
10.4.7 Sub-Group Analyses 
None 
10.4.8 Tabulation of Individual Participant Data 
None 
10.4.9 Exploratory Analyses 
The exploratory objectives are: 
• To molecularly profile tumors with whole exome sequencing, gene expression profiling, 
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• To genotype circulating-tumor DNA (ctDNA) from plasma and CSF and correlate to 
tissue genotyping. 
• 
To assess the pharmacokinetics (PK) of venetoclax and ibrutinib in the plasma and CSF 
• To study cytokine changes across VIPOR therapy 
These will be evaluated using descriptive methods. If any statistical tests are performed, they will 
be done without formal adjustment for multiple comparisons, but in the context of the number of 
tests performed. 
11 COLLABORATIVE AGREEMENTS 
N/A 
12 HUMAN PARTICIPANTS PROTECTIONS  
12.1 RATIONALE FOR PARTICIPANT SELECTION 
Participants from all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria outlined in the protocol.  
Participants with HIV infection will be excluded because the unknown effects of the combination 
targeted therapy on the underlying HIV infection are unknown and could be adverse. In addition 
there is potential for pharmacokinetic interactions with venetoclax, ibrutinib and lenalidomide and 
combination antiretroviral therapy.  
Pregnant participants and those not willing to stop nursing are excluded because of the potential 
teratogenic effects of therapy.  
12.2 PARTICIPATION OF CHILDREN 
Participants under the age of 18 are excluded because recurrent B-cell lymphomas are rare in 
young participants, and the inclusion of an occasional younger participant will not provide 
generalizable information that would justify their inclusion on this study. Additionally, no dosing 
or adverse event data are currently available on the use of VIPOR in participants <18 years of age. 
12.3 PARTICIPATION OF PARTICIPANTS UNABLE TO GIVE CONSENT 
Adults unable to consent may enroll in or be retained on this protocol because there is prospect of 
direct benefit from research participation (Section 12.4) and these participants, due to their disease, 
will likely be unable to consent. All participants ≥ age 18 who have capacity will be offered the 
opportunity to fill in their wishes for research and care and assign a substitute decision maker on 
the “NIH Advance Directive for Health Care and Medical Research Participation” form so that 
another person can make decisions about their medical care in the event that they become 
incapacitated or cognitively impaired during the course of the study.  
NOTE: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the participants and to identify an LAR, as needed.  
Please see section 12.5.1 for consent procedure.  

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12.4 RISK/BENEFIT ASSESSMENT 
12.4.1 Known Potential Risks 
12.4.1.1 Study Drug Risks 
The main risks associated with the study agents include hematologic side effects (neutropenia 
including febrile neutropenia, thrombocytopenia, anemia, and leukopenia), infusion-related 
reactions, gastrointestinal (diarrhea, nausea, vomiting, constipation), constitutional (fatigue), 
peripheral neuropathy and infection. Serious side effects requiring hospitalization are possible 
including tumor lysis syndrome, neutropenic fever, and severe infusion reactions. Additional 
toxicity may be seen with the combination of these study agents that was not seen with 
monotherapy or prior combination trials. The risks associated with research procedures (i.e., 
research blood and tissue collection, including planned analyses and risks associated with genetic 
research) are described in detail in the informed consent document. See Section 14 also. 
12.4.1.2 Risks of Tissue Biopsy 
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, conscious sedation will be used. Biopsies for research purposes are optional on this study. 
Rarely, there is a risk of infection at the sampling site.  
12.4.1.3 Risks of Urine, Saliva, Cheek/Buccal Collection 
There are no physical risks associated with urine or saliva collection and cheek/buccal swabs. 
12.4.1.4 Risks of EKG 
Side effects of EKG are skin irritation where EKG electrodes are placed. 
12.4.1.5 Risks of Bone Marrow Biopsy 
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually, the 
hipbone is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow 
is taken out. This procedure causes some pain. Very rarely, infection or bleeding may occur at the 
needle site. 
12.4.1.6 Ophthalmic Evaluation  
There are no long-term effect. Short term side effect include light sensitivity, blurry vision and 
trouble focusing on close objects (if using dilation) 
12.4.1.7 Lumbar Puncture 
Risks associated with lumbar puncture include headache, back pain, bleeding, and brainstem 
herniation. 
12.4.1.8 Fluid Collection by Ommaya Reservoir   
Withdrawing spinal fluid from an Ommaya Reservoir conveys a small risk of infection and a 
minor amount of discomfort from the needle puncture. 
12.4.1.9 Risks of Blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up to 
92 mL of blood may be collected at any day, up to 235 mL may be collected within 8 weeks. 

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12.4.1.10 Risks of Imaging 
CT, PET, and/ or MRI scans may be used to monitor a participant’s disease on this study. MRI 
scans can be claustrophobic. CT and PET scans expose a participant to radiation; the amount 
depends on the number of body areas scanned. In addition, CT, PET, and MRI scans involve use 
of contrast (oral and/or IV). An IV line may need to be inserted for administration of the contrast 
agent and can cause pain at the site where the IV is placed. There is also a small risk of bruising 
or infection. If a contrast agent is given with the scan, there is a small risk of having a reaction to 
the contrast. In the small group of participants who have a reaction, the most common symptoms 
are nausea, pain in the vein where the contrast was given, headache, a metallic or bitter taste in the 
mouth, and a warm or flushing feeling that lasts from 1-3 minutes. Rarely, these symptoms may 
require treatment. In very rare cases, people have had more severe allergic reactions that result in 
skin rashes, shortness of breath, wheezing, or lowering of the blood pressure. 
12.4.1.11  Risks of Radiation Exposure 
This study will involve radiation from the following sources: 
• Up to 8 CT scans of chest, abdomen pelvis in 1 year 
• Up to 8 whole body 18F-FDG PET scans in 1 year 
• Up to 2 CT scans for CT-guided biopsies in 1 year 
The maximum exposure in one year is 20 rem. This amount is more than would be expected from 
everyday background radiation. Being exposed to excess radiation can increase the risk of cancer. 
The risk of getting cancer from the radiation exposure in this study is 2.0 out of 100 (2.0%) and of 
getting a fatal cancer is 1.0 out of 100 (1.0%). 
12.4.1.12 
Non-Physical Risks of Genetic Research 
Risk of receiving unwanted information: 
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Participants will 
be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with participant’s, family members or health care providers. 
Risk related to possibility that information may be released: 
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the participants, family members or health care 
providers, this risk will be included in the informed consent document. 
Risk to family or relatives: 
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, participants will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with participants. 

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12.4.2 Known Potential Benefits 
The potential benefits could include shrinking of the tumor or lessening of symptoms, such as 
pain, that are caused by the cancer. See also Section 1.2.6. The results may help the investigators 
learn more about the disease and develop new treatments for participants with this disease. 
12.4.3 Assessment of Potential Risks and Benefits 
It is possible that treatment on this protocol may reduce cancer burden or lessen symptoms 
caused by cancer. While treatment on this protocol may not individually benefit participants, the 
knowledge gained from this study may help others in the future who have this cancer. Potential 
risks include the possible occurrence of any of a range of side effects listed above.  
12.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting. A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts, and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of 
the participant will be maintained. Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant/consent designee will be informed of the private nature of the 
discussion and will be encouraged to relocate to a more private setting if needed.  
NOTE: When required, witness signature will be obtained similarly as described for the 
investigator and participant as described below. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant. 
Manual (non-electronic) signature on electronic document: 
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures: 
• 
Adobe platform (which is not 21 CFR Part 11 compliant); or,   
• 
iMedConsent platform (which is 21 CFR Part 11 compliant) 
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.   
Both the investigator and the participant will sign the document using a finger, stylus, or mouse.  

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Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at: 
https://nih.sharepoint.com/sites/NCI-CCR-OCD-Communications/SitePages/OEC-
Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit  
12.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation 
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.5 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping   
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 

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Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NIH has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical site and by NCI CCR research staff will be secured and password protected. At the 
end of the study, all study databases will be archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
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criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
14 PHARMACEUTICAL INFORMATION 
14.1 VENETOCLAX  
14.1.1 Source, Acquisition and Accountability  
Venetoclax is a commercially available agent and will be purchased by the CCR and supplied to 
the Participants enrolled on the study by the NIH Clinical Center Pharmacy Department. 
14.1.2 Toxicities 
Please refer to the package insert.  
14.1.3 Administration Procedures 
Venetoclax should be taken with a meal and may be administered with ibrutinib, prednisone, and 
lenalidomide. If vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets 
are still intact, another dose may be given. Otherwise, no replacement dose is to be given. In cases 
where a dose of venetoclax is missed or forgotten, the participant should take the dose as soon as 
possible and ensure that the minimal interval between the current dose and the next dose is at least 
16 hours in order to avoid excessive drug accumulation after the next dose. 
Venetoclax will be dispensed to participants in bottles. All doses of venetoclax taken in the clinic 
or day hospital should be taken from the bottle dispensed to the participant. Unused venetoclax 
tablets dispensed during previous visits must be returned to the site and drug accountability records 
must be updated. Returned tablets must not be re-dispensed to anyone. Participants should return 
all used bottles to the site when they receive new study drug. See also Section 3.2 
14.1.4 Incompatibilities  
Venetoclax is a small molecule administered orally and is primarily metabolized by 
cytochrome P450 3A4 (CYP3A4). Concomitant use of venetoclax and strong inducers or 
inhibitors of CYP3A is contraindicated (see Sections 4.2 and 4.3). Please refer to the package 
insert and PDR for full drug interactions and toxicities. 
14.2 IBRUTINIB 
14.2.1 Source, Acquisition and Accountability 
Ibrutinib is a commercially available agent and will be purchased by the CCR and supplied to the 
Participants enrolled on the study by the NIH Clinical Center Pharmacy Department. 
14.2.2 Toxicities 
Please refer to the package insert. 
14.2.3 Administration Procedures 
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taken with or without food and may be administered with venetoclax, prednisone, and 
lenalidomide. Grapefruit or Seville orange juice should be avoided due to CYP3A inhibition. The 
capsules should be swallowed intact and participants should not attempt to open capsules or 
dissolve them in water. 
If a dose of ibrutinib is missed, it can be taken as soon as possible on the same day with a return 
to the normal schedule the following day. No extra capsules to make up missed doses of ibrutinib 
should be taken.  See also Section 3.2 
14.2.4 Incompatibilities  
Ibrutinib is a small molecule administered orally and is primarily metabolized by cytochrome P450 
3A4 (CYP3A4). Concomitant use of ibrutinib and strong inducers or inhibitors of CYP3A is 
contraindicated (see Sections 4.2 and 4.3). Please refer to the package insert and PDR for full drug 
interactions and toxicities. 
14.3 PREDNISONE 
14.3.1 Source, Acquisition and Accountability  
Prednisone is a commercially available agent and will be purchased by the CCR and supplied to 
the participants enrolled on the study by the NIH Clinical Center Pharmacy Department. Please 
refer to the package insert for additional guidance on drug preparation, handling and storage.  
14.3.2 Toxicity  
The most commonly reported toxicities have included insomnia; mood, appetite, and skin 
changes; gastrointestinal problems/pain; and headache, dizziness, and redistribution of body fat. 
Please refer to the package insert for a complete listing of all toxicities.  
14.3.3 Administration Procedures 
Prednisone will be administered orally per the drug administration schedule in Section 3.2  
14.3.4 Incompatibilities  
Please refer to the package insert and PDR for full drug interactions and toxicities. 
14.4 OBINUTUZUMAB  
14.4.1 Source, Acquisition and Accountability  
Obinutuzumab is a commercially available agent and will be purchased by the CCR and supplied 
to the participants enrolled on the study by the NIH Clinical Center Pharmacy Department. 
14.4.2 Administration Procedures 
Obinutuzumab will be administered by IV on Days 1 and 2 of each 21-day treatment cycle (Cycles 
1−6). Premedication will be used to reduce the risk of infusion related reactions (IRRs) as outlined 
in Section 3.2, prior to the obinutuzumab infusion.  
Hypotension may occur during obinutuzumab IV infusions. Consider withholding 
antihypertensive treatments for 12 hours prior to and throughout each obinutuzumab infusion, and 
for the first hour after administration.  

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14.4.3 Incompatibilities  
No formal drug interaction studies have been performed with obinutuzumab. Please refer to the 
package insert and PDR for full drug interactions and toxicities. 
14.5 LENALIDOMIDE  
14.5.1 Source, Acquisition and Accountability  
Lenalidomide is a commercially available agent and will be purchased by the CCR and supplied 
to the Participants enrolled on the study by the NIH Clinical Center Pharmacy Department. 
Lenalidomide will be provided in accordance with the Revlimid REMSTM program of Celgene 
Corporation. Per standard Revlimid REMSTM requirements, all physicians who prescribe 
lenalidomide for research participants enrolled into this study, and all research participants 
enrolled into this study, must be registered in, and must comply with all requirements of the 
Revlimid REMSTM program.  
Further 
information 
about 
the 
Revlimid 
REMSTM 
program 
is 
available 
at 
www.celgeneriskmanagement.com. 
Drug will be shipped on a per participant basis by the contract pharmacy to the clinic site for IND 
studies.  
NOTE: Prescriptions must be filled within 7 days for individuals of childbearing potential and 
within 14 days for all other risk categories. Only enough lenalidomide for one cycle of therapy 
will be supplied to the participant each cycle, unless otherwise agreed to by the 
investigator/Celgene in advance.  
14.5.2 Toxicities 
Please refer to the package insert. 
14.5.3 Administration procedures 
Lenalidomide should be taken orally at about the same time each day. The capsules should not be 
opened, broken, or chewed. Lenalidomide capsules should be swallowed whole, preferably with 
water, either with or without food, and may be administered with venetoclax, ibrutinib and 
prednisone.  
Individuals of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves.  
If less than 12 hours has elapsed since missing a dose, the participant can take the dose. If more 
than 12 hours has elapsed since missing a dose at the normal time, the participant should not take 
the dose, but take the next dose at the normal time on the following day. Do not take 2 doses at the 
same time. 
If a Day 1 (of any cycle) is delayed due to scheduling, instruct the participant that lenalidomide 
dosing should not be initiated until Day 1 assessments can occur.  
14.5.4 Incompatibilities  
For participants taking digoxin, periodic monitoring of digoxin plasma levels is recommended due 
to increased Cmax and AUC with concomitant lenalidomide therapy (please see prescribing 

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information).  
Participants taking concomitant therapies such as erythropoietin stimulating agents or estrogen 
containing therapies, may have an increased risk of venous thromboembolism (please see 
prescribing information). 
Results from human in vitro studies show that lenalidomide is neither metabolized by nor inhibits 
or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be 
participant to P450-based metabolic drug interactions (please see lenalidomide prescribing 
information).  
Please refer to the package insert and PDR for full drug interactions and toxicities. 
 
 
 

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34. 
Melani, C., et al., Phase 1b/2 Study of Vipor (Venetoclax, Ibrutinib, Prednisone, 
Obinutuzumab, and Lenalidomide) in Relapsed/Refractory B-Cell Lymphoma: Safety, 
Efficacy and Molecular Analysis. Blood, 2020. 136(Supplement 1): p. 44-45. 
35. 
Abrey, L.E., et al., Report of an international workshop to standardize baseline 
evaluation and response criteria for primary CNS lymphoma. J Clin Oncol, 2005. 23(22): 
p. 5034-43. 
36. 
Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J Clin Oncol, 
2007. 25(5): p. 579-86. 
37. 
Nanni, C., et al., Report of the 6th International Workshop on PET in lymphoma. Leuk 
Lymphoma, 2017. 58(10): p. 2298-2303. 
38. 
Child, C.G. and J.G. Turcotte, Surgery and portal hypertension. Major Probl Clin Surg, 
1964. 1: p. 1-85. 
39. 
Pugh, R.N., et al., Transection of the oesophagus for bleeding oesophageal varices. Br J 
Surg, 1973. 60(8): p. 646-9. 
 
 
 

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17 APPENDICES 
17.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
 
 

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17.2 APPENDIX B: CHILD-PUGH SCORE 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
[38], [39] 
 
 

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17.3 APPENDIX C: RISK OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES AND 
ACCEPTABLE BIRTH CONTROL METHODS FOR LENALIDOMIDE 
Risks Associated with Pregnancy  
The use of lenalidomide in pregnant and nursing individuals has not been studied nor has the effect 
of lenalidomide on human eggs and sperm. Lenalidomide is structurally related to thalidomide. 
Thalidomide is a known human teratogenic active substance that causes severe life-threatening 
birth defects. An embryofetal development study in animals indicates that lenalidomide produced 
malformations in the offspring of female monkeys who received the drug during pregnancy. The 
teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore, a risk minimization 
plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory Revlimid REMSTM program and be 
willing and able to comply with the requirements of Revlimid REMSTM.  
Criteria for individuals of childbearing potential (ICBP)  
This protocol defines an individual of childbearing potential as a sexually mature individual who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months).  
The investigator must ensure that: 
• 
Individuals of childbearing potential comply with the conditions for pregnancy risk minimization, 
including confirmation that she has an adequate level of understanding   
• 
Individuals  NOT of childbearing potential acknowledge that they understand the hazards and 
necessary precautions associated with the use of lenalidomide   
• 
Individuals who can father children taking lenalidomide acknowledge that they understand that 
traces of lenalidomide have been found in semen, that they understand the potential teratogenic risk 
if engaged in sexual activity with an individual of childbearing potential or pregnant 
individual, and that they understand the need for the use of a condom even if they have had a 
vasectomy, if engaged in sexual activity with an individual of childbearing potential or pregnant 
individual.   
Contraception   
Individuals of childbearing potential (ICBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days before 
starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. ICBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:  
• Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 

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o Tubal ligation  
o Partner’s vasectomy  
• Additional effective methods: 
o Condom for individuals who can father children 
o Diaphragm 
o Cervical Cap  
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of 
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be 
considered particularly in participants with neutropenia.  
Pregnancy Testing  
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for individuals of childbearing potential, including individuals of childbearing potential 
who commit to complete abstinence, as outlined below.  
Before starting lenalidomide  
Individuals of Childbearing Potential:  
ICBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
prescribing lenalidomide. The first pregnancy test must be performed within 10–14 days prior to 
prescribing lenalidomide and the second pregnancy test must be performed within 24 hours prior 
to prescribing lenalidomide. The participant may not receive lenalidomide until the Investigator 
has verified that the results of these pregnancy tests are negative.  
Individuals Who Can Father Children:  
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
individuals who are pregnant or of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy.  
During study participation and for 28 days following lenalidomide discontinuation  
Individuals of Childbearing Potential:  
• 
ICBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 
21 days of lenalidomide treatment, including dose interruptions and then every 21 days throughout 
the remaining duration of lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 30 following lenalidomide discontinuation.  If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 21 days of lenalidomide treatment, 
including dose interruptions, and then every 14 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 
14 and Day 30 following lenalidomide discontinuation.   
• 
At each visit, the Investigator must confirm with the ICBP that they are continuing to use two 
reliable methods of birth control at each visit during the time that birth control is required.   
• 
If pregnancy or a positive pregnancy test does occur in a study participant, lenalidomide must be 
immediately discontinued.   
• 
Pregnancy testing and counseling must be performed if a participant misses their period or if their 
pregnancy test or their menstrual bleeding is abnormal. Lenalidomide treatment must be 
temporarily discontinued during this evaluation.   

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• 
Individuals of childbearing potential must agree to abstain from nursing during study participation 
and for at least 28 days after lenalidomide discontinuation.   
Individuals Who Can Father Children:   
• 
Must practice complete abstinence or use a condom during sexual contact with individuals who are 
pregnant or of childbearing potential throughout the entire duration of lenalidomide treatment, 
during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if 
he has undergone a successful vasectomy.   
• 
If pregnancy or a positive pregnancy test does occur in the partner of an individual who can father 
children during study participation, the investigator must be notified immediately.   
• 
Individuals who can father children should not donate semen or sperm during therapy or for at least 
28 days following discontinuation of lenalidomide.   
Additional Precautions:   
• 
Participants should be instructed never to give lenalidomide to another person.   
• 
Participants should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide.   
• 
Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of therapy.  
• 
Any unused lenalidomide must be returned as instructed through the Revlimid REMSTM program.  
 
 
 

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6   CT scans (C/A/P) are to be performed in restaging only if systemic disease present on baseline CT and/or PET imaging. 
7   Adverse event evaluation begins immediately after the first dose of study drug and continues throughout the treatment/follow-up portion of the study. 
8   Archival and/or Fresh Tissue Biopsy for gene expression profiling, mutational analysis, and DNA/RNA sequencing are optional at both baseline and at   
     disease progression.