Phase II Study on the Combination of Ibrutinib and Venetoclax in Treatment naïve Patients With Waldenström Macroglobulinemia
Phase: PHASE2
Conditions: Waldenstrom Macroglobulinemia, MYD88 Gene Mutation
Sponsor: Dana-Farber Cancer Institute

NCI Protocol #: N/A 
DF/HCC Protocol #:19-651 
Protocol Version Date: 3.11.2022 
 
I 
 
NCI Protocol #: 
N/a. 
 
DF/HCC Protocol #: 19-651  
 
TITLE:  Phase II study on the combination of ibrutinib and venetoclax in treatment naïve 
patients with Waldenström Macroglobulinemia 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
450 Brookline Avenue  
 
 
 
 
 
 
 
 
 
Boston, MA 02215 USA 
 
 
Principal Investigator (PI): 
Jorge J. Castillo, MD 
 
Dana-Farber Cancer Institute 
 
Jorgej_castillo@dfci.harvard.edu 
 
Other Investigators: 
Steven P. Treon, MD, PhD 
 
Dana-Farber Cancer Institute 
 
Steven_treon@dfci.harvard.edu 
 
Project Manager: 
Kirsten Meid 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 USA 
Kirsten_meid@dfci.harvard.edu 
 
 
 
 
Agent(s):  Venetoclax & Ibrutinib 
 
 
IND #:  145237 
IND Sponsor: Jorge J. Castillo, MD 
 
 
Protocol Type / Version # / Version Date: 
Version #5 6.23.2022 
 
 

NCI Protocol #: N/A 
DF/HCC Protocol #:19-651 
Protocol Version Date: 6.23.2022 
 
II 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Registration 
Ibrutinib Administration 
1 4-week cycle  
Cycle 2  
Venetoclax dose ramp-up 
Stop Combination 
Therapy 
Event Monitoring for 4 
years or until death 
Cycles 3-24  
IVEN combination therapy 
(4 week cycles) 

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III 
 
TABLE OF CONTENTS 
 
SCHEMA ........................................................................................................................................ II 
1. 
OBJECTIVES ......................................................................................................................1 
1.1 
Study Design ............................................................................................................1 
1.2 
Primary Objectives ...................................................................................................2 
1.3 
Secondary Objectives ...............................................................................................2 
2. 
BACKGROUND .................................................................................................................2 
2.1 
Study Disease(s).......................................................................................................2 
2.2 
IND Agent Venetoclax ............................................................................................4 
2.3 
Other Agent: Ibrutinib .............................................................................................9 
2.4 
Rationale ................................................................................................................10 
2.5 
Correlative Studies Background ............................................................................10 
3. 
PARTICIPANT SELECTION ...........................................................................................11 
3.1 
Eligibility Criteria ..................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................12 
3.3 
Inclusion of Women and Minorities ......................................................................13 
4. 
REGISTRATION PROCEDURES ...................................................................................13 
4.1 
General Guidelines for DF/HCC Institutions ........................................................13 
4.1 
Registration Process for DF/HCC Institutions .......................................................13 
4.2 
General Guidelines for Other Investigative Sites ..................................................14 
4.3 
Registration Process for Other Investigative Sites .................................................14 
5. 
TREATMENT PLAN ........................................................................................................14 
5.1 
Treatment Regimen ................................................................................................14 
5.2 
Pre-Treatment Criteria ...........................................................................................15 
5.3 
Agent Administration .............................................................................................15 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................19 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................23 
5.6 
Duration of Follow Up ...........................................................................................24 
5.7 
Criteria for Taking a Participant Off Study ...........................................................24 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................24 
6.1 
Dose Reduction Guidelines for Venetoclax & Ibrutinib ........................................25 
6.2 
Venetoclax & Ibrutinib Dose Adjustments for AEs ..............................................26 
6.3 
Venetoclax Dose Modifications for first dose of Venetoclax (100 mg) and 
first dose escalation (200 mg and 400 mg) ............................................................28 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................29 
7.1 
Expected Toxicities ................................................................................................29 
7.2 
Adverse Event Characteristics ...............................................................................34 
7.3 
Adverse Event Reporting .......................................................................................35 

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IV 
 
7.4 
Reporting to the Food and Drug Administration (FDA) .......................................35 
7.5 
Reporting to Hospital Risk Management ...............................................................35 
7.6 
Routine Adverse Event Reporting .........................................................................36 
7.7 
Routine Adverse Event Reporting to AbbVIE .......................................................36 
7.8 
Expedited Reporting to Pharmacyclics, LLC ........................................................36 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................39 
8.1 
Venetoclax ..............................................................................................................39 
8.2 
Ibrutinib .................................................................................................................41 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................44 
9.1 
Laboratory Correlative Studies ..............................................................................44 
10. 
STUDY CALENDAR .......................................................................................................45 
11. 
MEASUREMENT OF EFFECT........................................................................................48 
11.1 
Antitumor Effect – Hematologic Tumors ..............................................................48 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................49 
12.1 
Data Reporting .......................................................................................................49 
12.2 
Data Safety Monitoring ..........................................................................................50 
12.3 
Multi-Center Guidelines ........................................................................................50 
12.4 
Collaborative Agreements Language .....................................................................50 
13. 
STATISTICAL CONSIDERATIONS...............................................................................50 
13.1 
Study Design/Endpoints.........................................................................................50 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................50 
13.3 
Stratification Factors ..............................................................................................51 
13.4 
Interim Monitoring Plan ........................................................................................51 
13.5 
Analysis of Primary Endpoint ................................................................................51 
13.6 
Analysis of Secondary Endpoints ..........................................................................52 
13.7 
Reporting and Exclusions ......................................................................................53 
14. 
PUBLICATION PLAN .....................................................................................................53 
14.1 
Protocol Amendments ............................................................................................53 
REFERENCES ..............................................................................................................................54 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................56 
APPENDIX B.  Child-Pugh Score for Subjects with Liver Impairment .......................................58 
APPENDIX C.  DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROME .....................................................................................................................59 
Appendix D: Management Recommendations for Laboratory Abnormalities for Venetoclax First 
Dose and Escalation ...........................................................................................................61 

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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a single-arm open-label Phase II study to evaluate the safety and efficacy of Ibrutinib 
combined with Venetoclax (IVEN) in symptomatic, treatment naive WM patients. Treatment will 
be administered daily to participants with WM, and participants will receive treatment for 24 28-
day cycles.  During the first cycle of therapy, participants will initiate Ibrutinib alone therapy, 
followed by dose escalation starting on Cycle 2 Day 1 to the target dose of Venetoclax with TLS 
prophylaxis.  After a maximum of 24 cycles of therapy participants will discontinue ibrutinib and 
venetoclax and enter follow-up for 4 years or death.   
 
A Screening visit will be conducted 30 days prior to Cycle 1, Day 1 of study drug administration. 
At the Screening visit, a medical history will be obtained, and a complete physical examination 
will be performed including vital signs and an ECOG performance status. A bone marrow aspirate 
and biopsy, and CT scanning of the chest, abdomen and pelvis will be done. Bone marrow and CT 
scans will not be repeated if collected within 90 days prior to Cycle 1 Day 1 visit. Clinical 
laboratory tests including a complete blood count plus differential, comprehensive chemistry panel 
(electrolytes, BUN, creatinine, albumin, total protein, total bilirubin, SGOT (AST), SGPT (ALT), 
alkaline phosphatase), magnesium, beta-2-microglobulin, serum and protein electrophoresis with 
quantification of immunoglobulins (IgM, IgG, IgA) and immunofixation studies, Von Willebrand 
factor, ristocetin cofactor and FVIII level, HIV, HBsAg, HBsAb, HBcAb and HCV antibody. 
Serum pregnancy tests for women of childbearing potential will also be performed at the Screening 
visit. Cryoglobulins and cold agglutinins will be obtained if clinically indicated. Coagulation 
studies (PT, PTT, PT-INR) and tumor lysis laboratories (calcium, phosphorus, LDH, and uric acid) 
will also be performed at baseline. .  
 
Participants who meet the eligibility requirements at the Screening visit will be enrolled in the 
study. To prevent the development of tumor lysis syndrome (TLS), dosing of venetoclax will not 
commence until the participants have completed 4 weeks of ibrutinib (Cycle 1).  Participants will 
be evaluated for development of tumor lysis syndrome (TLS) on Days 1 and 2 of venetoclax dose 
escalation days during the lead-in phase (Cycle 2). TLS, however, is an extremely rare occurrence 
in patients with WM. To err in the side of safety, all patients will receive allopurinol 300 mg PO 
once daily starting 72 hours prior to first dose of venetoclax and continuing at least to the end of 
Cycle 2.  
 
Patients will be evaluated for safety on the first day of each cycle (4 weeks ± 1 week) at cycle 2, 
and 3 and thereafter every 3 cycles (12 weeks ± 1 weeks) for the duration of therapy. Patients will 
also be evaluated for safety at each venetoclax dose escalation. Patients will be evaluated for 
response after completing 4 weeks of therapy. Response criteria updated at the Sixth International 
Workshop on Waldenström macroglobulinemia (Owen 2013) will be used to assess response, 
stable disease, and progressive disease. QOL questionnaire will be administered at Cycles 1, 4, 7, 
13, 19, EOT, and every 6 months during follow-up. 
 
The Sponsor-Investigator and other study investigators instructed all participants to undergo 
cardiac screenings, which included labwork, ECG, and Echocardiograms after 3 events of 

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ventricular arrhythmia, including 2 fatal, occurred on this study.  Consultation with cardiology 
and cardiac stress tests were advised for some participants.    
 
Study treatment for all participants was terminated by the Sponsor-Investigator in March of 2022 
due to 4 events of ventricular arrhythmia.  As of 4/1/22 all participants were notified and 
instructed to stop study treatment and accrual was permanently discontinued.  Follow-up will 
continue for 4 years or until death, per protocol.   
 
1.2 
Primary Objectives 
 
• To evaluate the rate of VGPR or better of the combination Ibrutinib + Venetoclax (IVEN) in 
participants with treatment naïve Waldenström macroglobulinemia within 24 cycles of 
therapy. 
 
1.3 
Secondary Objectives 
 
• To evaluate the rate of CR with IVEN in participants with symptomatic, treatment naïve WM 
at 6, 12 and 24 cycles of therapy. 
• To evaluate the best overall response to IVEN in participants with symptomatic, treatment 
naïve WM. 
• To evaluate the rate of VGPR or better at 30 months post treatment initiation. 
• To evaluate median time to response, median time to major response and median time to 
VGPR to IVEN in participants with symptomatic, treatment naïve WM. 
• To evaluate the 24-, 36-, 48-, 60-month Progression Free Survival (PFS) of IVEN in 
participants with symptomatic treatment naïve WM. 
• To evaluate the overall survival for participants treated with IVEN 
• To evaluate the time to next treatment with IVEN 
• To evaluate the effect of IVEN in the bone marrow burden of disease in participants with 
symptomatic treatment naïve WM. 
• To evaluate the impact of CXCR4 mutations on response to IVEN in participants with 
symptomatic treatment naïve WM. 
• To evaluate the safety profile of IVEN in participants with symptomatic treatment naïve 
WM. 
• To evaluate the impact of IVEN in the participants’ QOL. 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
The current state of Waldenström macroglobulinemia (WM) 
 
WM is a rare B-cell lymphoproliferative disorder characterized by the uncontrolled accumulation 
of IgM-producing lymphoplasmacytic cells. Such malignant cells accumulate in the bone marrow, 
liver, spleen and lymph nodes. WM is diagnosed by the presence of lymphoplasmacytic cells in 
the bone marrow and an IgM monoclonal spike (M-spike) identified in a serum protein 

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electrophoresis (SPEP). The incidence of WM in the United States (US) is 3 per million persons 
per year accounting for 1500 new cases per year.  
 
Recently, our group identified a recurrent mutation in the MYD88 gene (MYD88 L265P), which 
is seen in over 90% of cases with WM [1]. The occurrence of this mutation in WM has since been 
validated in several independent cohorts [2-5]. In contrast, the MYD88 L265P gene mutation was 
not detected in patients with IgM myeloma and was detected in less than 10% of patients with 
marginal zone lymphoma. The high specificity and sensitivity of the MYD88 L265P gene mutation 
has obvious diagnostic implications in patients in whom a diagnosis of WM is suspected but 
uncertain. The MYD88 L265P gene mutation has shown to support growth and survival of WM 
cells in several studies. A knockdown model of MYD88 showed decreased survival of MYD88 
L265P expressing WM cells, whereas survival was more enhanced by knock-in of mutant versus 
wild-type MYD88 [6]. MYD88 acts as an adaptor molecule in toll-like receptor (TLR) and 
interleukin-1 receptor (IL-1R) signaling [7]. Following stimulation of TLR or IL-1R, MYD88 is 
recruited to the activated receptor complex as a homodimer which complexes with IL-1R-
associated kinase 4 (IRAK4) and subsequently activates IRAK1 and IRAK2 [8]. IRAK1 activation 
then leads to NF-κB activation via IκBα phosphorylation [9]. Recently, a study has shown that 
MYD88 L265P also activates the Bruton’s Tyrosine Kinase (BTK) pathway [6]. In this pre-clinical 
study, the activation of BTK by MYD88 could be abrogated using BTK kinase inhibitors. 
 
Another study from our group reported the occurrence of recurrent somatic CXCR4 gene 
mutations in approximately 30-40% of WM patients [10]. The somatic mutations occur in the C-
terminal domain and are like those observed in patients with WHIM (Warts, 
Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. These mutations regulate 
signaling of CXCR4 by its ligand SDF-1a [11]. In WM patients, two classes of CXCR4 mutations 
occur: non-sense (CXCR4WHIM/NS) and frameshift (CXCR4WHIM/FS) mutations [10, 12]. Non-sense 
and frameshift mutations are equally divided among WM patients, and over 30 different types of 
CXCR4 mutations have been identified. Preclinical studies with the most common CXCR4 S338X 
mutation in WM have shown sustained signaling of AKT, ERK and BTK following SDF-1a 
binding in comparison with wild-type CXCR4, as well increased cell growth and survival of WM 
cells [13]. 
 
The B-cell lymphoma-2 (BCL-2) family of proteins is central to the regulation of apoptosis. 
Altered responses to normal apoptotic signals are one of the hallmarks of cancer and they are 
connected to defects in the apoptotic machinery in cancer cells. Apoptosis occurs via activation of 
two different pathways, the extrinsic pathway, triggered by the activation of the cell surface death 
receptors, and the intrinsic pathway, followed by the perturbation of mitochondrial membrane 
integrity. Studies have shown that the intrinsic pathway is tightly controlled by the interactions 
between the pro- and anti-apoptotic BCL-2 family proteins [14]. Twenty-five known members of 
the BCL-2 protein family can be grouped functionally according to their pro- and anti-apoptotic 
effects, as well as structurally according to the BCL-2 homology (BH) regions they contain. The 
six known anti-apoptotic family members, BCL-2, Bcl-xL, Mcl-1, Bcl-w, Bcl-b and A1, contain 
four BH domains (BH1-4) and a transmembrane domain (TM). Pro-apoptotic proteins are 
subdivided into two classes: multi-domain members, such as Bax, Bak and Bok, which contain 
and share homology in the BH1, BH2, BH3 and BH4 domains and BH3-only proteins, including 
Bad, Bim, Puma, Bid, Bik, Noxa, Hrk and Bmf, which show homology only in the BH3 domain. 

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The overall and major response rates were 100% and 83%, respectively, and the 18-month PFS 
was 92%. CXCR4 mutations were associated with lower rates of VGPR. 
 
2.4 
Rationale 
 
The clinical course of WM is variable and although patients might experience an overall survival 
(OS) measured in decades [22, 23], WM remains incurable with current therapeutic regimens. 
Hence, the disease course is characterized by continual relapses, each harder to treat than the 
previous one. Additionally, many of the disabling symptoms associated with the disease, such as 
hyperviscosity, fatigue, anemia or neuropathy, can be exacerbated by our therapy [24]. Hence, the 
careful evaluation of agents with novel mechanisms of action is needed to improve the quality of 
life (QOL), and response and survival rates in patients with WM. 
 
Of note, no CR rates have been seen with single-agent ibrutinib therapy, and the rate of VGPR 
was 10-15% at 12 months. Therefore, investigating agents with increased activity that can induce 
deeper responses is warranted. 
 
The combination of ibrutinib and venetoclax is being examined in patients with CLL and MCL 
and appears to be safe and well tolerated. In patients with CLL, after 8 weeks of ibrutinib 
monotherapy (420 mg/day), venetoclax was added initially at a dose of 10 mg/day with weekly 
escalations to 20 mg, 50 mg, 100 mg, 200 mg to a final dose of 400 mg/day [25]. In MCL, patients 
received 4 weeks of ibrutinib (560 mg/day), followed by introduction of venetoclax (weekly ramp-
up to target 400 mg/day) [26]. 
 
Hypothesis: 
The combination of ibrutinib and venetoclax (IVEN) is associated with a high rate of very good 
partial response in participants with symptomatic treatment naïve Waldenström 
Macroglobulinemia. 
 
2.5 
Correlative Studies Background 
 
MYD88 L265P is a recently identified somatic mutation present in >90% of WM patients but in 
<5% of patients with other related processes such as CLL or MZL with plasmacytic differentiation 
or IgM myeloma [1]. Many groups have now validated the presence of this somatic mutation in 
WM patients. MYD88 L265P supports growth and survival of WM cells through both IRAK1 and 
IRAK4 [1] as well as by activation of Bruton tyrosine kinase (BTK) [6]. Based on these findings, 
we conducted a clinical trial using the BTK inhibitor ibrutinib in 63 patients with 
relapsed/refractory WM [18]. In this study, ibrutinib showed to be safe and effective. Median 
hemoglobin improved from 10.5 g/dl to 12.6 g/dl and IgM decreased from 3610 mg/dl to 1340 
mg/dl. Bone marrow involvement decreased from 70% to 45% with a best ORR of 81% and a 
major response rate of 57%. The major response rate was 77% for patients with wild-type CXCR4 
vs. 30% in those with WHIM-like CXCR4 mutations. Decreases in serum IgM as well as 
improvements in hemoglobin were greater in patients with wild-type CXCR4.  
 
In recent studies, the MYD88 and CXCR4 mutational status are predictive of clinical status, 
response to therapy and survival outcomes [12, 27]. Activating MYD88 as well as nonsense and 

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frameshift 
WHIM-like 
CXCR4 
somatic 
mutations 
are 
common 
in 
Waldenström 
macroglobulinemia. CXCR4 nonsense mutations are present in aggressive cases including 
hyperviscosity syndrome, and MYD88 status is a determinant of survival. The MYD88 L265P 
mutational analysis by allele-specific PCR and CXCR4 mutational analysis by Sanger sequencing 
will be performed by the Bing Center for Waldenström Macroglobulinemia in Boston, MA. 
 
Eligibility for the study includes known MYD88 mutation and will be based on testing at a CLIA 
certified laboratory.  If the participant has had MYD88 mutation testing previously performed by 
a CLIA accredited testing facility, with results determined to be acceptable by the Investigator, 
those results may be used for eligibility determination. 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Participants must meet the following criteria on screening examination to be eligible to 
participate.  Screening evaluations including consent, physical exam, and laboratory 
assessments will be done within 30 days prior to Cycle 1 Day 1.  Bone marrow biopsy & 
aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1. 
 
 
Clinicopathological diagnosis of Waldenström macroglobulinemia [28]. 
 
 
Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.  
 
 
Symptomatic disease meeting criteria for treatment using consensus panel criteria from the 
Second International Workshop on Waldenström macroglobulinemia [29]. 
 
 
Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must 
undergo plasmapheresis prior to treatment initiation.  
 
 
Age > 18 years 
 
 
ECOG performance status ≤2 (see Appendix A) 
 
 
Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum IgM 
level of  >2 times the upper limit of normal of each institution is required 
 
 
At the time of screening, participants must have acceptable organ and marrow function as defined 
below: 
− 
Absolute neutrophil count 
≥500/uL (no growth factor permitted) 
− 
Platelets 
≥50,000/uL (no platelet transfusions permitted) 
− 
Hemoglobin 
≥ 7 g/dL (transfusions permitted) 
− 
Total bilirubin 
< 1.5 x institutional ULN 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN 
− 
Estimated GFR  
 
 
≥30 mL/min 
 

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Females of childbearing potential (FCBP) must use one reliable form of contraception or have 
complete abstinence from heterosexual intercourse during the following time periods related to 
this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation 
from the study. FCBP must be referred to a qualified provider of contraceptive methods if 
needed. FCBP must have a negative serum pregnancy test at screening.  
 
 Men must agree to use a latex condom during treatment and for up to 90 days after the last dose 
of ibrutinib or venetoclax during sexual contact with a FCBP  
 
 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study:  
 
 
Participants who have one or more prior systemic therapies for WM. 
 
 
Participants who are receiving any other investigational agents. 
 
 
Participants with known CNS lymphoma. 
 
 
Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B 
virus (HBV) or hepatitis C (HCV) requiring active treatment.  Note: Participants with serologic 
evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive 
anti-HBc from IVIG may participate. 
 
 
Concurrent administration of medications or foods that are moderate or strong inhibitors or 
inducers of CYP3A within 7 days prior to first dose of study drug. 
 
 
Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C 
(Appendix B). 
  
 
Concurrent administration of warfarin. 
 
 
Concurrent systemic immunosuppressant therapy within 21 days of the first dose of study drug.  
 
 
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
  
 Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose 
of the study drug.  
 
 Known bleeding disorders (e.g., congenital von Willebrand’s disease or hemophilia) 
 
 History of stroke or intracranial hemorrhage within 6 months prior to enrollment.  
 
 Major surgery within 4 weeks of first dose of study drug.  
 

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 Malabsorption syndrome or other condition that precludes enteral route of administration. 
 
 Female participants who are pregnant, breastfeeding, or planning to become pregnant while 
enrolled in this study or within 90 days of last dose of study drug.   
 
 Male participants who plan to father a child while enrolled in this study or within 90 days after 
the last dose of study drug 
 
 Participants with known history of alcohol or drug abuse. 
 
 Participants with inability to swallow pills. 
 
3.2.19 On any active therapy for other malignancies with the exception of topical therapies for basal cell 
or squamous cell cancers of the skin. 
 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
 Participants with a history of non-compliance to medical regimens. 
 
 Participants who are unwilling or unable to comply with the protocol. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.1 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed. 
 

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4.2 
General Guidelines for Other Investigative Sites 
   
N/a 
 
4.3 
Registration Process for Other Investigative Sites 
 
N/a 
 
5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
participant’s malignancy. 
 
5.1 
Treatment Regimen 
 
Venetoclax and Ibrutinib will be administered daily, with 28 consecutive days defined as a 
treatment cycle. Ibrutinib will be administered for a maximum of 24 cycles.  Venetoclax will be 
administered for a maximum of 23 cycles. Participants will be initiated on Ibrutinib on Cycle 1 
Day 1, and Venetoclax dose escalation will begin on Cycle 2 Day 1 (+/- 2 days), starting at 100 
mg PO QD for 1 week.  Participants will then be escalated to 200 mg PO QD for 1 week and 
then to the target dose of 400 mg PO QD for the remainder of the study.   
 
At the completion of 24 cycles of therapy, participants will stop all treatment and enter follow-up 
for four years or until death.    
 
Treatment will be administered on an outpatient basis, except as specified below.  Reported 
adverse events and potential risks are described in Section 7.  Appropriate dose modifications are 
described in Section 6. 
 
Study treatment for all participants was terminated by the Sponsor-Investigator in March of 2022 
due to 4 events of ventricular arrhythmia.  As of 4/1/22 all participants were notified and 
instructed to stop study treatment and accrual was permanently discontinued. 
  
Table 5-1 
Regimen Description 
Agent 
Premedications; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Ibrutinib 
Not applicable 
 
420mg 
PO 
QD 
28 days 
(4 weeks) 
 
Venetoclax Allopurinol 300 mg QD beginning 
72 hours prior to first administration 
and continuing through Cycle 2 for 
TLS prophylaxis; Oral hydration 
(2L per day) for 24 hours prior to 
See 
Table  
6-1. 
PO 
QD 

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dose escalation and the Day of and 
day after 
*Order of administration of Ibrutinib and Venetoclax does not matter.  The medications should 
be taken at approximately the same time. 
 
5.2 
Pre-Treatment Criteria 
 
Cycle 1 Day 1 results do not need to meet eligibility parameters.  Day 1 chemistry and 
hematology laboratories must be reviewed prior to treatment. 
 
Participants must meet the following criteria on Day 1 of cycles with clinic visits (i.e. 1, 2, 3, 4, 
7, 10, etc.).  For venetoclax dose escalation days during Cycle 2, all below criteria must be met 
except for the neutrophil count (refer to section 6.2):   
• No grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic 
and/or antidiarrheal therapy) 
• No grade 4 or unmanageable nonhematologic grade 3 toxicities 
• Neutrophil count ≥500/ mm3 (growth factor permitted) 
• Platelet count ≥50,000/ mm3 in the presence of bleeding (platelet transfusion permitted, 
including on day of treatment) 
• Platelet count ≥25,000 mm3 without bleeding (platelet transfusion permitted, including 
on day of treatment) 
 
 
Cycle 1 Day 1 
 
Participants will begin ibrutinib 420 mg PO QD on Cycle 1 Day 1 and continue it as a single 
agent for 4 weeks to mitigate the risk of tumor lysis syndrome (TLS).  Participants will self-dose 
ibrutinib on an outpatient basis. 
 
 
Cycle 2 Venetoclax dose escalation 
 
Participants will return to clinic on Cycle 2 Day 1 to begin combination therapy with ibrutinib 
and venetoclax.  Venetoclax will be administered at the DFCI, or a participating site, infusion 
room on the first day of treatment, and at the first dose of each escalation (C2D8 and C2D15), 
and participants will be monitored for tumor lysis syndrome.   
 
5.3 
Agent Administration 
 
 
Venetoclax 
 
All participants will begin venetoclax at 100 mg PO once daily on Cycle 2 Day 1 (+/- 2 days) for 
7 days, followed by escalation to 200 mg PO once daily (Cycle 2 Day 8) for 7 days and then 400 
mg PO once daily (Cycle 2 Day 15) for 14 days.  If participants require dose adjustments or 
delays, Cycle 3 will not commence until the participant has taken venetoclax 400 mg for 7 
consecutive days.  Participants will continue venetoclax for a maximum of 23 cycles, or until 
unacceptable toxicity or disease progression.   At the completion of 24 cycles of therapy 
participants will discontinue all protocol therapy and enter follow-up until next therapy or death.  

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Dose reductions due to toxicity will be permitted on information seen in Table 6-1. 
 
The study drug venetoclax will be administered in the DFCI, or participating site, infusion room 
on the first dose of each dose escalation (C2D1, C2D8, C2D15, etc.) until a dose of 400 mg PO 
daily is reached. Otherwise, venetoclax will be self-administered, and participants will be 
instructed to write in a diary daily, documenting that the drug was taken. Participants will be 
instructed to take the study drug at approximately the same time each day. Participants will also 
be instructed on how to complete the diary. If a dose is missed, it can be taken up to 6 hours after 
the scheduled time with a return to the normal schedule the following day.  If it has been greater 
than 6 hours, the dose should not be taken, and the patient should take the next dose at the 
scheduled time the next day.  The missed dose will not be made up and must be returned to the 
site at the next scheduled visit; this must be documented in the study diary.  Furthermore, they 
will be instructed to call the PI or research nurse if vomiting occurs. If the pills are vomited, this 
should be noted on the patient diary, but a replacement dose should not be taken that day. All 
dosages prescribed and dispensed to the participant, and all dose changes during the study must 
be recorded. 
 
One cycle of venetoclax is once daily, oral administration for 4 weeks ± 1 week. Venetoclax 
should be taken with a meal, preferably low-fat.  Prescriptions for venetoclax will be written for 
daily administration for 1 cycle for participants in cycle 3 and will be written for daily 
administration for 12 weeks ± 1 week for participants being seen every 12 weeks starting on 
Cycle 4 Day 1. For cycle 2, a new prescription will be written for each dose escalation (i.e. 1 
week of dosing for C2D1 at starting dose, 1 week of dosing for C2D8 at escalated dose, and 2 
weeks of dosing for C2D15 at target dose).  Participants who have difficulties reaching the 
maximum target dose during dose escalation may have additional prescriptions written during 
Cycle 2.  Drug accountability will be done at each study visit; unused drug and diaries will be 
collected from the participant, unused drug will be counted and returned to the pharmacy to be 
destroyed. A new prescription for either one cycle or three cycles, as detailed above, will be 
filled by the participant, and they will be given a new diary.   
 
Medication labels will comply with US legal requirements and be printed in English. The storage 
conditions for study drug will be described on the medication label. 
Tumor Lysis Syndrome Prophylaxis (Refer to Section 6.3 for Recommendations for Initial 
Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS & 
refer to Appendix C for Definition of Laboratory and Clinical TLS)) 
 
First Dose of Venetoclax  
 
Tumor lysis syndrome prophylaxis must be initiated in all participants irrespective of their TLS 
risk category prior to the first dose of Venetoclax. TLS prophylaxis includes: 
• An oral agent to reduce the uric acid level (e.g., allopurinol) to be initiated at least 72 hours 
prior to dosing. Treatment should be continued until at least Cycle 2 Day 28 based on the 
ongoing risk of TLS development. Participants allergic to allopurinol must use another uric 
acid reducer.   
• Oral hydration consisting of fluid intake of 2 L per day starting at least 24 hours prior to 

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the start of treatment for all participants prior to first dose and continued for at least 24 
hours after dosing and all the chemistries laboratory values remain within ULN. Oral 
hydration is recommended beyond 24 hours post-dose for participants who demonstrate 
any laboratory changes. 
• Patients who are unable to maintain such oral hydration will receive IV hydration of 1 L in 
the outpatient setting on day 1 of venetoclax dosing in addition to oral hydration. In 
participants for whom volume overload is considered a significant risk, hospitalization 
should be considered. 
• Chemistry and hematology laboratory tests are to be collected and sent to local laboratory 
within 72 hours prior to the first dose of venetoclax. These laboratory values must be 
reviewed by the investigator. The investigator's decision to proceed with venetoclax 
treatment initiation may be based on these laboratory values. 
• Chemistry laboratory tests must be performed by local laboratory STAT at 0 hour (pre-
dose, within 4 hours before venetoclax administration), 8 hours post-dose (+/-30 minutes), 
and 24 hours (+/- 1 hour) after the first dose of venetoclax 100, 200 and 400 mg. Pre-dose 
laboratory values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration. Results from pre-dose laboratory 
values are not required to be available prior to initiating venetoclax treatment. Participants 
must remain at the hospital, or clinic, until the 8-hour laboratory values have been reviewed 
by the investigator. 
• Day 2 dose should not be taken until the 24 hours post-dose chemistry laboratory values 
are reviewed by the investigator.  Day 2 dose does not need to be administered in the clinic. 
• If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Cycle 2 Day 7 (day 7 of venetoclax dosing) in the outpatient 
setting. 
• If any significant laboratory changes are observed within the first 24 hours after initiation 
of dosing, see section 6.3 and Appendix D for recommendations on management. 
Additional laboratory assessments may be performed per investigator discretion. 
• All 24-hour post-dose laboratory assessments (Chemistry and Hematology) may be taken 
within a +/- 1-hour window, if necessary. 
 
First Dose of Venetoclax at Dose Escalation to 200 mg or 400 mg  
 
All participants, irrespective of their risk category, must receive the following TLS prophylaxis 
measures prior to subsequent dose increases of Venetoclax: 
• Continue administration of an oral uric acid reducer as indicated above.  
• Oral hydration consisting of fluid intake of approximately 2 L/day starting at least 24 hours 
prior to each dose escalation and continued for at least 24 hours after the dose. In participants 
who are unable to maintain such oral hydration, IV hydration with 1 L of 0.9% normal saline 
will be given in the outpatient setting on the day of dose escalation. In participants for whom 
volume overload is considered a significant risk, hospitalization should be considered. 
• For participants who receive their subsequent dose escalations in the outpatient clinic setting, 
Chemistry laboratory tests will be performed by the investigative site laboratory at 0 hours 
(pre-dose, within 4 hours before venetoclax administration), 8 hours post-dose (+/-30 minutes) 
and 24 hours post-dose (+/- 1 hour) administration. Hematology laboratory tests should be 

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performed at 0 hour (pre-dose, within 4 hours before venetoclax administration).  These 
laboratory values must be reviewed in real time by the investigator. Pre-dose laboratory values 
will be collected and used as baseline to assess potential electrolyte abnormalities occurring 
post venetoclax administration.  More frequent monitoring may be requested at the discretion 
of the investigator.  
• Participants must remain at the hospital, or clinic, until the 8-hour laboratory values have been 
reviewed by the investigator. 
• Day 2 dose should not be taken until the 24 hours post-dose chemistry laboratory values are 
reviewed by the investigator. Day 2 dose does not need to be administered in the clinic. 
• If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued for 7 days in the outpatient setting. Additional laboratory assessments 
may be performed per investigator discretion. 
• All 24-hour post-dose laboratory assessments (Chemistry and Hematology) may be taken 
within a +/- 1-hour window, if necessary. 
• For participants who are hospitalized during subsequent dose escalations, Chemistry and 
Hematology laboratory tests will be collected and sent to local laboratories upon admission. 
Chemistry tests will be performed by local laboratory STAT at 0 hour (pre-dose, within 4 hours 
before venetoclax administration), 4, 8, 12 (+/- 30 minutes) and 24 (+/- 1 hour) hours post 
dose. These laboratory values must be reviewed in real time by the investigator. Pre-dose 
laboratory values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration. 
o IV hydration should be started with a target of approximately 2 L per day, or as 
clinically appropriate, for participants who are hospitalized. 
o Hematology laboratory tests will be performed 24 hours post-dose.  
o The 24-hour post-dose laboratory results must be reviewed by the investigator prior to 
the participant leaving the hospital or receiving any additional doses of the study drug. 
• Chemistry and Hematology laboratory tests for all participants treated in the outpatient 
setting must be collected within 72 hours prior to the first dose of each dose escalation, and 
results must be reviewed by the investigator prior to each escalation. For participants 
demonstrating any clinically significant laboratory abnormalities, additional prophylactic 
treatment should be administered prior to dosing (see section 6.3 for recommendations on 
management; Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome [TLS]). 
 
 
Ibrutinib 
 
Ibrutinib 420 mg will be prescribed per the FDA package label, administered orally once daily. 
Ibrutinib will be self-administered, and participants will be instructed to write in a diary daily, 
documenting that the drug was taken.  The capsules should be taken around the same time each 
day with 8 ounces (approximately 240 mL) of water. The capsules should be swallowed intact and 
participants should not attempt to open capsules or dissolve them in water. Participants will be 
reminded that dietary habits around the time of ibrutinib intake should be as consistent as possible 
throughout the study. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville 
oranges should be avoided for the duration of the study (see section 5.3).  
 

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If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible within 
6 hours, with a return to the normal schedule the following day. The participant should not take 
extra capsules to make up the missed dose. The participant will be instructed to document missed 
drug doses in the study diary.  Furthermore, they will be instructed to call the PI or research nurse 
if vomiting occurs. If the pills are vomited, this should be noted on the patient diary, but a 
replacement dose should not be taken that day. All dosages prescribed and dispensed to the 
participant, and all dose changes during the study must be recorded. 
 
One cycle of ibrutinib is once daily, oral administration for 4 weeks +/- 1 week.  At each study 
visit, enough ibrutinib will be dispensed until the next cycle.  For visits occurring monthly, one 
cycle of capsules in a bottle will be dispensed.  For visits occurring every 12 weeks +/-1 weeks 
three cycles of capsules will be dispensed.  Study drug may be shipped to participants through a 
traceable courier.  Drug accountability will be done at each study visit; unused drug and diaries 
will be collected from the participant, unused drug will be counted and returned to the pharmacy 
to be destroyed.  Returned capsules must not be re-dispensed to any participant. 
 
Dose reductions due to toxicity will be permitted on information seen in Section 6. 
 
Participants will be treated with ibrutinib for up to 24 cycles or until progression, unacceptable 
toxicity, or decision to withdraw from the trial.  Participants will then discontinue ibrutinib and 
enter follow-up for four years or until death.   
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Participants will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the participant about any new medications he/she is or has taken 
after the start of the study drug. 
 
Anti-emetics are permitted if clinically indicated. Standard supportive care medications are 
permitted. All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to 
start and after start of study drug, including physical therapy and blood transfusions, should be 
recorded. The following restrictions apply during the entire duration of the study: 
• 
No other investigational therapy should be given to participants. 
• 
No anticancer agents other than the study medications should be given to participants. If 
such agents are required for a patient, then the patient must first be withdrawn from the 
study. 
• 
Growth factors (i.e. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) can 
be administered prophylactically, except for eligibility, and may be prescribed at the 
discretion of the treating physician for treatment-related hematologic events in 
accordance with ASCO guidelines, and to meet re-treatment criteria. 
• 
Transfusions of red blood cells can be administered to meet eligibility and for treatment-
related hematologic events in accordance with ASCO guidelines, and to meet re-
treatment criteria. 

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• 
Transfusions of platelets can be administered for treatment-related hematologic events in 
accordance with ASCO guidelines, and to meet re-treatment criteria.  They may not be 
administered to meet eligibility. 
• 
Warfarin or vitamin K antagonists should not be administered. 
• 
Participants requiring the initiation of therapeutic anticoagulation therapy (eg, 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 drug is restarted. 
• 
Use ibrutinib with caution in participants requiring other anticoagulants or medications 
that inhibit platelet function. In an in vitro platelet function study, inhibitory effects of 
ibrutinib on collagen-induced platelet aggregation were observed. Supplements such as 
fish oil and vitamin E preparations should be avoided during treatment with ibrutinib. 
Bleeding events of any grade, including bruising and petechiae, occurred in participants 
treated with ibrutinib. Ibrutinib should be held at least 3 to 7 days pre- and post-surgery 
depending upon the type of surgery and the risk of bleeding (see Section 5.4.1). 
Participants with congenital bleeding diathesis have not been studied. 
• 
Administration of moderate or strong CYP3A4 inhibitors and inducers should be 
avoided.  Alternatives should be sought if possible.  During the dose escalation phase, 
moderate or strong CYP3A4 inhibitors and inducers are prohibited. See table 5-2 below 
for ibrutinib and venetoclax dose modification guidelines during CYP3A treatment. 
• 
Grapefruit and grapefruit juice affect CYP450 and P-glycoprotein activity and should 
therefore be avoided.   
• 
In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors. 
• 
No chronic treatment with systemic steroids (at dosages equivalent to prednisone >20 
mg/day) or other immunosuppressive agents. Topical or inhaled corticosteroids are 
allowed. 
 
 
 
 
 
 
 
 

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Table 5-2 Ibrutinib & Venetoclax Dose Modification Guidance for CYP3A 
Inhibitors/Inducers after Dose Escalation 

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Patient 
Population 
Co-administered Drug 
Recommended Ibrutinib 
Dose for the Duration of 
the Inhibitor Usea 
Recommended Venetoclax 
Dose for the Duration of 
the Inhibitor Use 
B-Cell 
Malignancies 
Mild CYP3A inhibitors 
420 mg. No dose adjustment 
required. 
No dose adjustment 
required. 
Moderate CYP3A 
inhibitors 
280 mg once daily. 
Reduce the venetoclax dose 
by 50% during co-
administration.   
Voriconazole  
Posaconazole at doses 
less than or equal to 
suspension 200 mg BID  
140 mg once daily. 
 
Reduce the venetoclax dose 
by at least 75% during co-
administration.  After 
discontinuation of CYP3A 
inhibitor, wait for 2-3 days 
before increasing venetoclax 
dose back to 
maintenance/target dose. 
Other strong CYP3A 
inhibitors 
Posaconazole at higher 
dosesb  
Avoid concomitant use and 
consider alternative with less 
CYP3A inhibitory potential. 
If these inhibitors will be 
used short-term (such as 
anti-infectives for seven 
days or less), interrupt 
ibrutinib. 
If the benefit outweighs the 
risk, and long-term dosing 
with a CYP3A inhibitor is 
required (more than seven 
days), reduce ibrutinib dose 
to 140 mg once daily for the 
duration of the inhibitor use. 
a. 
Monitor for adverse reactions to IMBRUVICA and interrupt or modify dose as recommended (see Dosage and 
Administration). 
b. 
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole IV 
injection 300 mg once daily, posaconazole delayed-release tablets 300 mg once daily). 
 
After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib. 
Avoid concomitant use of systemic strong CYP3A inducers (e.g., carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided below in table 5-3.  
 
 
 
Table 5-3 Moderate and Strong Inhibitors and Inducers of CYP3A4/5 
Inhibitors of CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
Moderate inhibitors: 
Strong CYP3A inducers: 

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Boceprevir 
Clarithromycin 
Cobicistat 
Conivaptan 
Danoprevir/ritonavir 
Elvitegravir/ritonavir 
Idelalisib 
Indinavir 
Itraconazole 
Ketoconazole 
Mibefradil 
Lopinavir/ritonavir 
Nefazodone 
Nelfinavir 
Ritonavir 
Paritaprevir/ritonavir combinations 
Posaconazle 
Squinavir 
Telaprevir 
Telithromycin 
Tipranavir/ritonavir 
Voriconazole 
Amprenavir 
Aprepitant 
Atazanavir 
Cimetidine 
Ciprofloxacin 
Clotrimazole 
Crizotinib 
Cyclosporine 
Darunavir/ritonavir 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Imatinib 
Isavuconazole 
Tofisopam 
Verapamil 
 
 
 
 
 
Avasimibe 
Carbamazepine 
Enzalutamine 
Mitotane 
Phenytoin 
Rifampin 
St. John’s wort 
 
Moderate CYP3A inducers: 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
 Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm080499.htm or http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
Antiplatelet Agents and Anticoagulants  
 
Guidelines for Ibrutinib Management with Surgeries or Procedure 
 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The mechanism for 
the bleeding events is not well understood.  Consider the benefit-risk of withholding ibrutinib for 
at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of 
bleeding. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), combination treatment may 
continue for 24 cycles, or until one of the following criteria applies: 
• Dose delays of >28 days for either ibrutinib or venetoclax* 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• Participant decides to withdraw from the protocol therapy 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 

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*Participants may be continued on protocol therapy at the discretion of the Principal Investigator. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
Study treatment for all participants was terminated by the Sponsor-Investigator in March of 2022 
due to 4 events of ventricular arrhythmia.  As of 4/1/22 all participants were notified and 
instructed to stop study treatment and accrual was permanently discontinued. 
 
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
5.6 
Duration of Follow Up 
 
Participants will be followed for a maximum of 6 years from Cycle 1 Day 1, with 4 years of 
follow-up or until death, whichever occurs first.  Participants removed from protocol therapy for 
unacceptable adverse event(s) will be followed at a minimum until resolution or stabilization of 
the adverse event. Participants will be followed for progression free survival until documented 
disease progression or initiation of new therapy.  After this, they will be followed for survival 
until the conclusion of the follow-up period. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure is the 
participant’s status is updated in OnCore in accordance with DF/HCC policy REGIST-OP-1. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). All adverse events 
experienced by participants will be collected from the time of the first dose of study treatment, 

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through the study and until 30 days after the last dose of study treatment. Participants continuing 
to experience toxicity at the off-treatment visit may be contacted for additional assessments until 
the toxicity has resolved or is deemed irreversible. 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted. If administration of Venetoclax or Ibrutinib must be interrupted because of 
unacceptable toxicity, drug dosing will be interrupted or modified according to rules described in 
Section 6.1.  
 
If dose reductions of Venetoclax are needed during the dose escalation period, dose escalation 
should continue on a weekly basis to reach the targeted dose of 400 mg PO daily (e.g. if a 
participant cannot tolerate the 400mg dose escalation, they should be reduced back to 200mg for 
1 week, and then re-challenged at 400mg the following week, etc.). In this case, Cycle 2 could last 
for >4 weeks.  Once at goal dose of 400 mg PO daily, dose reductions are permitted down to 100 
mg PO daily before a patient is taken off study. However, patients will remain on study to assess 
for progression. If a participant requires a dose delay of > 28 days of either ibrutinib or venetoclax, 
then the participant must be discontinued from the study, unless permitted to resume after 
discussion with the Principal Investigator.  If a participant requires permanent discontinuation of 
either ibrutinib or venetoclax, then the participant will be taken off study. 
 
6.1 
Dose Reduction Guidelines for Venetoclax & Ibrutinib 
 
Table 6-1 Venetoclax Dose Modification Guidelines 
Dose Level 
Venetoclax 
Dose Level 1 
Venetoclax 
Dose Level -1 
Venetoclax 
Dose Level -2 
Cycle 2 Day 1 Starting 
dose  
100 mg QD 
- 
- 
 Cycle 2 Day 8 Escalation  
200 mg QD 
100 mg QD 
- 
Cycle 2 Day 15 
Escalation, and all cycles 
thereafter 
 
400 mg QD 
 
200 mg QD 
 
100 mg QD 
 
Table 6-2 Ibrutinib Dose Modification Guidelines 
Dose Level 
Ibrutinib Dose and 
Schedule 
Dose Level 1 
420 mg QD 
-1 
280 mg QD 
-2 
140 mg QD 
 
Table 6-3 Drug Modification/Discontinuation Actions for Venetoclax related (possibly, 
probably, definitely) events or pre-specified events per section 6.2 (i.e. nausea, vomiting, 
diarrhea, neutropenia, thrombocytopenia) 
• 1st Hold: Venetoclax until recovery from criteria to hold; may restart at original dose level. 
• 2nd Hold: Venetoclax until recovery from criteria to hold; restart at -1 dose level. 

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• 3rd Hold: Venetoclax until recovery from criteria to hold; restart at -2 dose level (if 
applicable, see table 6-1) 
• 4th Hold: Discontinue Venetoclax  
Table 6-4 Drug Modification/Discontinuation Actions for Ibrutinib related (possibly, 
probably, definitely) events or pre-specified events per section 6.2 (i.e. nausea, vomiting, 
diarrhea, neutropenia, thrombocytopenia) 
• 1st Hold: Ibrutinib until recovery from criteria to hold; may restart at original dose level. 
• 2nd Hold: Ibrutinib until recovery from criteria to hold; restart at -1 dose level. 
• 3rd Hold: Ibrutinib until recovery from criteria to hold; restart at -2 dose level  
• 4th Hold: Discontinue Ibrutinib 
 
6.2 
Venetoclax & Ibrutinib Dose Adjustments for AEs 
 
Nausea 
Management/Next Dose for Venetoclax Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until < Grade 2 if persistent despite 
optimal antiemetic therapy.  Resume per 
Table 6-3. 
Hold until < Grade 2 if persistent 
despite optimal antiemetic therapy.  
Resume per Table 6-4. 
Grade 4 
Hold until < Grade 2.  Resume per Table 
6-3. 
Hold until < Grade 2.  Resume per 
Table 6-4. 
Recommended management:  antiemetics. 
 
Vomiting 
Management/Next Dose for Venetoclax Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until < Grade 2 if persistent despite 
optimal antiemetic therapy.  Resume per 
Table 6-3. 
Hold until < Grade 2 if persistent 
despite optimal antiemetic therapy.  
Resume per Table 6-4. 
Grade 4 
Hold until < Grade 2.  Resume per Table 
6-3. 
Hold until < Grade 2.  Resume per 
Table 6-4. 
Recommended management:  antiemetics. 
 
Diarrhea 
Management/Next Dose for Venetoclax Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until < Grade 2 if persistent despite 
optimal antidiarrheal therapy.  Resume 
per Table 6-3. 
Hold until < Grade 2if persistent 
despite optimal antidiarrheal therapy.  
Resume per Table 6-4. 
Grade 4 
Hold until < Grade 2.  Resume per Table 
6-3. 
Hold until < Grade 2.  Resume per 
Table 6-4. 
Recommended management:  Loperamide antidiarrheal therapy. 
 
Neutropenia 
Management/Next Dose for Venetoclax Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose 
No change in dose 

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Neutropenia 
Management/Next Dose for Venetoclax Management/Next Dose for Ibrutinib 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose.  Hold until <Grade 2 
if infection and/or fever present.  Resume 
per Table 6-3. 
No change in dose.  Hold until <Grade 
2 if infection and/or fever present.  
Resume per Table 6-4. 
Grade 4 
Hold if grade 4  >7 days until < Grade 3.  
Resume per Table 6-3. 
Hold if grade 4  >7 days until < Grade 
3.  Resume per Table 6-4. 
*Administer G-CSF or growth factors for neutropenia as indicated. 
 
Thrombocytopenia 
Management/Next Dose for 
Venetoclax 
Management/Next Dose for 
Ibrutinib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until < Grade 2 if bleeding present.  
No change in dose in the absence of 
bleeding.  Resume per Table 6-3. 
Hold until < Grade 2 if bleeding 
present. No change in dose in the 
absence of bleeding.  Resume per 
Table 6-4. 
Grade 4 
Hold until < Grade 3.  Resume per Table 
6-3. 
Hold until < Grade 3.  Resume per 
Table 6-4. 
*Platelet transfusions for thrombocytopenia permitted. 
 
Non-Hematological 
Toxicities not 
otherwise specified* 
Management/Next Dose for 
Venetoclax 
Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold until < Grade 2. Resume per 
Table 6-3. 
Hold until < Grade 2. Resume per 
Table 6-4. 
Grade 4 
Hold until < Grade 2. Resume per 
Table 6-3. 
Hold until < Grade 2. Resume per 
Table 6-4. 
* If the investigator determines that the toxicity is only attributable to either Venetoclax or Ibrutinib, 
but not both, dosing of the other medication may be continued. 
 
 
Ibrutinib Dose Modification for Hepatic Impaired Participants 
 
Participants who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on 
study should be managed per standard dose modification guidelines in Section 6.2. Ibrutinib is 
metabolized in the liver and therefore participants with clinically significant chronic hepatic 
impairment at the time of Screening (Child- Pugh class C) are excluded from study participation. 
Concomitant use of strong CYP inhibitors is not permitted in participants with chronic hepatic 
impairment. Refer to Appendix D for Child-Pugh classification. Please refer to Table 6.2.1 for 
dose modifications due to hepatic impairment.  
 
Table 6.2.1. 
Dose Modification Guidance for Hepatic Impaired Participants 

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Child Pugh class A 
(Mild hepatic 
impairment)* 
Child Pugh Class B 
(Moderate hepatic 
impairment)** 
Child Pugh class 
C  
(Severe hepatic 
impairment)  
 
Ongoing at 
time of 
enrollment  
Develops 
during 
study  
Ongoing at 
time of 
enrollment  
Develops 
during study  
Develops during 
study  
Ibrutinib 
Dose 
(daily)  
280 mg  
280mg 
140 mg 
140 mg  
Hold until 
improves to 
moderate [Class 
B] or better) 
* If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In 
the event that additional reduction is needed, ibrutinib should be held for non-hepatic toxicity 
until resolution. 
** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until 
resolution.  
 
6.3 
Venetoclax Dose Modifications for first dose of Venetoclax (100 mg) and first dose 
escalation (200 mg and 400 mg) 
 
First Dose of Venetoclax or Dose Escalation 
• Within the first 24 hours after either the first dose or dose escalation, if laboratory values 
suggestive of laboratory tumor lysis syndrome are observed (see Table 6-5), the patient 
should be hospitalized for monitoring and the investigator notified. Use 0-4 hour pre-dose 
values for each escalation day for comparison for TLS determination.  No additional 
venetoclax doses should be administered until resolution. Rapidly rising serum potassium is a 
medical emergency. 
• Nephrology (or other acute dialysis service) should be contacted/consulted (per institutional 
standards to ensure emergency dialysis is available) on admission for any participant 
hospitalized prophylactically or in response to laboratory changes. 
• IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr 
rounded to the nearest 10 mL (target 150 to 200 mL/hr; not < 50 mL/hr). Modification of 
fluid rate should also be considered for individuals with specific medical needs. 
• Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, vomiting, 
diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status 
changes, confusion and seizures). If any clinical features are observed, recheck potassium, 
phosphorus, uric acid, calcium and creatinine within 1 hour STAT. 
• Vital signs should be taken at time of all blood draws or any intervention. 
• If a diagnosis of laboratory or clinical TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be per institutional protocols. 
 
In addition to Table 6-5 below, for participants receiving the first dose of Venetoclax: 
• For potassium increase ≥ 0.5 mmol/L from pre-dose baseline, or any value > 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT and 
refer to Appendix D for further management, unless determined to be not clinically indicated 

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by the investigator. 
• For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate binder and 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT, unless 
determined to be not clinically indicated by the investigator. 
 
See Appendix D for additional recommendations on management of laboratory abnormalities not 
meeting the definition of laboratory TLS. 
 
Table 6-5 Laboratory TLS 
 
To meet the definition of laboratory TLS participants must experience two or more of the 
following criteria post-dose within a 24-hour span, and within seven days of initiating venetoclax 
therapy 
or escalating the dose of venetoclax: 
• Potassium > 6.0 mmol/liter 
• Phosphorus > 4.5 mg/dL 
• Corrected calcium < 7.0 mg/dL, or ionized calcium <1.12 
• Uric acid > 8.0 mg/dL 
• Increase in serum creatinine of 0.3 mg/dL 
 
If TLS (laboratory or clinical) is diagnosed, hold venetoclax dosing until resolution to baseline 
and initiate supportive care per institutional guidelines.  Upon resolution, resume dosing and 
consider additional monitoring and hospitalization for subsequent dose escalation. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  Adverse 
events will be captured after study treatment initiation and through 30 days after the last dose of 
study treatment.  The following list of reported and/or potential AEs (Section 7.1) and the 
characteristics of an observed AE (Section 7.2) will determine whether the event requires 
expedited reporting in addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting. 
 
 
Adverse Events List 
 
7.1.1.1 
Adverse Event List(s) for Venetoclax 
 
Most subjects (93.8%) receiving venetoclax monotherapy reported at least 1 adverse 
event. The most common adverse events were neutropenia (32.7%), diarrhea (36.8%), nausea 
(35.8%), and fatigue (24.5%). 
 

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7.1.1.2 
Adverse Event List(s) for Ibrutinib 
 
Bleeding-related events  
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. 
Initially, subjects were excluded from participation in specific ibrutinib Phase 2 and 3 studies if 
they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists 
should not be administered concomitantly with ibrutinib unless specified in the protocol. 
Supplements such as fish oil and vitamin E preparations should be avoided.  In an in vitro platelet 
function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation were 
observed. Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit 
platelet function may increase the risk of bleeding. See Section 5.4 for guidance on concomitant 
use of anticoagulants, antiplatelet therapy and/or supplements. Ibrutinib should be held at least 3 
to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.  See 
Section 5.4.1 for guidance on ibrutinib management with surgeries or procedures.   
 
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Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness, syncope, chest discomfort or new onset of dyspnea) 
should be evaluated clinically, and if indicated, have an ECG performed. For cardiac arrhythmias 
which persist, consider the risks and benefits of ibrutinib treatment and follow the protocol dose 
modification guidelines (see Section 6). 
 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly.  
 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for 
gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical 
evaluation should be made to rule out other etiologies such as Clostridium difficile or other 
infectious agents. Should symptoms be severe or prolonged follow the protocol dose modification 
guidelines (see Section 6). 
 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects for 
new onset of hypertension or hypertension that is not adequately controlled after starting ibrutinib. 
Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as 
appropriate. 
 
Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated 
with ibrutinib. Some of these infections have been associated with hospitalization and death. 
Consider prophylaxis according to standard of care in subjects who are at increased risk for 
opportunistic infections.  Although causality has not been established, cases of progressive 
multifocal leukoencephalopathy (PML) and hepatitis B reactivation have occurred in subjects 
treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, chills, 
weakness, confusion, vomiting and jaundice) and appropriate therapy should be instituted as 
indicated. 
 
Non-Melanoma Skin Cancer  
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients for 
the appearance of non-melanoma skin cancer. 
 
Rash  
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases of 
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been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs and 
symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be observed 
closely for rashes and treated symptomatically, including interruption of the suspected agent as 
appropriate. In addition, hypersensitivity-related events including erythema, urticaria, and 
angioedema have been reported. 
 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from 
baseline and an absolute count >5,000/µL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects with CLL/small lymphocytic lymphoma (SLL) treated with 
ibrutinib as single agent. This effect has also been observed in some subjects with MCL treated 
with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and should not be 
considered progressive disease in the absence of other clinical findings. In both disease types, 
lymphocytosis typically occurs during the first month of ibrutinib therapy and typically resolves 
within a median of 8.0 weeks in subjects with MCL and 14 weeks in subjects with CLL/SLL. A 
large increase in the number of circulating lymphocytes (eg, >400,000/mcL) has been observed in 
some subjects.  
 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib and/or venetoclax therapy. Subjects at risk 
of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor subjects 
closely and take appropriate precautions. 
 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt 
ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines as needed (Section 6).  

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7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  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. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 

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- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Adverse Event Reporting  
 
 
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI. 
 
 
Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form.  
 
 
DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
Protocol-Specific Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
N/a 
 
7.4 
Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.5 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy.  
 

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7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
7.7 
Routine Adverse Event Reporting to AbbVIE 
 
Adverse Events & Pregnancy. In addition to compliance with all FDA reporting requirements 
pursuant to 21 C.F.R. § 312, the Principal Investigator shall: 
a. Report to AbbVie (A) all pregnancies and all serious adverse events experienced by a study 
subject receiving an AbbVie product within 24 hours of learning of the pregnancy/event 
regardless of the relationship of the event to the AbbVie product; and (B) any pregnancies 
experienced by a partner of a Study subject receiving AbbVie product within one business 
day of becoming aware of such partner pregnancy; and (C) all non-serious adverse events 
of tumor lysis syndrome.  Principal Investigator shall make available to AbbVie promptly 
such records as may be necessary and pertinent to investigate any such pregnancy/event, if 
specifically requested by AbbVie.. 
i. 
Serious AE (SAE) means any untoward medical occurrence that meets one of the 
following criteria: 
i. Results in death 
ii. Is life-threatening 
iii. Requires inpatient hospitalization for >24 hours or prolongation of 
hospitalization 
iv. Is a congenital anomaly 
v. Results in persistent or significant disability/incapacity 
vi. Other serious (Important Medical Events) Events that do not fit the other 
outcomes but may require medical or surgical intervention to prevent one 
of the other outcomes.   
b. copy AbbVie on the submission to the FDA of events meeting the definition of IND safety 
reports at the time of submission to the Agency; and 
c. notify AbbVie upon any subject receiving an AbbVie Product whose pregnancy has 
resulted in a negative outcome or untoward event during the course of pregnancy or upon 
delivery.   
AbbVie’s contact for reporting serious adverse drug experiences, pregnancy experiences, non-
serious adverse events of tumor lysis syndrome, and communication of FDA submissions of 
IND safety reports shall be  PPDINDPharmacovigilance@abbvie.com  
 
7.8 
Expedited Reporting to Pharmacyclics, LLC 
 
All serious adverse events and AESIs (initial and follow-up information) will be reported on 
FDA Medwatch (Form 3500A) and sent via email (AEintakePM@pcyc.com) or fax ((408) 215-
3372) to Pharmacyclics Drug Safety, Pharmacovigilance & Epidemiology (DSP&E) or designee, 
within 24 hours of the event. Pharmacyclics may request follow-up and other additional 
information from the Sponsor Investigator. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 

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discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct. 
• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.  
 
A serious adverse event (SAE) based on International Conference on Harmonisation (ICH) and 
EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward 
medical occurrence that at any dose: 
• 
Results in death (i.e., the AE actually causes or leads to death). 
• 
Is life-threatening. Life-threatening is defined as an AE in which the subject was at risk 
of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe. If either the investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• 
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize the subject or 
subject may require intervention to prevent one of the other outcomes listed in this 
definition. Examples of such events are intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias, or convulsion that does not 
result in hospitalization; or development of drug dependency or drug abuse. 
• 
Any pregnancy occurring in a female participant or female partner of a male participant 
must be reported from the time of first dose up until 90 days after the last dose of study 
drug.  This should be reported on the Pregnancy Report Form Part 1.  All pregnancies 
will be followed for outcome, which is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, the 
newborn infant will be followed until 30 days old by completing the Pregnancy Report 
Form Part II. Any congenital anomaly/birth defect noted in the infant must be reported 
as a SAE. 
 
 
 

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Adverse Events of Special Interest (AESI) 
 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or f ax to Pharmacyclics Drug Safety, or 
designee, within 24 hours of awareness.  
 
7.8.1.1 
Major Hemorrhage 
 
Major hemorrhage is defined as any of the following:  
• 
Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*.  
• 
Any treatment-emergent serious adverse events of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 
or higher AE per CTCAE v5. 
 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 7.7.1 above. 
 
 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject or female partner of a male subject must immediately inform the investigator if 
she becomes pregnant from the time of consent to 90 days after the last dose of study drug(s). 
Any female subjects receiving study drug(s) who become pregnant must immediately 
discontinue study drug. The investigator should counsel the subject, discussing any risks of 
continuing the pregnancy and any possible effects on the fetus.  
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Any pregnancy occurring in a female subject or female partner of a male subject must be 
reported from the time of first dose up until 90 days after the last dose of study drug(s). Any 
occurrence of pregnancy must be recorded on the Pregnancy Report Form Part I and sent via 
email or fax to Pharmacyclics Drug Safety, Pharmacovigilance & Epidemiology (DSP&E) or 
designee, per SAE reporting timelines of learning of the event. All pregnancies will be followed 
for outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery 
of the fetus. For pregnancies with an outcome of live birth, the newborn infant will be followed 
until 30 days old by completing the Pregnancy Report Form Part II. Any congenital 
anomaly/birth defect noted in the infant must be reported as a SAE. 
 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 

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protocol-specified follow-up periods including post-progression follow-up for overall survival. If 
observed, enter data in the corresponding eCRF. 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Venetoclax 
 
 
Description 
 
Venetoclax (ABT-199) has the molecular formula C45H50ClN7O7S and a molecular weight of 
868.44. ABT- 199 is a light yellow to dark yellow powder and is freely soluble in vinylpyrrolidone 
dimer; soluble in polyethylene glycol (PEG) 400; very slightly soluble in 1% (w/v) Cremophor 
RH40, and is practically insoluble in water. There are no optical isomers.  
 
 
Form 
 
Venetoclax (ABT-199) is provided as a yellow film-coated tablet in 50 and 100mg strength. 100mg 
tablets will be supplied for this study.  
 
 
Storage and Stability 
 
Venetoclax tablets will be supplied in blister cards or bottles and supplied by AbbVie. See label 
for storage conditions. 
 
The investigational products are for investigational use only and are to be used only within the 
context of this study. The study drug supplied for this study must be maintained under adequate 
security and stored under the conditions specified on the label.  
 
 
Compatibility 
 
N/a. 
 
 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
 
Availability 
 
Venetoclax is provided by AbbVIE, Inc.  The study drug will be labeled and handled as open-label 
material, and packaging labels will fulfill all requirements specified by governing regulations. 
 

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Preparation 
 
Venetoclax (ABT-199) is provided as a yellow film-coated tablet in 50 and 100mg strength. 100mg 
tablets will be supplied for this study in blister cards of 8 or 16, or in 120 count bottles which must 
not be opened and re- packaged. Additionally, the bottles cannot be opened for removal and 
destruction of excess pills to prevent a large overage quantity.  It will be packaged in high density 
polyethylene (HDPE) plastic bottles to accommodate the study design. Each bottle or blister card 
will be labeled per regulatory requirements. Labels must remain affixed to the bottle or blister 
card.  
 
 
Administration 
 
Venetoclax (ABT-199) should be self-administered daily by the participant and should be taken at 
approximately 30 minutes after a  meal, at approximately the same time each day. Venetoclax 
should be administered with 8 ounces (approximately 240 mL) of water (avoid GRAPEFRUIT 
JUICE due to CYP3A4 inhibition). The tablets should be swallowed intact. If a dose is missed, it 
can be taken up to 6 hours after the scheduled time with a return to the normal schedule the 
following day. If it has been greater than 6 hours, the dose should not be taken and the participant 
should take the next dose at the scheduled time the next day. The missed dose will not be made up 
and must be returned to the site at the next scheduled visit.  
 
Dietary habits around the time of Venetoclax intake should be as consistent as possible throughout 
the study. If the pills are vomited this should be noted on the diary, but a replacement dose should 
not be taken that day. A study diary will be used to aid with study drug administration compliance.  
Except for cycle 2 which may be longer, one cycle of Venetoclax is once daily, oral administration 
for 4 weeks ± 1 week. At each study visit, enough Venetoclax will be dispensed until the next 
cycle. For cycle 2, a new prescription will be written for each dose escalation (i.e. 1 week of dosing 
for C2D1 at starting dose, 1 week of dosing for C2D8 at escalated dose, and 2 weeks of dosing for 
C2D15 at target dose).  Participants who have difficulties reaching the maximum target dose 
during dose escalation may have additional prescriptions written during Cycle 2.  For visits 
occurring monthly (every 4 weeks ± 1 week), one cycle of pills (5 weeks of venetoclax therapy) 
will be dispensed. For visits occurring every 12 weeks ± 2 weeks), three cycles of pills (14 weeks) 
will be dispensed.  
 
 
Ordering 
 
Venetoclax (ABT-199) is an investigational agent and will be supplied free-of-charge from 
AbbVIE, Inc. 
 
The contact for ordering is: 
 
iisoncologysupport@abbvie.com 
 
 
Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 

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Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
 
Destruction and Return 
 
Unused venetoclax tablets will be returned by the participant, collected and counted at each 
study visit, and will be returned to pharmacy for destruction. Unused supplies of venetoclax 
should be destroyed according to institutional policies. Destruction will be documented in the 
Drug Accountability Record Form.  
 
8.2 
Ibrutinib 
 
 
Description 
 
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis). 
Ibrutinib exhibited 18% to 23% oral bioavailability in rats and 7% to 11% oral bioavailability in 
dogs. The mean terminal half-life of ibrutinib after oral administration ranged from 1.7 to 3.1 
hours in mice, 1 to 4.7 hours in rats, and 3.3 to 6.4 hours in dogs. In healthy subjects and in 
patients with B-cell malignancies, ibrutinib is readily absorbed with a 
median time to maximum concentration (Tmax) of 1 to 2 hours and half-life of 4 to 6 hours.There 
are no effects of mild and moderate renal impairment on drug clearance. . A hepatic impairment 
study was performed in non-cancer subjects administered a single dose of 140 mg ibrutinib under 
fasting conditions. Ibrutinib AUClast increased 2.7-, 8.2- and 9.8-fold in subjects with mild (n = 6; 
Child-Pugh Class A), moderate (n = 10; Child-Pugh Class B) and severe (n = 8; Child-Pugh 
Class C) hepatic impairment, respectively. The free fraction of ibrutinib also increased with 
degree of impairment, with 3.0%, 3.8%, and 4.8% in subjects with mild, moderate, and severe 
liver impairment, respectively, compared to 3.3% in plasma from matched healthy controls 
within this study. The corresponding increase in unbound ibrutinib exposure (AUCunbound,last) is 
estimated to be 4.1-, 9.8-, and 13-fold in subjects with mild, moderate, and severe impairment, 
respectively. The recommended doses for patients with mild and moderate liver impairment are 
280 mg/day and 140 mg/day (Child-Pugh Class A and B, respectively). It is recommended not to 
administer ibrutinib to subjects with severe hepatic impairment (Child-Pugh Class C). In vitro 
studies have indicated that ibrutinib is metabolized extensively by cytochrome P450 (CYP) 3A4. 
 
 
Form 
 
The structure of ibrutinib is: 
 

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Ibrutinib is a white to off-white crystalline solid. Ibrutinib has a single chiral center and is the R-
enantiomer. Ibrutinib product is manufactured for Pharmacyclics LLC by a contract manufacturer.  
 
Ibrutinib PO Hard Gelatin Capsule is an oral formulation containing micronized ibrutinib and the 
following compendial excipients: microcrystalline cellulose (NF); croscarmellose sodium (NF); 
sodium lauryl sulfate (NF); may contain magnesium stearate (NF). The 140 mg strength contains 
140 mg of the active ingredient, ibrutinib, adjusted for water content and purity in a size 0, gray, 
hard gelatin capsule. Capsules are packaged in 60-cc high-density polyethylene (HDPE) bottles 
with an induction seal and a child resistant screw top cap. Each bottle is distributed by 
Pharmacyclics LLC. The number of capsules per bottle is indicated on the label.   
 
 
Storage and Stability 
 
Ibrutinib should be stored according to the package insert. 
 
 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
 
Availability 
 
Ibrutinib is provided by Pharmacyclics, LLC.  The study drug will be labeled and handled as open-
label material, and packaging labels will fulfill all requirements specified by governing regulations 
 
 
Preparation 
 
Ibrutinib capsules are packaged in 60-cc high-density polyethylene (HDPE) bottles with an 
induction seal and a child resistant screw top cap. 140mg capsules will be supplied for this study 
in 92 or 120 count bottles which must not be opened and re-packaged.  Additionally, the bottles 
cannot be opened for removal and destruction of excess pills to prevent a large overage quantity. 
Each bottle will be labeled per regulatory requirements. Labels must remain affixed to the bottle. 
 
 
Administration 
 
Ibrutinib 420 mg will be prescribed per the FDA package label, administered orally once daily. 
Ibrutinib will be self-administered, and participants will be instructed to write in a diary daily, 
documenting that the drug was taken.  The capsules should be taken around the same time each 
day with 8 ounces (approximately 240 mL) of water. The capsules should be swallowed intact and 
participants should not attempt to open capsules or dissolve them in water. Participants will be 
reminded that dietary habits around the time of ibrutinib intake should be as consistent as possible 
throughout the study. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville 
oranges should be avoided for the duration of the study (see section 5.3).  
 
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible within 
6 hours, with a return to the normal schedule the following day. The participant should not take 

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extra capsules to make up the missed dose. The participant will be instructed to document missed 
drug doses in the study diary.  Furthermore, they will be instructed to call the PI or research nurse 
if vomiting occurs. If the pills are vomited, this should be noted on the patient diary, but a 
replacement dose should not be taken that day. All dosages prescribed and dispensed to the 
participant, and all dose changes during the study must be recorded. 
 
One cycle of ibrutinib is once daily, oral administration for 4 weeks +/- 1 week.  At each study 
visit, enough ibrutinib will be dispensed until the next cycle.  For visits occurring monthly, one 
cycle of capsules in a bottle will be dispensed.  For visits occurring every 12 weeks +/-1 weeks 
three cycles of capsules will be dispensed.  Study drug may not be shipped to the participant 
without approval from Pharmacyclics, LLC and may not be dispensed to anyone other than the 
participant. Drug accountability will be done at each Day 1 study visit; unused drug and diaries 
will be collected from the participant, unused drug will be counted and returned to the pharmacy 
to be destroyed.  Returned capsules must not be re-dispensed to any participant. 
 
 
Ordering 
 
Ibrutinib will be provided free-of-charge.  Ibrutinib will be supplied by Pharmacyclics LLC. 
Participating sites will order ibrutinib directly from Pharmacyclics LLC. Ibrutinib orders will be 
emailed to ist.ctep@pcyc.com. 
 
 
Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
 
Destruction and Return 
 
Unused ibrutinib capsules will be returned by the participant, collected and counted at each study 
visit, and will be returned to pharmacy for destruction. Unused supplies of ibrutinib should be 
destroyed according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form.  
 
 
Overdose  
 
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1,400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingest more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
 
 
 

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
 
Assessment of MYD88 L265P and CXCR4 WHIM genotyping. 
 
Genomic and transcriptional studies 
Serial whole exome (WES) and transcriptome studies will be performed using bone marrow 
aspirates (40 ml in 2 heparinized syringes and 2 purple tops) and peripheral blood (PB) samples 
(2 lavender tops) that will be collected from all study participants at baseline, cycles 7, 13, and 
EOT.  This will include genotyping for MYD88 and CXCR4.  Bone marrow (BM) and peripheral 
blood (PB) mononuclear cells will be isolated by density gradient centrifugation, and WM 
lymphoplasmacytic cells isolated from BM aspirates by CD19+ selection using immunomagnetic 
MACS micro-beads (Miltenyi-Biotech, Auburn, CA). By previous studies, the purity of isolated 
B-cells (CD19+) was over 90%, and median clonal B-cell population by light chain restriction was 
>95% by this method. CD19-depleted PBMC will be used as normal paired tissue. High molecular 
weight DNA will be isolated using Allprep DNA/RNA mini kit (Qiagen, Valencia, CA). Library 
construction and WES of paired-end clones will be performed by the Center for Cancer Genomic 
Discovery at the Dana-Farber Cancer Institute. Read sequences will be aligned to reference 
genome NCBI Build 37. High confidence somatic variants will be identified using CGAT version 
1.3 with a somatic score of 0.1, giving an estimated one false somatic single nucleotide variant per 
17.7 Mb of DNA. Copy number will be estimated by %GC normalized read depth, and acquired 
uniparental disomy (aUPD) identified as copy-neutral loss of heterozygosity. Allele imbalance 
will be determined by percentage of reads mapping to the minor allele at heterozygous SNPs 
averaged over 100 Kb. Transcriptome studies will be performed using Illumina HiSeq platform. 
Gene expression will be inferred from read counts, and correlated to genomic findings and 
response to therapy. Categorical comparisons will be analyzed using the Fisher’s exact probability 
test, and the Mann-Whitney U-test to evaluate ordinal comparisons. Benjamini Hochberg 
correction will be used for multiple comparison testing with a p-value < 0.05 deemed to be 
significant. Calculations will be performed with R (R Foundation for Statistical Computing, 
Vienna, Austria). Confirmatory and additional exploratory studies will also be performed on 
collected DNA and RNA that are relevant to WM pathobiology and treatment outcome. 
 
The samples will be used until depletion.   
 
 
 
 
 
 
 
 

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4For patients who demonstrate therapy-related hematological toxicity, more frequent CBC evaluations are strongly recommended. 
 
5Coagulation profile. Prothrombin time (PT) will be performed at screening and repeated as clinically indicated. PT will be reported as 
well as the international normalized ratio (INR) and PTT.  
 
6For women of childbearing potential only: Serum pregnancy test is required at screening. 
 
 
7QOLs should be performed at C1, C4, C7, C13, C19, EOT, and every 6 months thereafter through follow-up. 
  
8 QOL can be collected via telephone or email 
 
9 Physical exam, and weight need to be collected at every other visit starting at Cycle 7 (i.e. C7D1, C13D1, C19D).   
 
10 Participants will undergo assessments during follow-up until time to progression or new therapy.   After PD or new therapy initiation, 
participants will be followed for survival status only 
 
11 Participants who have experienced disease progression or started new therapy will be followed for survival status only every 6 months 
(+/- 2 weeks) 
 
 

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11. MEASUREMENT OF EFFECT 
 
For the purposes of this study, participants should be evaluated for response every 4 weeks ± 1 
week for cycles 2, 3 and 4, and thereafter every 12 weeks ± 1 weeks for the remaining cycles, 
and within 4 weeks ± 2 weeks from when a participant is removed from trial or when treatment 
is completed.  IgMs measured intra-cycle during Cycle 1 and 2 should not be used for response 
or nadir determination.  Post-treatment, patients will continue to be followed-up every 12 weeks 
± 2 weeks for 3 years. Participants will be assessed for efficacy by consensus panel criteria 
according to section 11.1.2 below adopted from the Sixth International Workshop on WM [30].  
 
11.1 
Antitumor Effect – Hematologic Tumors 
 
 Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment will 
be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for response: Only those participants who have measurable disease present at 
baseline, have received at least one cycle of  therapy, and have had their disease re-
evaluated will be considered evaluable for response. These participants will have their 
response classified according to the definitions stated below. (Note: Participants who 
exhibit objective disease progression or die prior to the end of cycle 1 will also be considered 
evaluable.) 
 
 
Response Criteria Modified VIth IWWM (NCCN 2014)  
 
Participants may undergo plasmapheresis when clinically indicated.  Those who undergo 
plasmapheresis will be unevaluable for any response assessment for 28 days.  If plasmapheresis 
occurs between screening and Cycle 1 Day 1, the screening serum IgM should be used for 
response determination. 
 
Complete Response (CR): A complete response (CR) is defined as having resolution of WM 
related symptoms, normalization of serum IgM levels with complete disappearance of IgM 
paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. A complete 
response requires reconfirmation demonstrating normal serum IgM levels, and absence of IgM 
paraprotein by immunofixation by a measurement repeated at least 2 weeks later. 
 
Very Good Partial Response (VGPR): is defined as >90% reduction in serum IgM levels, or 
normalization of serum IgM levels with persistent IgM monoclonal spike in SPEP or 
immunofixation. 
 
Partial Response (PR): Partial response (PR) is defined as achieving a >50% reduction in serum 
IgM levels. 
 
Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM 
levels. 

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Progressive Disease (PD): Progressive disease (PD) is defined as occurring when a greater than 
25% increase in serum IgM level occurs with an absolute increase of at least 500 mg/dL from the 
lowest attained response value, or progression of clinically significant disease related 
symptom(s). Reconfirmation of the initial IgM increase is required when IgM is the sole criterion 
for progressive disease confirmation.  Death from any cause or initiation of a new anti-neoplastic 
therapy will also be considered a progression event. For participants on active therapy who are 
on an ibrutinib drug hold for > 7 days, serum IgM levels will be considered unevaluable for 
response assessment. Patient must be on ibrutinib for >2 consecutive weeks to be considered 
eligible for serum IgM response assessment. An increase of 1 cm in any axis for adenopathy, or 
2 cm in the craniocaudal axis of the spleen will be considered evidence of progression of 
extramedullary disease.  Development of Bing Neel syndrome, or other extramedullary disease 
manifestations, as well as disease transformation will be considered as progressive events. 
 
Stable Disease (SD): Stable disease is defined as having <25% change in serum IgM levels, in 
the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or 
symptoms of WM. 
 
Overall Response Rate (ORR): Includes patients who achieved MR, PR, VGPR and CR. 
 
11.1.1 Time-to-event definition 
 
• Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression (including initiation of new therapy or death). Median, 
2-year and 4-year landmark PFS analysis will be determined. 
• Overall survival (OS) is defined as the duration of time from start of treatment to time of 
death or last follow-up. Median, 2-year and 4-year landmark OS analysis will be 
determined. 
• The duration of response (DOR) for a given participant will be defined as the number of days 
from the day the criteria are met for ORR to the date that PD or death are objectively 
documented. If a participant is still responding, then the participant's data will be censored at 
the last study visit at which a tumor assessment was performed. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
 
Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
 

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Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team. 
 
The DSMC will review the protocol up to four times a year with the frequency determined by the 
outcome of previous reviews. Information to be provided to the committee may include: up-to-
date participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
12.3 
Multi-Center Guidelines 
 
• N/a 
 
12.4 
Collaborative Agreements Language 
N/a. 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a single-arm open-label Phase II study to evaluate the safety and efficacy of Ibrutinib 
combined with Venetoclax (IVEN) in symptomatic, treatment naïve WM patients.   
 
Study treatment for all participants was terminated by the Sponsor-Investigator in March of 2022 
due to 4 events of ventricular arrhythmia.  As of 4/1/22 all participants were notified and 
instructed to stop study treatment and accrual was permanently discontinued. 
 
13.1 
Study Design/Endpoints 
 
The primary endpoint of the current study is: 
• To evaluate the rate of VGPR or better of the combination Ibrutinib + Venetoclax (IVEN) in 
participants with symptomatic, treatment naïve WM, within 24 months of therapy. 
 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 

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Following a Fleming’s one step approach, and assuming a null (H0) VGPR or better rate of 25% 
(based on previous experience on single-agent ibrutinib efficacy in previously untreated patients 
with WM), and an alternative (H1) VGPR rate of 45%, a total of 50 evaluable patients need to be 
accrued to show the proposed difference with an alpha (2-sided type I error) of 0.03 and a power 
(1-beta or type II error) of 87%.  Assuming 10% drop out or unevaluable rate, up to 55 
participants will be enrolled.  If 19 or more participants obtain a VGPR then the combination of 
ibrutinib and venetoclax warrants further evaluation.  If fewer than 19 participants obtain a 
VGPR, the combination should not continue further evaluation. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
6 
= 
8 
Not Hispanic or Latino 
10 
+ 
32 
= 
42 
Ethnic Category: Total of all 
participants 
12 (A1) 
+ 
38 (B1) 
= 
50 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
 
+ 
 
= 
 
Asian 
 
+ 
1 
= 
1 
Black or African American 
1 
+ 
1 
= 
2 
Native Hawaiian or other Pacific 
Islander 
 
+ 
 
= 
 
White 
11 
+ 
36 
= 
42 
Racial Category: Total of all 
participants 
12 (A2) 
+ 
38 (B2) 
= 
50(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 
Stratification Factors 
 
N/a. 
 
13.4 
Interim Monitoring Plan 
 
N/a. 
 
 
13.5 
Analysis of Primary Endpoint 
 
Continuous variables will be presented as medians and interquartile ranges.  Categorical variables 
will be presented as numbers and proportions. Responses will be defined based on the criteria 
established by the 6th International Workshop on WM. The outcome of interest will be achievement 
of VGPR or better at 24 months from treatment initiation. For this study, a VGPR rate of 25% or 
less will be considered H0, and a VGPR of at least 45% for patients on IVEN will be considered 
H1. Participants who have completed at least 4 weeks (1 cycle) of n therapy are 
evaluable.  Participants who are evaluable and discontinue protocol therapy for any reason prior 
to Cycle 2 Day 1 will be considered to be non-responders. 
 

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13.6 
Analysis of Secondary Endpoints 
 
The secondary endpoints are: 
 
• To evaluate the rates of CR with IVEN in participants with symptomatic treatment naïve 
WM at 6, 12 and 24 cycles of therapy. 
• To evaluate the best overall response to IVEN in participants with symptomatic, treatment 
naïve WM. 
• To evaluate the rate of VGPR at 30 months post treatment initiation. To evaluate median 
time to response, median time to major response and median time to VGPR to IVEN in 
participants with symptomatic, treatment naïve WM. 
• To evaluate the 24-, 36-, 48-, 60-month Progression Free Survival (PFS) of IVEN in 
participants with symptomatic treatment naïve WM. 
• To evaluate the overall survival of participants treated with IVEN 
• To evaluate the time to next treatment with IVEN 
• To evaluate the effect of IVEN in the bone marrow burden of disease in participants with 
symptomatic treatment naïve WM. 
• To evaluate the impact of CXCR4 mutations on response to IVEN in participants with 
symptomatic treatment naïve WM. 
• To evaluate the safety profile of IVEN in participants with symptomatic treatment naïve 
WM. 
• To evaluate the impact of IVEN in the participants’ QOL. 
 
Continuous variables will be presented as medians and interquartile ranges.  Categorical 
variables will be presented as numbers and proportions Responses will be defined based on the 
criteria established by the 6th International Workshop on WM.  Secondary outcomes will include 
the rate of VGPR at 30 months from treatment initiation, and the rate of progression-free survival 
(PFS) at 24, 36, 48 and 60 months from initiation of study treatment.  Overall survival will also 
be evaluated as a secondary endpoint.   
 
PFS analysis will be performed using the Kaplan-Meier methodology, and participants will be 
censored at the time of last relevant assessment if they have not demonstrated the event of 
interest by the end of the study. Interim analyses for safety and efficacy will be performed when 
15 patients had completed 6 and 12 months of study treatment. 
 
In recent studies, the MYD88 and CXCR4 mutational status are predictive of clinical status, 
response to therapy and survival outcomes (Cao 2013, Treon 2013, Treon 2014). Activating 
MYD88 as well as nonsense and frameshift WHIM-like CXCR4 somatic mutations are common 
in Waldenström macroglobulinemia. CXCR4 nonsense mutations are present in aggressive cases 
including hyperviscosity syndrome, and MYD88 status is a determinant of survival. The MYD88 
L265P mutational analysis by allele-specific PCR and CXCR4 mutational analysis by Sanger 
sequencing will be performed by the Bing Center for Waldenström Macroglobulinemia in 
Boston, MA. 
 

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13.7 
Reporting and Exclusions 
 
 
Evaluation of Toxicity 
 
All participants who receive at least one dose of any test material during the study will be 
included in the safety analysis.    
 
 
Evaluation of the Primary Efficacy Endpoint 
 
All participants who have completed at least 4 weeks of protocol therapy will be included in the 
evaluation of primary efficacy endpoint. Each participant should be assigned a response category 
based on the response criteria in Section 11.1.2.  
 
14. PUBLICATION PLAN 
 
The results should be made public within 12 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
14.1 
Protocol Amendments 
Any amendments to the Protocol or Informed Consent Form must be sent to Pharmacyclics & 
AbbVIE for review and approval prior to submission to the IRB.  Written verification of IRB 
approval will be obtained before any amendment is implemented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Epidemiology and End Results database. Br J Haematol. 2015. 169(1): 81-9. 
24. 
Treon SP. How I treat Waldenstrom macroglobulinemia. Blood. 2015. 126(6): 721-32. 
25. 
Hillmen P, Rawstron A, Munir T, et al. THE INITIAL REPORT OF THE BLOODWISE 
TAP CLARITY STUDY COMBINING IBRUTINIB AND VENETOCLAX IN 
RELAPSED, 
REFRACTORY 
CLL 
SHOWS 
ACCEPTABLE 
SAFETY 
AND 
PROMISING EARLY INDICATIONS OF EFFICACY. Haematologica. 2017. 102(s2): 
S570. 
26. 
Tam CSL, Roberts AW, Anderson MA, et al. Combination ibrutinib (Ibr) and venetoclax 
(Ven) for the treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of 
the phase 2 AIM study. J Clin Oncol. 2017. 35(15_suppl): 7520-7520. 
27. 
Cao Y, Hunter ZR, Liu X, et al. CXCR4 WHIM-like frameshift and nonsense mutations 
promote ibrutinib resistance but do not supplant MYD88(L265P) -directed survival 
signalling in Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015. 168(5): 701-
7. 
28. 
Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom's 
macroglobulinemia: consensus panel recommendations from the Second International 
Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003. 30(2): 110-5. 
29. 
Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy 
in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second 
International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003. 30(2): 
116-20. 

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30. 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenstrom 
macroglobulinaemia: update from the VIth International Workshop. Br J Haematol. 2013. 
160(2): 171-6. 
 
 
 
 
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 

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APPENDIX B.  CHILD-PUGH SCORE FOR SUBJECTS WITH LIVER IMPAIRMENT 
 
 
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:  
1. Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964;50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding 
oesophageal varices.  The British journal of surgery, 1973;60:646-9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C.  DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROME 
 
 
 
Metabolic    
 
Criteria for Classification of                        Criteria for 
Classification of 
Abnormality                 Laboratory Tumor Lysis Syndrome             Clinical Tumor Lysis 
Syndrome 
 
 
Hyperuricemia              Uric acid > 8.0 mg/dl 
(475.8µmol/liter)   
                                        in adults or above the upper limit of 
the 
                                        normal range for age in children  
 
Hyperphosphatemia       Phosphorus > 4.5 mg/dl 
(1.5mmol/liter)  
                                        in adults or > 6.5 mg/dl (2.1 
mmol/liter) 
   
                                       in children 
 
Hyperkalemia                 Potassium > 6.0 mmol/liter                             Cardiac dysrhythmia or 
sudden death                                                               
       
                                                                      
probably or definitely caused by                                 
 
 
 
                          
hyperkalemia 
 
 
Hypocalcemia               Corrected calcium < 7.0 mg/dl                        Cardiac dysrhythmia, 
sudden death,  
  
                  (1.75 mmol/liter) or ionized calcium              seizure, neuromuscular 
irritability  
 
                  <1.12 (0.3 mmol/liter) † 
     
    (tetany, paresthesias, 
muscle twitching, 
 
 
 
 
 
    Carpopedal spasm, Trousseau’s sign,  
 
 
 
 
                          Chvostek’s sign, laryngospasm, or 
 
 
 
 
 
    bronchospasm), hypotension, or heart 
 
 
 
 
 
    failure probably or definitely caused 
by 
 
 
 
 
 
    hypocalcemia. 
 
Acute kidney injury‡      Not Applicable 
                       
     Increase in the serum 
creatinine   level 
of  0.3 mg/dl (26.5 µmol/liter) (or a               

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single value > 1.5 times the upper 
limit of the age-appropriate normal 
range if no baseline creatinine 
measurement is available) or the 
presence of oliguria, defined as an 
average urine output < 0.5 ml/kg/hr 
for 6 hrs 
 
 
†     The corrected calcium level in milligrams per deciliter = measured calcium level in 
milligrams per deciliter + 0.8 × (4-  albumin in grams per deciliter). 
‡      Acute kidney injury is definited as an increase in the creatinine level of at least 0.3 mg per 
deciliter (26.5 µmol per liter) or a period of oliguia lasting 6 hours or more. By definition, if 
acute kidney injury is present, the patient has clinical tumor lysis syndrome. Data about acute 
kidney injurt from Levin at al. 
 
Note:       In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be 
present during the same 
24-hour period within 3 days before the start of therapy or up to 7 afterward. Clinical 
tumor lysis syndrome requires the presence of laboratory tumor lysis syndrome plus an 
increased creatinine level, seizures, cardiac dysrhythmia, or death. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: MANAGEMENT RECOMMENDATIONS FOR LABORATORY ABNORMALITIES 
FOR VENETOCLAX FIRST DOSE AND ESCALATION  
 
The following table includes recommendations for the management of laboratory abnormalities 
in the setting of venetoclax first dose and dose escalation.  If laboratory TLS is suspected or 
confirmed, venetoclax should be stopped until resolution and treatment should be administered 
per institutional guidelines.  Otherwise, additional monitoring will be at the discretion of the 
investigator and venetoclax may be continued. 
 
Abnormality 
Dose Modification and Management 
recommendation 
Laboratory Events 
Hyperkalemia (Including rapidly rising potassium) 
Potassium ≥ 0.5 mmol/L increase 
from prior value (even if potassium 
within normal limits [WNL])  
 
*Hospitalization at discretion of 
investigator 
 
**If sample is hemolyzed, sample 
should be re-taken before any 
intervention is instituted 
• Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1-2 hours STAT. If further ≥ 0.2 
mmol/L increase in potassium, but still < upper 
limit of normal (ULN), manage as per potassium ≥ 
ULN. Otherwise recheck in 1 hour. 
• Resume per protocol testing if change in potassium 
is < 0.2 mmol/L, and potassium < ULN, and no 
other evidence of tumor lysis. 
• At the discretion of the investigator, may recheck 
prior to hospitalization. If stable or decreased, and 
still WNL, hospitalization is at the discretion of the 
investigator. Potassium, phosphorus, uric acid, 
calcium and creatinine must be rechecked within 24 
hours. 
Potassium > upper limit of normal 
but less than (6 mmol/L) 6 mEq/L 
and/or asymptomatic 
 
*Hospitalization at discretion of 
investigator 
 
**If sample is hemolyzed, sample 
should be re-taken before any 
intervention is instituted 
• Consider performing ECG. 
• Consider Kayexalate 60 g (or Resonium A 60 g). 
• Consider furosemide 20 mg IV × 1. 
• If there is ECG/telemetry evidence of life-
threatening arrhythmia, the patient should be sent 
to ED and managed accordingly 
• Recheck potassium, phosphorus, uric acid, calcium 
and creatinine STAT within 1-2 hours of 
intervention. 
• If potassium < ULN on recheck and no evidence of 
tumor lysis, resume per protocol. 
• If potassium > ULN but less than 6 mmol/L 1-2 
hours later and no evidence of tumor lysis, treat as 
potassium > ULN but less than 6 mmol/L. 
• If potassium >6 mmol/L, the patient should be sent 
to ED for further management 
Potassium ≥ 6.0 mmol/L (6.0 
mEq/L) and/or symptomatic (e.g., 
• Perform STAT EKG 
• The patient should be sent to ED for further 

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muscle cramps, weakness, 
paresthesias, nausea, vomiting, 
diarrhea) 
 
*Hospitalization Indicated 
 
**If sample is hemolyzed, sample 
should be re-taken before any 
intervention is instituted 
management  
Hyperuricemia 
Uric acid ≥ 8.0 but <10 mg/dL (476 
μmol/L) 
 
*Hospitalization at discretion of 
investigator 
• IVF and recheck 
• Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1-2 hours STAT. 
Uric acid ≥ 10 mg/dL (595 μmol/L) 
 
OR 
 
Uric acid ≥ 8.0 mg/dL (476 
μmol/L) with 25% increase and 
creatinine increase ≥ 0.3 mg/dL (≥ 
0.027 mmol/L) from pre-dose level 
 
*Hospitalization Indicated 
• The patient should be sent to ED for further 
management 
Hypocalcemia 
Corrected Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L) 
AND 
Patient symptomatic (e.g., muscle 
cramps, hypotension, tetany, 
cardiac arrhythmias) 
 
*Hospitalization Indicated 
• The patient should be sent to ED for further 
management 
Hyperphosphatemia 
Phosphorus ≥ 5.0 mg/dL 
(1.615 mmol/L) with ≥ 0.5 mg/dL 
(0.16 mmol/L) increase 
 
*Hospitalization at discretion of 
investigator 
• Consider administering a phosphate binder (e.g., 
aluminum hydroxide, calcium carbonate, 
sevelamer hydroxide, or lanthanum carbonate). 
• Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 hr STAT.  If phosphorus <5.0 
mg/dL 1-2 hours later and no evidence of tumor 
lysis, resume per protocol. 
• Send to ED per clinician judgement  
Creatinine 
 
Increase ≥ 25% from baseline 
• Start or increase rate of IV fluids. 

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*Hospitalization at discretion of 
investigator 
• Recheck potassium, phosphorus, uric acid, calcium 
and creatinine in 1 to 2 hours STAT.  Resume per 
protocol testing if no further >25% increase. 
• Send to ED per clinician judgement