Clinical trial NCT02956382
Conditions: Refractory Follicular Lymphoma Relapsed Follicular Lymphoma
Keywords: Ibrutinib Venetoclax Follicular Refractory Relapsed Lymphoma
Sponsor: Georgetown University
Start date: 2017-03-01; Completion date: 2024-03-07
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.

Detailed description:
In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines. The investigators theorize that the combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific toxicity.

Arms: arm 1: Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg

Each medication is taken daily. Treatment cycles are 28 days long. arm 2: Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg

Each medication is taken daily. Treatment cycles are 28 days long. arm 3: Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg

Each medication is taken daily. Treatment cycles are 28 days long. arm 4: Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg

Each medication is taken daily. Treatment cycles are 28 days long. arm 5: The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion.
Interventions: intervention 1: Ibrutinib intervention 2: Venetoclax
Intervention descriptions: intervention 1: Ibrutinib is dispensed as a capsule. intervention 2: Venetoclax is dispensed as a tablet.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
v 14 July 2022 
TITLE: 
Ibrutinib and Venetoclax in Relapsed and Refractory Follicular 
Lymphoma 
PROTOCOL NUMBER: 
2016-0014 
STUDY DRUGS: 
Ibrutinib, Venetoclax 
INVESTIGATOR: 
Study Chair 
Chaitra Ujjani, MD 
Seattle Cancer Care Alliance 
ujjani@uw.edu 
Tel 205-612-7405; 206-606-1955 
 
Principal Investigator 
Kieron Dunleavy, MD 
Medstar Georgetown University Hospital  
Lombardi Comprehensive Cancer Center 
Tel 202-444-2223, Fax 202-444-4971 
Kieron.M.Dunleavy@medstar.net  
 
DATE FINAL: 
14 July 2022 
 
 
PREVIOUS PROTOCOL VERSIONS:   
03FEB2016 
03MAR2016 
06APR2016 
20MAY2016 
24AUG2016 
15SEP2016 
27DEC2016 
27MAR2017 
01JUN2017 
17JUL2017 
10AUG2017 
10OCT2017 
16APR2018 
11SEP2018 
04MAR2019 
15JAN2020 
09 June 2020 
16OCT2020 
01NOV2021 
 


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v 14 July 2022 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
ABBREVIATIONS ........................................................................................................................8 
1. 
BACKGROUND ...................................................................................................................10 
1.1. 
Follicular Lymphoma.........................................................................................................10 
1.1.2 
Treatment Options .......................................................................................................11 
1.2. 
Ibrutinib..............................................................................................................................11 
1.3. 
Summary of Nonclinical Data with Ibrutinib ....................................................................13 
1.3.1. 
Pharmacology ..............................................................................................................13 
1.3.2. 
Toxicology ...................................................................................................................13 
1.3.2.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility ..........................................13 
1.4. 
Summary of Clinical Data with Ibrutinib ..........................................................................14 
1.4.1 
Pharmacokinetics and Product Metabolism ...........................................................14 
1.5. 
Summary of Clinical Safety with Ibrutinib ........................................................................15 
1.5.1. 
Risks with Ibrutinib......................................................................................................17 
1.5.1.1. 
Bleeding-related events ..........................................................................................17 
1.5.1.2. 
Cardiac Arrhythmias ..............................................................................................17 
1.5.1.3. 
Cytopenias..............................................................................................................18 
1.5.1.4. 
Diarrhea..................................................................................................................18 
1.5.1.5. 
Infections................................................................................................................18 
1.5.1.6. 
Non-melanoma Skin Cancer ..................................................................................18 
1.5.1.7. 
Rash........................................................................................................................18 
1.5.1.8. 
Tumor Lysis Syndrome..........................................................................................19 
1.5.1.9. 
Hypertension ..........................................................................................................19 
1.6. 
Venetoclax .........................................................................................................................20 
1.6.1. 
Bcl-2 Function in the Antiapoptotic Pathway ..............................................................20 
1.6.2. 
Summary of Non-clinical Data with Venetoclax .........................................................21 
1.6.2.1. 
Pharmacology ........................................................................................................21 
1.6.2.2. 
Toxicology .............................................................................................................21 
1.6.2.3. 
Carcinogenesis, Mutagenesis, Impairment of Fertility ..........................................21 
1.7. 
Summary of Clinical Data with Venetoclax ......................................................................22 
1.7.1 
Pharmacokinetics and Product Metabolism .................................................................22 
1.8. 
Summary of Clinical Safety with Venetoclax ...................................................................23 
1.8.1. 
Risks with Venetoclax .................................................................................................23 
1.8.1.1. 
Tumor Lysis Syndrome..........................................................................................23 
1.8.1.2. 
Neutropenia ............................................................................................................23 
1.8.1.3. 
Diarrhea..................................................................................................................23 
1.8.1.4. 
Food Effect.............................................................................................................24 
1.8.1.5. 
Infections................................................................................................................24 
1.8.1.6. 
Other Hematological Effects ..................................................................................24 
1.8.1.7. 
Other Malignancies ................................................................................................24 
1.8.1.8. 
Reproductive System Effects .................................................................................25 
1.9. 
Study Rationale ..................................................................................................................25 
1.10. Correlative Science Background ........................................................................................25 
2. 
STUDY OBJECTIVES ........................................................................................................27 


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v 14 July 2022 
2.1. 
Phase I Study......................................................................................................................27 
2.1.1. 
Primary Objective ........................................................................................................27 
2.1.2. 
Secondary Objective ....................................................................................................27 
2.2. 
Phase II Study ....................................................................................................................27 
2.2.1. 
Primary Objective ........................................................................................................27 
2.2.2. 
Secondary Objective ....................................................................................................27 
3. 
ELIGIBILITY CRITERIA ..................................................................................................28 
3.1. 
Inclusion Criteria ...............................................................................................................28 
3.2. 
Exclusion Criteria ..............................................................................................................29 
3.3 Inclusion of Women and Minorities ........................................................................................31 
4. 
REQUIRED DATA ..............................................................................................................31 
4.1. 
Screening Phase .................................................................................................................31 
4.2. 
Schedule of Events .............................................................................................................32 
STAGING .....................................................................................................................................33 
5. 
STUDY DESIGN ..................................................................................................................34 
5.1. 
Overview of Study Design .................................................................................................34 
5.2. 
Treatment Plan ...................................................................................................................34 
5.3. 
Prophylaxis and Management of Tumor Lysis Syndrome ................................................36 
5.3.1. 
Prophylaxis for Tumor Lysis Syndrome ......................................................................36 
5.3.2. 
Hospitalization .............................................................................................................37 
5.4. 
Pharmacokinetics ...............................................................................................................38 
5.4.1. 
Objective ......................................................................................................................38 
5.4.2. 
Methods........................................................................................................................38 
5.4.3. 
Schedule .......................................................................................................................39 
6. 
MODIFICATIONS AND MANAGEMENT OF TOXICITY ..........................................40 
6.1. 
Overdose ............................................................................................................................40 
6.2. 
Dose Modification for Adverse Reactions .........................................................................40 
6.2.1.1. 
Leukocytosis/Leukostasis ......................................................................................41 
6.2.1.2. 
Dose Modification for Subjects with Hepatic Impairment ....................................41 
7. 
CONCOMITANT MEDICATIONS/PROCEDURES ......................................................42 
7.1. 
Permitted Concomitant Medications ..................................................................................42 
7.2. 
Medications to be used with caution ..................................................................................43 
7.2.1. 
CYP3A Inhibitors/Inducers .........................................................................................43 
7.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib or 
Venetoclax .....................................................................................................................................45 
7.2.3. 
QT Prolonging Agents .................................................................................................45 
7.2.4. 
Antiplatelet Agents and Anticoagulants ......................................................................45 
7.3. 
Prohibited Concomitant Medications ................................................................................45 
7.4. 
Guidelines for Ibrutinib and Venetoclax Management with Surgeries or Procedure ........45 
 
Minor Surgical Procedures ..........................................................................................46 
 
Major Surgical Procedures ...........................................................................................46 
8. 
DEFINITION OF DOSE LIMITING TOXICITY ............................................................46 
8.1. 
Non-hematologic toxicity ..................................................................................................46 
8.2. 
Hematologic Toxicity ........................................................................................................47 
9. 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION ............................47 


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v 14 July 2022 
9.1. 
Ibrutinib..............................................................................................................................47 
9.2. 
Venetoclax .........................................................................................................................47 
10. CORRELATIVE SCIENCE COMPANION STUDY .......................................................48 
10.1. Next-Generation Sequencing .............................................................................................48 
10.2. BCL-2 Family Proteins ......................................................................................................48 
10.3. Tumor Cell Cultures ..........................................................................................................49 
11. SUBJECT COMPLETION AND WITHDRAWAL .........................................................49 
11.1. Completion .........................................................................................................................49 
11.2. Withdrawal from Study Treatment ....................................................................................50 
12. STATISTICAL METHODS AND ANALYSIS .................................................................50 
12.1. Phase I study ......................................................................................................................50 
12.2. Phase II Study ....................................................................................................................51 
12.3. Toxicity Evaluation ............................................................................................................51 
12.4. Target Accrual and Study Duration ...................................................................................52 
12.5. Correlative Science Statistical Considerations ..................................................................52 
12.5.1. 
Mutations of Resistance ...............................................................................................52 
12.5.2. 
BCL-2 Family Proteins ................................................................................................52 
12.5.3. Tumor Cell Cultures ........................................................................................................52 
13. ADVERSE EVENT REPORTING .....................................................................................52 
13.1. Definitions..........................................................................................................................53 
13.1.1. 
Adverse Events ............................................................................................................53 
13.1.2. 
Serious Adverse Events ...............................................................................................54 
13.1.3. 
Severity Criteria (Grade 1-5) .......................................................................................55 
13.1.4. 
Causality (Attribution) .................................................................................................55 
13.2. Unexpected Adverse Events ..............................................................................................56 
13.3. Special Reporting Situations ..............................................................................................56 
13.4. Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ...................................................................................................................................56 
13.4.1. 
Assessment of Adverse Events ....................................................................................56 
13.4.2. 
Adverse Event Reporting Period .................................................................................57 
13.4.3. 
Pregnancy .....................................................................................................................57 
13.4.4. 
Other Malignancies ......................................................................................................58 
13.4.5. 
Adverse Events of Special Interest (AESI) ..................................................................59 
13.5. Expediting Reporting Requirements for Serious Adverse Events .....................................59 
14. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ......................60 
14.1. Regulatory and Ethical Compliance ..................................................................................60 
14.2. Enrollment..........................................................................................................................60 
14.3. Informed Consent...............................................................................................................61 
14.4. Case Report Forms and Record Maintenance ....................................................................61 
14.5. Publication of Study Results ..............................................................................................61 
14.6. Study Discontinuation ........................................................................................................62 
15. REFERENCES .....................................................................................................................64 
APPENDIX I REFERENCE SAFETY INFORMATION FOR IBRUTINIB .......................67 
APPENDIX II FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX 
(FLIPI)  .........................................................................................................................................68 


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v 14 July 2022 
APPENDIX III ECOG PERFORMANCE SCALE..................................................................71 
APPENDIX IV   COCKCROFT- GAULT FORMULA FOR ESTIMATED CREATININE 
CLEARANCE ..............................................................................................................................71 
APPENDIX V        MEDICATION CALENDAR ....................................................................72 
APPENDIX VI       DRUGS TO BE AVOIDED OR USED WITH CAUTION ......................74 
APPENDIX VII  LUGANO REVISED RESPONSE CRITERIA FOR NON-HODGKIN 
LYMPHOMA 32 ...........................................................................................................................75 
APPENDIX VIII  RECOMMENDATIONS FOR INITIAL MANAGEMENT OF 
ELECTROLYTE ABNORMALITIES AND PREVENTION OF TUMOR LYSIS 
SYNDROME ................................................................................................................................77 
APPENDIX IX DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROME ................................................................................................................................79 
APPENDIX X CHILDS PUGH CLASSIFICATION ...............................................................80 
APPENDIX XI IBRUTINIB PK SAMPLE COLLECTION ...................................................81 
APPENDIX XII CORRELATIVE STUDY SAMPLE SUBMISSION ...................................83 
 
 
 


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v 14 July 2022 
SYNOPSIS 
 
Study Title: 
Ibrutinib and Venetoclax in Relapsed and Refractory Follicular 
Lymphoma 
Protocol Number: 
2016-0014 
Study Phase: 
1b/2 
Study Duration: 
24 months 
Objectives: 
Phase I study: 
Primary Objective: To determine the recommended phase II doses of ibrutinib 
and venetoclax when combined in relapsed and refractory follicular lymphoma 
Secondary Objective: To determine the pharmacokinetics of ibrutinib and 
venetoclax when dosed in combination in relapsed and refractory follicular 
lymphoma 
Phase II study: 
Primary Objective: To determine the efficacy of ibrutinib and venetoclax when 
combined in relapsed and refractory follicular lymphoma 
Secondary Objective: To determine the safety and tolerability of ibrutinib and 
venetoclax when combined in relapsed and refractory follicular lymphoma  
Study Design: 
This is a phase I/II study in which patients will be enrolled in a standard 3+3 
design.  Once the maximum tolerated dose is determined, there will be a 17-
patient phase II study using Simon’s Minimax 2-stage design.  
Inclusion 
Criteria: 
Refer to Section 
4.0 for the 
complete and 
detailed list of 
inclusion/exclusion 
criteria. 
 
Relapsed or refractory, histologically confirmed grade 1-3a follicular 
lymphoma which requires therapy  
 
Must have received at least one prior systemic therapy 
 
All risk by FLIPI 0-5 factors 
 
No prior BTK inhibitor or BCL-2 inhibitor 
 
ECOG performance status of ≤ 2 
Required Initial Lab Values 
ANC 
Hemoglobin 
Platelet count 
 
≥ 1000/uL* 
>8.0 g/dL* 
≥ 50,000/uL* 
AST and ALT 
≤ 2.5 x ULN* 
Total bilirubin 
≤ 1.5 x ULN*,** 
CrCl 
> 50 mL/min*** 
PT/INR and PTT (aPTT)  
<1.5 x ULN 
*Unless attributable to disease, See Section 3 
**Unless attributable to Gilbert’s syndrome 
***Use of Cockcroft-Gault actual weight 
Exclusion 
Criteria: 
 
Chemotherapy, monoclonal antibody, or small molecule inhibitor  21 
days prior to first administration of study treatment 


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v 14 July 2022 
 
Concurrent systemic immunosuppressant therapy < 4 weeks of the first 
dose of study drug (e.g. cyclosporine A, tacrolimus, etc. or chronic 
administration of > 20 mg day of prednisone or equivalent) 
 
Known allergy to xanthine oxidase inhibitors and/or rasburicase for 
subjects at risk for tumor lysis syndrome 
 
Infection requiring systemic treatment that was completed ≤14 days  
 
Significant unresolved toxicities from prior anti-cancer therapy 
 
Known bleeding disorders (e.g. von Willebrand’s disease) or hemophilia. 
 
History of stroke or intracranial hemorrhage within 6 months 
 
Known history of HIV 
 
Active hepatitis C or hepatitis B infection. Subjects who are positive for 
hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C 
antibody must have a negative polymerase chain reaction (PCR) result 
before enrollment. Those who are PCR positive will be excluded.   
 
Subjects with chronic liver disease with hepatic impairment Child-Pugh 
class B or C (See Appendix X) 
 
Major surgery within 4 weeks of first dose of study drug. 
 
Concomitant use of warfarin or other Vitamin K antagonists. 
 
Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor 
within 7 days prior to the first dose of ibrutinib or subjects who require 
continuous treatment with a strong CYP3A inhibitor (See Appendix VI) 
 
Lactating or pregnant. 
 
Current or history of graft versus host disease 


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v 14 July 2022 
Study Treatment: 
Phase I study: 
Three patients will be enrolled at Dose Level 0 (DL0): Ibrutinib 420 
mg daily and Venetoclax 400 mg daily.  Each cycle is 28-days. 
Patients will be monitored for dose limiting toxicity (DLT) during 
Cycle 1.  Patients will receive the combination until progression or 
unacceptable toxicity. Patients will be followed throughout the 
duration of therapy through progression until next line of therapy.  
Dose Levels 
Dose Level  
Ibrutinib  
Venetoclax  
0 
420 mg 
400 mg 
1 
560 mg 
400 mg 
2 
560 mg 
600 mg 
 
Phase II study: 
Patients will be enrolled at the recommended phase II dose. Duration of 
therapy will depend on depth of response. Patients who achieve a complete 
remission may discontinue therapy after 24 cycles. These patients must 
undergo a PET-CT during Cycle 24 to confirm they are still in a complete 
remission prior to discontinuation.  Patients who achieve a partial response 
will continue therapy until progression or unacceptable toxicity. Patients will 
be followed throughout the duration of therapy through progression until next 
line of therapy. Patients who achieve a complete remission and discontinue 
therapy after 24 cycles will be monitored closely with serial imaging and may 
be reinitiated on treatment within one year of discontinuation for either 
progression of disease or at the discretion of the treating physician. 
 
Participating 
Centers: 
MedStar Georgetown University Hospital 
Hackensack University Medical Center 
Seattle Cancer Care Alliance 
ABBREVIATIONS 
AE 
AESI 
ALT 
AML 
AST 
AUC 
BCR 
BTK 
CDUS 
Adverse event 
Adverse events of special interest 
Alanine transaminase 
Acute myeloid leukemia 
Aspartate transaminase 
Area under the curve 
B-cell receptor 
Bruton-tyrosine kinase 
Clinical data update system 


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v 14 July 2022 
CI 
CLL 
Cmax 
CR 
CRF 
CTCAE 
Confidence interval 
Chronic lymphocytic leukemia 
Peak concentration 
Complete response 
Case report form  
NCI Common Terminology Criteria for Adverse Events 
DCF 
DLBCL 
DLT 
Data clarification form 
Diffuse large B-cell lymphoma 
Dose limiting toxicity 
DMC 
DMSO 
Data Monitoring Committee 
Dimethyl sulfoxide 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders (4th edition) 
ECG 
ECOG 
Electrocardiogram 
Eastern Cooperative Oncology Group 
EDC 
FCBP 
FL 
Electronic data capture 
Female of childbearing potential 
Follicular lymphoma 
GCP 
GELF 
Good Clinical Practice 
Groupe d’Etude des Lymphomes Folliculares 
HBsAg 
HBV 
HCV 
HDPE 
Hepatitis B surface antigen 
Hepatitis B virus 
Hepatitis C virus 
High-density polyethylene  
HIV 
human immunodeficiency virus 
IAC 
IB 
Interim Analysis Committee 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
IVF 
Institutional Review Board 
Intravenous fluids 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LC-MS/MS 
LDH 
MCL 
Liquid chromatography/mass spectrometry/mass spectrometry 
Lactate dehydrogenase 
Mantle cell lymphoma 
MedDRA 
MM 
Medical Dictionary for Regulatory Activities 
Multiple myeloma 


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v 14 July 2022 
MRU 
MTD 
NCCN 
NGS 
NHL 
ORR 
OS 
PCR 
Medical Resource Utilization 
Maximal tolerated dose 
National Comprehensive Cancer Network 
Next-Generation Sequencing 
Non-Hodgkin lymphoma 
Overall response rate 
Overall survival 
Polymerase chain reaction 
PD 
PFS 
P-gp 
Pharmacodynamic 
Progression-free survival 
P-glycoprotein 
PK 
PML 
Pharmacokinetic 
Progressive multifocal leukoencephalopathy 
PQC 
PR 
Product Quality Complaint 
Partial response 
PRO 
QD 
SAE 
SD 
SJS 
TEAE 
TLS 
Tmax 
Vd 
Vss 
patient-reported outcome(s) 
Daily 
Serious adverse event 
Stable disease 
Stevens-Johnson Syndrome 
Treatment-emergent adverse event 
Tumor lysis syndrome 
Time to reach maximum concentration 
Volume of distribution 
Volume of distribution at steady state 
USP 
United States Pharmacopeia 
1. BACKGROUND 
1.1. Follicular Lymphoma 
1.1.1 Disease Biology 
The most common of the indolent non-Hodgkin lymphomas (NHL), follicular lymphoma, 
represents 25% of all NHLs in the United States.  The median age at diagnosis is 60 years, and 
the majority of patients present with advanced-stage disease.  While the pathogenesis of 
follicular lymphoma is not completely established, the hallmark chromosomal abnormality found 
in > 90% of patients is the t(14;18) translocation.  This rearrangement of the BCL-2 oncogene 
results in overexpression of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein, which 
contributes to lengthy tumor cell survival.  


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v 14 July 2022 
The pathogenesis of the follicular lymphoma is an intricate, multistep process.  The t(14;18) 
translocation is attributed to as the first genetic hit necessary for the development of the disease.  
As many healthy individuals are also found to have this translocation, Bcl-2 is not the sole 
culprit for malignant transformation.  The B-cell receptor (BCR) is a critical factor in the 
development of the disease, as its active tonic signaling leads to recruitment of the spleen 
tyrosine kinase and activation of multiple downstream pathways including Bruton’s tyrosine 
kinase (BTK) and phosphatidylinositol-3-kinase (PI3K), ultimately resulting in malignant 
lymphocyte maturation, proliferation and survival.  
1.1.2 Treatment Options 
Follicular lymphoma is characterized by a variable clinical course.  Asymptomatic patients can 
be closely monitored for years without treatment, while symptomatic patients require more 
immediate therapy. Indications for treatment are defined by the GELF (Groupe d’Etude des 
Lymphomes Follicularies) criteria:  single lesion > 7cm, three nodal sites > 3 cm, splenomegaly, 
cytopenias, effusions, and threat of or evidence of organ compression. [1]  
Whereas symptomatic patients with limited stage follicular lymphoma have several options 
including single-agent rituximab, radiation, and chemoimmunotherapy depending on their 
performance status and comorbidities, chemoimmunotherapy is currently the standard of care for 
those with advance-stage disease. Either BR (bendamustine and rituximab) or R-CHOP 
(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are reasonable options 
for induction. [2,3] 
Despite high response rates to chemoimmunotherapy, patients inevitably relapse, and further 
treatment options are necessary. Approved options include chemoimmunotherapy with the same 
or alternative chemoimmunotherapy regimen. Responses in the second-line setting, however, are 
not as high or durable. Aside from chemoimmunotherapy, approved options include 
radioimmunotherapy, which is cumbersome in the fact that it requires the incorporation of an 
experienced nuclear medicine team. [4] Furthermore, the patient must fulfill certain criteria in 
terms of complete blood count levels and limited prior exposure to radiation. Idelalisib, a potent 
inhibitor of the delta isoform of PI3K, was approved for patients with relapsed follicular 
lymphoma who have received at least two prior systemic therapies. [5] The indication in 
follicular lymphoma was based on the results of a phase II trial in patients with rituximab-
refractory indolent NHL. Of the 72 patients with follicular lymphoma, the ORR was 56% and 
only 10 patients achieved a CR. The median progression-free survival (PFS) was 11 months and 
the median duration of response was 12.5 months.  Given these suboptimal responses for patients 
with relapsed disease, further treatment options are necessary. 
1.2. Ibrutinib  
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of BTK.  
Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling pathways and thus 
prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and selected members of 


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v 14 July 2022 
the kinase family with 10-fold specificity compared with non-BTK kinases.  Ibrutinib 
(IMBRUVICA®) is approved in over 80 countries, including the United States (US) and 
European Union (EU) for indications covering the treatment of patients with mantle cell 
lymphoma (MCL) who have received at least 1 prior therapy, patients with chronic lymphocytic 
leukemia (CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with a deletion of the 
short arm of chromosome 17 (del17p), patients with Waldenström’s macroglobulinemia (WM), 
patients with Marginal Zone Lymphoma (MZL) who require systemic therapy and have received 
at least one prior anti-CD20-based therapy, and adult patients with cGVHD after failure of 1 or 
more lines of systemic therapy. 
B-cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the BCR, which is activated by binding to antigen.  Antigen 
binding induces receptor aggregation and the clustering and activation of multiple tyrosine 
kinases, which in turn activate further downstream signaling pathways. [6] 
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from 
mutations and translocations acquired during normal B-cell development. [7] Several lines of 
evidence suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies.   
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease X-
linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic diseases 
are characterized by reduced BCR signaling and a failure to generate mature B-cells.  The BTK 
protein is expressed in most hematopoietic cells with the exception of T-cells and natural killer 
cells, but the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells. [8]   
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from the 
plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain maximal 
pharmacodynamic activity for 24 hours postdose at dose levels ≥2.5 mg/kg. In Study PCYC-
04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 
560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug 
administration. 
For the most up to date and comprehensive nonclinical and clinical information regarding 
ibrutinib background, safety, efficacy, and in vitro and in vivo preclinical activity and toxicology 
of ibrutinib, refer to the latest version of the ibrutinib Investigator's Brochure. 


13 
 
v 14 July 2022 
1.3. Summary of Nonclinical Data with Ibrutinib 
For the most comprehensive nonclinical information regarding ibrutinib, refer to the current 
version of the Investigator's Brochure.  
1.3.1. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of the BTK. [10]  In vitro, ibrutinib is 
a potent inhibitor of BTK activity (IC50 = 0.39 nM).  The irreversible binding of ibrutinib to 
cysteine-481 in the active site of Btk results in sustained inhibition of Btk catalytic activity and 
enhanced selectivity over other kinases that do not contain a cysteine at this position.  When 
added directly to human whole blood, ibrutinib inhibits signal transduction from the B-cell 
receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression. [13]  
For more detailed and comprehensive information regarding nonclinical pharmacology, refer to 
the current Investigator’s Brochure. 
1.3.2. 
Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. In vivo safety pharmacology assessments performed in a cardiovascular 
study in telemetry-monitored dogs showed PR interval prolongation, lowered heart rate and 
shortening of QT interval corrected for heart rate (QTc). Based on data from rat and dog 
including general toxicity studies up to 13 weeks duration, the greatest potential for human 
toxicity with ibrutinib is predicted to be in lymphoid tissues (lymphoid depletion) and the 
gastrointestinal tract (soft feces/diarrhea with or without inflammation). Additional toxicity 
findings seen in only one species with no observed human correlate in clinical studies to date 
include pancreatic acinar cell atrophy (rat), minimally decreased trabecular and cortical bone 
(rat) and corneal dystrophy (dog). In studies in pregnant rats and rabbits, ibrutinib administration 
was associated with malformations (teratogenicity) at ibrutinib doses that result in approximately 
14 and 2 times the exposure (area under the concentration-time curve [AUC]) in patients 
administered the dose of 560 mg daily, respectively. Fetal loss and reduced fetal body weights 
were also seen in treated pregnant animals. Carcinogenicity studies have not been conducted 
with ibrutinib. In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic. 
No effects on fertility or reproductive capacities were observed in a study in male and female 
rats. 
For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current IB.  
1.3.2.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 


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v 14 July 2022 
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
1.4. Summary of Clinical Data with Ibrutinib 
For the most comprehensive clinical information regarding ibrutinib, refer to the current IB. 
1.4.1 Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses increased with substantial intersubject variability. The 
mean half-life (t1/2) of ibrutinib ranged from 4 to 6 hours, with a median time to maximum 
plasma concentration (Tmax) of 1 to 2 hours. Despite the doubling in mean systemic exposure 
when dosed with food, the favorable safety profile of ibrutinib allows dosing with or without 
food. Ibrutinib is extensively metabolized primarily by CYP 3A4 mediated metabolic pathways. 
The on-target effects of metabolite PCI-45227 are not considered clinically relevant. Steady-state 
exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure. About 8% of 
ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with creatinine clearance 
(CrCL) >30 mL/min. Patients with severe renal impairment or patients on dialysis have not been 
studied. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-
fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe 
(Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The 
safety of ibrutinib has not been evaluated in patients with hepatic impairment. 
For the most comprehensive pharmacokinetics (PK) and product metabolism, please refer to the 
current version of the IB. 
      1.4.2  Summary of Clinical Efficacy with Ibrutinib in Follicular Lymphoma 
The ORR with ibrutinib in follicular lymphoma in 40 heavily pretreated patients was 30% and 
median PFS of 9.9 months. [10] Efficacy was also noted in patients with marginal zone 
lymphoma. [11] Many of the responses with ibrutinib are partial, however, and drug resistance 
can develop. Therefore, efforts have been made to improve upon its efficacy, such as 
combination with chemotherapy. In a phase Ib study of ibrutinib and R-CHOP (rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone) in treatment naïve patients with B-cell 
NHL, the ORR was 100% (CR 73%) and 1-year PFS was 90%. [12] The regimen was well-
tolerated with the most common adverse events being neutropenia, nausea, and 
thrombocytopenia. Ibrutinib is also being studied in combination with other targeted therapies. 
The Alliance for Clinical Trials in Oncology is conducting a phase I trial of rituximab, 


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v 14 July 2022 
lenalidomide, and ibrutinib in patients with previously untreated follicular lymphoma 
(NCT01829568). Preliminary (unpublished) data indicate activity and the lack of dose limiting 
toxicities with this combination. 
1.5. Summary of Clinical Safety with Ibrutinib  
Integrated safety data for a total of 1,971 subjects with hematologic malignancies from 17 
combination therapy studies that have completed primary analysis or final analysis included in 
the CSR as of 12 November 2019 are briefly summarized below. Therapies used in combination 
with ibrutinib in these studies, included BR (bendamustine and rituximab), FCR (fludarabine, 
cyclophosphamide, and rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone), cytarabine, azacytidine, dexamethasone, durvalumab, 
lenalidomide with cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone +/- 
rituximab (EPOCH-R), nivolumab and obinutuzumab. The median duration of ibrutinib exposure 
for subjects with hematologic malignancies receiving ibrutinib as combination therapy was 5.8 
months and the mean was 11.0 months.  
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=1,971): 
Most frequently reported 
TEAEs  10% a   
Most frequently reported 
Grade 3 or 4 TEAEs  2% a  
Most frequently reported 
Serious TEAEs  1% b  
Neutropenia 
Neutropenia 
Neutropenia 
Diarrhea 
Diarrhea 
Diarrhea 
Nausea 
Platelet count decreased 
Thrombocytopenia 
Thrombocytopenia 
Thrombocytopenia 
 
Fatigue 
Fatigue 
Anemia 
Anemia 
Anemia 
Pyrexia 
Pyrexia 
Neutrophil count decreased 
Pneumonia 
Hypokalemia 
Rash maculo-papular 
Febrile neutropenia 
Upper respiratory tract 
infection 
Constipation 
Pneumonia 
Febrile neutropenia 
Hypokalemia 
Atrial fibrillation 
Cellulitis 
Urinary tract infection 


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v 14 July 2022 
Vomiting 
Headache 
Cough 
Muscle spasms 
Pneumonia 
Oedema peripheral 
Arthralgia 
Decreased appetite 
Abdominal pain 
Back pain 
Platelet count decreased 
Neutrophil count decreased 
Lymphocyte count increased 
White blood cell count 
decreased 
Hypertension 
Urinary tract infection 
 
Contusion 
Myalgia 
Rash maculo-papular 
Dyspnea 
Insomnia 
Atrial fibrillation 
Hypertension 
Hyponatremia 
Lymphocyte count decreased 
White blood cell count 
decreased 
Urinary tract infection 
Hyperglycemia 
 
Leukocytosis 
Leukopenia 
Lymphocyte count decreased 
Syncope 
Sepsis 
Lung infection 
Acute kidney injury 
 
Dyspnoea 
Dehydration 
 


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v 14 July 2022 
Peripheral sensory 
neuropathy 
Stomatitis 
Dizziness 
Pain in extremity 
Infusion related reaction 
Blood creatinine increased 
Febrile neutropenia 
a Source is Table 8 of IB (v13)                  b Source is Table 9 of IB (v13) 
 
For more detailed information refer to the current version of the IB. See Appendix I for most 
recent Reference Safety Information with Ibrutinib. 
1.5.1. 
Risks with Ibrutinib 
1.5.1.1. 
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. In an in vitro platelet function study, inhibitory 
effects of ibrutinib on collagen-induced platelet aggregation were observed, refer to Section X. 
Use of either anticoagulant or antiplatelet agents concomitantly with ibrutinib increases the risk 
of major bleeding. A higher risk for major bleeding was observed with anticoagulant than with 
antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when 
co-administered with ibrutinib. Monitor for signs or and symptoms of bleeding. See Section 
7.2.4 for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. 
Supplements such as fish oil and vitamin E preparations should be avoided. 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 7.4 for guidance on ibrutinib management with surgeries or procedures. 
Subjects with congenital bleeding diathesis have not been studied. 
1.5.1.2. 
Cardiac Arrhythmias 
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. 


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v 14 July 2022 
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 6.2) 
1.5.1.3. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly. 
1.5.1.4. 
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 6.2).  
1.5.1.5. 
Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. 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 (reference Section Error! Reference source not found.). 
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. 
1.5.1.6. 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer. 
1.5.1.7. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm than in the 
ofatumumab arm in Study 1112. Most rashes were mild to moderate in severity. Isolated cases of 
severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
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 


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v 14 July 2022 
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. 
1.5.1.8. 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions. 
 
1.5.1.9. 
Hypertension 
Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in 
subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout 
treatment with ibrutinib as appropriate. 1.5.1.10  
Interstitial lung disease 
 
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 (see Section 6).  
 
1.5.1.11 
Cerebrovascular Accidents 
Although causality has not been established, cases of cerebrovascular accident, transient 
ischemic attack, and ischemic stroke including fatalities have been reported with the use of 
ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or 
hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to 
the occurrence of these events is recommended. 
Long-term safety 
The long-term safety data over 5 years from 1,178 subjects (treatment-naїve CLL/SLL n = 162, 
relapsed/refractory CLL/SLL n=646, and relapsed/refractory MCL n=370) treated with ibrutinib 
were analyzed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 
months) with 70% and 52% of subjects receiving treatment for more than 2 years and 4 years, 
respectively. The median duration of treatment for MCL was 11 months (range, 0 to 87 months) 
with 31% and 17% of subjects receiving treatment for more than 2 years and 4 years, 
respectively. The overall known safety profile of ibrutinib-exposed subjects remained consistent, 
other than an increasing prevalence of hypertension, with no new safety concerns identified. The 
prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2 – 
3), 9% (year 3- 4), and 9% (year 4-5). The incidence for the 5-year period was 11%.  
 


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v 14 July 2022 
1.6.     Venetoclax  
1.6.1. 
 Bcl-2 Function in the Antiapoptotic Pathway 
Programmed cell death (apoptosis) is responsible for removal of aged and damaged cells from a 
healthy multicellular organism, and the balance between cell survival and cell death, as 
maintained by apoptosis, is critical for normal development and homeostasis of multicellular 
organisms. Distinct from the signaling pathways downstream of the B-cell receptor (i.e. BTK, 
PI3K), the Bcl-2 family of proteins is a crucial mediator of B-cell survival. Bcl-2 family proteins 
are important regulators of the intrinsic apoptosis pathway, and were first identified in FL. In 
contrast to other known oncogenes, Bcl-2 does not stimulate cellular proliferation, but rather 
inhibits programmed cell death by protecting cells from a wide variety of proapoptotic stimuli, 
including cytokine withdrawal, irradiation, cytotoxic drugs, heat, and deregulated oncogenes. 
 
Resistance to apoptosis is one hallmark of neoplasms. [13] Drug-induced restoration of the 
apoptotic pathway can therefore be a viable treatment strategy for cancer.  Selective killing of the 
tumor cells may be achieved because, unlike normal cells, tumor cells are under continuous 
stress and therefore reliant on aberrant apoptotic signaling to stay alive. [14] Overexpression of 
antiapoptotic Bcl-2 family members is associated with tumor initiation, disease progression, and 
drug resistance, and thus Bcl-2 family members are compelling targets for antitumor therapy. 
Apoptosis also plays an essential role in the immune system, where the elimination of self-
reactive cells is important in the selection of both T cells and B cells during the development of 
an immune response. Failure of the immune system to eliminate self-reactive lymphocytes is 
believed to be one of the leading causes of autoimmune disease. [15] The anti-apoptotic protein 
Bcl-2 has been demonstrated to regulate apoptosis in lymphoid tissues, and is a key factor in 
immune response resolution and in the elimination of autoreactive lymphocytes. 
 
Venetoclax is a novel, orally available small molecule Bcl-2 family protein inhibitor that binds 
with > 500-fold higher affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to other Bcl-2 
family proteins Bcl-XL (Ki – 48 nM) and Bcl-w (Ki – 245 nM). Overexpression of antiapoptotic 
Bcl-2 family proteins is associated with increased resistance to chemotherapy, and antagonism of 
the action of these proteins might enhance response to such therapy and overcome resistance. 
Antiapoptotic Bcl-2 family members are associated with tumor initiation, disease progression, 
and drug resistance, making them compelling targets for antitumor therapy. In vitro, venetoclax 
demonstrated broad cell killing activity against a panel of lymphoma and leukemia cells 
including B-cell follicular lymphomas (FLs), mantle cell lymphomas (MCLs), diffuse large B-
cell lymphomas (DLBCLs), and acute myeloid leukemias (AMLs). Venetoclax was especially 
potent against cell lines expressing high levels of Bcl-2. Leukemia and lymphoma cell lines 
bearing the t(14;18) translocation were significantly more sensitive to venetoclax than non-
mutated cell lines. 
 
Venetoclax inhibits subcutaneous xenograft growth of human tumor cell lines derived from 
ALL, NHL, and AML, and is highly efficacious using various doses and regimens. The drug is 
also active in models of disseminated ALL and AML. Venetoclax enhanced the activity of a 
broad variety of chemotherapeutic agents (e.g., R-CHOP, bendamustine, rituximab, and 
bortezomib) in other human hematological xenograft models. Leukemia and lymphoma cell lines 
bearing the t(14;18) chromosome translocation are significantly more sensitive to venetoclax 


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v 14 July 2022 
than nonmutated lines. Venetoclax also demonstrated potent killing of MM cell lines and 
primary tumor samples bearing the t(11;14) translocation, which tend to express high levels of 
Bcl-2 relative to Mcl-1. 
1.6.2. 
Summary of Non-clinical Data with Venetoclax 
1.6.2.1. 
Pharmacology  
The pharmacokinetic profile of venetoclax was evaluated in multiple animal species. In mouse, 
rat, monkey and dog, the venetoclax pharmacokinetic profile was characterized by low plasma 
clearance and low volumes of distribution. Half-lives ranged from 2.2 hours in monkey to 12 
hours in dog. Food had a marked effect on the oral bioavailability in dog.  
1.6.2.2. 
Toxicology 
On the basis of nonclinical safety pharmacology and toxicology evaluations of venetoclax, and 
on the basis of nonclinical and human studies of related antiapoptotic Bcl-2 family protein 
inhibitors, potential mechanism-based toxicities may include lymphopenia and neutropenia, 
signs of tumor lysis, reduction in red cell mass, decreased spermatogenesis, skin swelling, and 
hair hypopigmentation. Thrombocytopenia has not been observed in toxicology studies in mice 
and dogs. These findings are consistent with venetoclax as a Bcl-2 specific (Bcl-XL sparing) 
inhibitor. Consequently, thrombocytopenia is not expected to be a dose limiting toxicity (DLT) 
clinically.  
 
In vitro studies have shown that venetoclax is metabolized primarily by CYP3A4; thus, co-
administration of venetoclax with drugs that inhibit CYP3A4 (such as ketoconazole) is predicted 
to cause a significant increase in the exposure of venetoclax and will be undertaken with caution. 
 
For more detailed and comprehensive information regarding venetoclax, refer to the current 
version of the Investigator’s Brochure. 
1.6.2.3. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
The nonclinical toxicology of venetoclax has been evaluated in repeated-dose studies in mice 
and dogs with up to 4 weeks of once daily oral dosing (and with 4-week recovery periods) and in 
dogs with 2 weeks of dosing (18-week recovery period); safety pharmacology studies 
(cardiovascular, neurofunctional, and pulmonary); and in genetic toxicity tests (Ames and in 
vitro chromosome aberrations assays). The primary toxicities associated with venetoclax 
administration included effects on the hematologic system (lymphocytes and red blood cell 
parameters) in mice and dogs and on the male dog reproductive system. There was no evidence 
of genotoxicity of venetoclax. 
 
Male dog reproductive effects consisted of markedly reduced numbers of spermatogonia in the 
testes at all venetoclax dose levels after 4 weeks of dosing, with progression to severe decreases 
in the numbers of all germ cells in testes during the 4-week recovery period. Male mice did not 
have testicular changes associated with venetoclax administration. The translatability of the 
testicular findings in dogs to humans is unknown, but this change may be related to venetoclax 


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v 14 July 2022 
pharmacology, as one or more members of the Bcl-2 family of proteins play a role in 
spermatogenesis. [16] In view of the potential treatment benefits of venetoclax, this finding is 
anticipated not to impact the treatment of subjects with advanced hematologic malignancies. 
1.7. Summary of Clinical Data with Venetoclax 
1.7.1 Pharmacokinetics and Product Metabolism 
Venetoclax has high protein binding to human, rat, dog, and monkey plasma proteins (> 99.9%). 
In rats, venetoclax was widely distributed into, kidneys, spleen, heart, lungs, small intestine, and 
white fat, but was poorly distributed in testes, brain, muscle, and bone. Metabolism was the 
major route of elimination with biliary excretion of the parent drug playing the secondary role in 
rats. Venetoclax showed moderate metabolic stability in in vitro hepatic systems across species 
tested, except for low to moderate stability in dog hepatocytes. Volumes of distribution at steady 
state (Vss) were low to moderate in all species, with values increasing from 0.30 L/kg in dog to 
1.1 L/kg in rat. Plasma clearance values were low in all species, decreasing from a high of 0.27 
L/hr•kg in monkey to a low of 0.02 L/hr•kg in dog. 
 
Formulation-dependent bioavailability was noted following oral administration in all species. 
The initial pharmacokinetic studies using a 10% dimethyl sulfoxide (DMSO) in PEG-400 
solution formulation provided baseline bioavailability values ranging from a low of 8.6% in 
monkey to highs of 26.8% in mouse and 27.8% in dog. Plasma concentrations obtained from fed 
dogs were 30% to 50% higher than those obtained from fasted animals. 
 
In vivo, venetoclax was metabolized by CYP3A4. 
 
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be found 
in the current version of the Investigator's Brochure. 
 
          1.7.2  
Clinical Efficacy with Venetoclax in Lymphoma 
 
As a single agent, Venetoclax achieved an ORR of 48% in a phase I study of patients with 
multiply relapsed/refractory NHL (n=40). [17] Responses were noted in DLBCL, mantle cell 
lymphoma, Waldenstrom’s and follicular lymphoma. A greater percentage of responses occurred 
at the higher dose of 600 mg. Two dose limiting toxicities (Grade 3 febrile neutropenia, Grade 4 
neutropenia) occurred at this dose.  Dosing modifications including a lead-in period and step-
wise dose escalation were developed to help prevent the occurrence of tumor lysis syndrome. 
Grade 3 laboratory TLS occurred after the initial dose in one patient with bulky mantle cell 
lymphoma (>10 cm) and one with DLBCL. Common toxicities included nausea and diarrhea. 
Venetoclax is currently being studied in combination with BR (bendamustine and rituximab) in a 
phase I study of relapsed/refractory NHL (NCT01594229) and will be studied in an upcoming 3-
arm phase II study of BR+ Venetoclax, BR, and R+ Venetoclax (NCT02187861) in 
relapsed/refractory follicular lymphoma. 


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v 14 July 2022 
1.8. Summary of Clinical Safety with Venetoclax 
As of 03 February 2014, a total of 153 subjects have been enrolled in Study M12-175 and had 
data available for the study (95 in Arm A and 58 in Arm B). Most common adverse events in 
CLL/SLL subjects were diarrhea (38.9%), neutropenia (37.9%), nausea (34.7%), upper 
respiratory tract infection (30.5%), fatigue (27.4%), and cough (20.0%). The most common 
adverse events in NHL subjects were nausea (32.8%), diarrhea (24.1%), and fatigue and upper 
respiratory tract infection (20.7% each). The most common adverse events reported for all 
subjects in the study were nausea (34.0%), diarrhea (33.3%), neutropenia (29.4%), upper 
respiratory tract infection (26.8%), and fatigue (24.8%). The most common events grade 3 or 
above reported in CLL/SLL subjects were neutropenia (34.7%) and anemia (10.5%), and in NHL 
subjects were anemia (15.5%) and neutropenia (10.3%). Overall, the most common adverse 
events Grade 3 and above reported in all subjects were neutropenia (25.5%) and anemia (12.4%). 
1.8.1. 
Risks with Venetoclax 
1.8.1.1. 
Tumor Lysis Syndrome  
As a result of on-target effects, the potential for tumor lysis syndrome (TLS) was identified early 
in the program.  
Overall, the clinical data strongly support that the risk of TLS with venetoclax in CLL/SLL 
subjects is characterized as highest when initiating venetoclax dosing, especially with a higher 
initial dose of venetoclax, as well as being greater in subjects with a large tumor burden. The 
available data suggest that in non-CLL subjects the risk of TLS is low. It is being closely 
monitored among subjects with AML, NHL and MM. There have two cases of TLS in NHL, one 
patient with DLBCL and one patient with mantle cell lymphoma. 
1.8.1.2. 
Neutropenia 
Clinical data from the oncology studies suggest that the neutropenia adverse events are observed 
among subjects who receive venetoclax as a single agent or in combination with other 
therapeutic agents, with slightly higher frequency observed in combination studies. Even though 
neutropenia and febrile neutropenia adverse events of grade 3 or higher are observed, serious 
events of neutropenia and febrile neutropenia that are related to venetoclax administration or lead 
to discontinuations are few across the entire venetoclax oncology program. The assessment of 
neutropenia in the study population of subjects with hematological malignancies is confounded 
by various factors that could affect bone marrow reserves, including older age, multiple prior 
therapies, disease infiltrating the bone marrow, and the use of growth factor prior to entering the 
studies.  
1.8.1.3. 
Diarrhea 
Approximately one-third of CLL/SLL and one-fourth of NHL subjects receiving venetoclax 
reported diarrhea, primarily low-grade in nature. Other frequently reported gastrointestinal event 
was nausea.  


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v 14 July 2022 
1.8.1.4. 
Food Effect 
Preliminary pharmacokinetic data indicate that compared with fasting conditions, food increased 
venetoclax bioavailability by 3- to 4-fold. It is recommended that all venetoclax doses be 
administered within 30 minutes after the completion of breakfast or the subject's first meal of the 
day during a regular treatment cycle. All ongoing venetoclax studies follow this 
recommendation. 
1.8.1.5. 
Infections 
Approximately one-fourth of NHL subjects receiving venetoclax reported upper-respiratory 
infections. Serious infections have been reported in the oncology clinical studies; however, these 
events are confounded by the underlying disease, comorbidities, and other immunosuppressive 
medications.  To date, no clear relationship has been noted between serious infectious events and 
neutropenia.  The types of infectious events observed generally have been consistent with those 
anticipated in the elderly population of heavily pretreated subjects with hematologic 
malignancies.  The most common infection adverse events include upper respiratory, lower 
respiratory tract infections, and urinary tract infections.   
1.8.1.6. 
Other Hematological Effects 
Anemia has been reported in the oncology studies with slightly higher frequency when 
venetoclax was combined with other chemotherapeutic agents; however most of the events were 
not serious and were confounded by disease factors in the hematological cancer population.  
Thrombocytopenia adverse events, including grade 3 events and higher, have been reported in 
the oncology studies, with slightly higher frequency in studies in which venetoclax is combined 
with other chemotherapeutic agents.  However, most of the events were not serious and 
assessment of these events is confounded by the subjects’ underlying disease state and 
preexisting thrombocytopenia, including autoimmune thrombocytopenia in several subjects. 
Hemoglobin/hematocrit values and red blood cell counts and indices as well as platelet counts 
should be monitored for all subjects. 
Lymphopenia has been observed in preclinical studies.  No serious opportunistic infections 
attributed to venetoclax dosing have been reported in the clinical program.   
1.8.1.7. 
Other Malignancies 
To date, a total of 10 serious second primary malignancies, excluding non-melanoma skin 
cancers, have been reported across the oncology program; all are confounded by age, multiple 
prior therapies, and other host characteristics.  No pattern was observed in the occurrence of 
second primary cancers, and none were considered to be related to venetoclax. 


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v 14 July 2022 
1.8.1.8. 
Reproductive System Effects 
There is potential for decreased spermatogenesis.  Non-reversible depletion of testicular germ 
cells has been observed in dogs at all doses tested after 4 weeks of dosing. 
 
In the oncology studies, male subjects should be instructed to consider sperm banking before 
treatment with venetoclax if they are considering preservation of fertility.   
1.9. 
Study Rationale   
In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in 
mantle cell lymphoma and chronic lymphocytic leukemia cell lines. [18] Data have demonstrated 
synergy between the two agents in various other B-cell NHL cell lines. [19] We theorize that the 
combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for 
patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific 
toxicity.   
 
1.10. 
Correlative Science Background 
As targeted therapies become more ubiquitously used in the treatment of follicular lymphoma, 
accurate predictive biomarkers are crucial for the management of patients. The focus of the 
correlative science portion of this study is to identify potential mechanisms of resistance to the 
combination of ibrutinib and venetoclax, in order improve treatment selection for patients with 
relapsed and refractory follicular lymphoma. 
1.10.1 Mutations of Resistance 
Although active in indolent B-cell malignancies, cases of primary and secondary resistance to 
ibrutinib have emerged. To better understand the mutations of secondary resistance in CLL, 
whole exome sequencing was performed on peripheral blood samples from patients prior to 
starting therapy and at the time of progression. [20] Of the 6 patients who relapsed after 
achieving a durable response with ibrutinib, 5 had developed new cysteine-to-serine mutations in 
BTK at position 481 (C481S). This mutation disrupted covalent binding and allowed for 
reversible binding of BTK by ibrutinib, resulting in 25-fold less potent BTK inhibition and 
acquired resistance. Two patients had developed new mutations of PLCγ2: arginine to 
tryptophan at 665 (R665W), leucine to phenylalanine at 845 (L845F), and serine to tyrosine at 
707 (S707Y).  As PLCγ2 is downstream of BTK, these gain-of-function mutations lead to 
autonomous BCR signaling, independent of BTK, and disease progression. A limited data set 
suggests BTKC481S is also a culprit of secondary resistance to ibrutinib in mantle cell 
lymphoma. [21] Preclinical studies in ibrutinib-resistant diffuse large B-cell lymphoma 
(DLBCL) cell lines possessing either BTKC481or PLCγ2 R665W have demonstrated the ability 
to be re-sensitized to ibrutinib with co-administration of BCL-2 inhibitors, resulting in inhibition 
of cell growth, cell adhesion, and migration. [19] These data suggest that some B-cell NHL may 
utilize alternative survival pathways, including BCL-2, which can be exploited through other 


26 
 
v 14 July 2022 
targeted therapies.  There are currently no mutational data regarding ibrutinib sensitivity or 
resistance available in FL. [10] Mutations associated with resistance to BCL-2 inhibitors in FL 
have not yet been established either. Based on the above-mentioned observations, we believe 
next generation sequencing (NGS) to be a potentially effective tool for the identification of key 
predictors of response and resistance to the doublet regimen. Genetic profiles will be obtained 
from pretreatment tumor samples for NGS in order to help recognize potentially clinically 
significant mutations or alterations of the genome. 
1.10.2. BCL-2 Family Proteins 
Theorized mechanisms of resistance to BCL-2 inhibition include upregulation of the 
antiapoptotic members of the BCL-2 family, such as BCL-XL, MCL1, and BCL-W. In vitro 
studies of the first generation BCL-2 inhibitor, ABT-737, have demonstrated drug resistance via 
upregulation of BCL-XL and BCL2A1 in CLL lymph node models. [22] In a different CLL 
lymph node model, made resistant to venetoclax through stimulation with CD40 and IL4, 
upregulation of BCL-XL was also noted. [23] In follicular lymphoma cell lines, higher levels of 
the proapoptotic BIM were associated with increased sensitivity to BCL-2 inhibition; whereas 
cells with acquired resistance after continuous exposure to venetoclax were found to have 
increased levels of MCL-1. [24] Co-administration of venetoclax and either BCL-XL or MCL-1 
inhibitors resulted in synergistic cell death in resistant cell lines, supporting the direct correlation 
of these anti-apoptotic proteins and venetoclax resistance. [25] Additional alterations in 
venetoclax-resistant B-cell lymphoma cell lines (follicular, mantle cell, DLBCL) included 
change in level of BCL-2 expression and decrease in pro-apoptotic proteins (BAX, BIM, 
NOXA). 
 
Preclinical studies of venetoclax and ibrutinib in DLBCL cell lines have shown that higher levels 
of BCL-2 expression were associated with greater sensitivity to single-agent venetoclax than 
lower levels. [19] In addition, single-agent ibrutinib increased BCL-2 expression and sensitivity 
to venetoclax. Pretreatment samples from patients who responded to ibrutinib had lower BCL-2 
expression; whereas a high BCL-2 mutation rate was observed in patients who responded poorly 
to ibrutinib. Concurrent administration of ibrutinib and venetoclax resulted in complete tumor 
growth inhibition in a DLBCL (activated B-cell subtype) murine model. There are currently no 
data available from follicular lymphoma clinical trials evaluating the correlation between BCL-2 
family members and sensitivity to venetoclax.  Similarly, the clinical implications of the pro- and 
antiapoptotic members of the BCL-2 family have not been evaluated in patients receiving 
concurrent venetoclax and ibrutinib. Levels of expression of various BCL-2 family member 
proteins will be assessed on tumor samples prior to treatment, bone marrow biopsy samples after 
achieving a complete response, and tumor samples at progression in order to understand the 
implications of these proteins in terms of response to therapy, development of resistance, and the 
ability to overcome resistance. 
1.10.3. Tumor Cell Cultures and Drug Sensitivity 


27 
 
v 14 July 2022 
The survival and proliferative activity of FL is thought to be highly dependent on the micro-
environment within involved lymph nodes and in the bone marrow, where tumor cells are 
intimately associated with a variety of stromal cells within the so-called follicular lymphocyte 
niche. [26] Thus, although established FL cell lines have proven useful for modeling the role of 
various mutations on the sensitivity and resistance profile of the disease to therapeutic agents, 
these models, by their nature, ignore the contribution of tumor-stromal cell interactions.  To 
address this concern, several co-culture models have been used in recent years that seek to model 
these interactions between tumor cell lines, or cells derived from patient bone marrow or lymph 
nodes, and a variety of fresh or immortalized bone-marrow stromal cells, mesenchymal cells, and 
dendritic cells. [27-30] These models have been used to probe the interactions between the tumor 
and stromal cells and how they influence the behavior of each other, but they have also been 
used to test drug sensitivity.  This study will evaluate the feasibility of using patient-derived 
follicular lymphoma cells isolated from bone marrow aspirates to be grown in simple and co-
culture systems in order to evaluate sensitivity to venetoclax and ibrutinib.  
2. 
STUDY OBJECTIVES  
2.1. Phase I Study 
2.1.1. 
Primary Objective 
 To determine the recommended phase II doses of ibrutinib and venetoclax for 
combination in relapsed and refractory follicular lymphoma 
2.1.2. 
Secondary Objective 
 To determine the pharmacokinetics of ibrutinib and venetoclax when dosed in 
combination in relapsed and refractory follicular lymphoma 
2.2. Phase II Study 
2.2.1. 
Primary Objective 
 To determine the efficacy of ibrutinib and venetoclax when combined in relapsed 
and refractory follicular lymphoma 
2.2.2. 
Secondary Objective 
 To determine the safety and tolerability of ibrutinib and venetoclax when 
combined in relapsed and refractory follicular lymphoma 
2.3      Exploratory Objectives 
 To evaluate mutations of resistance via next-generation sequencing to the regimen 
when administered in combination in relapsed and refractory follicular lymphoma 
 To evaluate for an association between BCL-2 and other family member protein 
levels of expression and efficacy of the regimen 


28 
 
v 14 July 2022 
 To evaluate the feasibility of developing tumor cell cultures from bone marrow 
aspirates with lymphomatous involvement in order to better characterize activity 
of the combination 
 
3. 
ELIGIBILITY CRITERIA 
3.1. 
  Inclusion Criteria 
1. Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa 
which requires therapy defined by at least one of the following: 
o     Constitutional symptoms  
o     Cytopenias 
o     High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic 
splenomegaly, organ compression or compromise, ascites, pleural effusion) 
o     Any other clinical indication for treatment per investigator discretion. For example, 
patients with masses that do not fulfill the above stated dimensions but require therapy as 
determined by treating physician are eligible.      
2. Must have received at least one prior systemic therapy 
3. All risk by FLIPI 0-5 factors (Appendix I) 
4. Measurable disease 
Measurable disease must be present either on physical examination or imaging studies; 
non-measurable disease alone is not acceptable. Any tumor mass > 1.5 cm is acceptable. 
Lesions that are considered non-measurable include the following: 
o    Bone lesions (lesions if present should be noted) 
o    Ascites 
o    Pleural/pericardial effusion 
o    Lymphangitis cutis/pulmonis 
o    Bone marrow (involvement by lymphoma should be noted) 
5. Adequate hematologic function independent of transfusion and growth factor support for 
at least 3 weeks prior to screening unless attributable to disease. Defined as:  
o    ANC >1000 cells/mm3 (1.0 x 109/L).                            
   ANC > 500 cells/mm3 is permissible if due to disease. 
o    Platelet count >50,000 cells/mm3 (50 x 109/L) unless attributable to disease.     
   Platelet count > 20,000 cells/mm3 is permissible if due to disease. 
o    Hemoglobin >8.0 g/dL. 
6. Adequate hepatic and renal function defined as: 


29 
 
v 14 July 2022 
o Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper 
limit of normal (ULN)  
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 5 is 
permissible if due to disease. 
o Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin) 
Bilirubin ≤3 x ULN is permissible if due to disease. 
o Estimated Creatinine Clearance ≥50 ml/min (Cockcroft-Gault based on actual 
weight) 
7. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN. 
8. Men and women ≥ 18 years of age. 
9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II) 
10. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - 
no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; 
OR history of bilateral oophorectomy). Female subjects of childbearing potential must 
have a negative serum pregnancy test upon study entry. 
11. Male and female subjects who agree to use highly effective methods of birth control (e.g., 
condoms, implants, injectables, combined oral contraceptives, some intrauterine devices 
[IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 30 
days after the last dose of study drug 
3.2. Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
1. Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor 21 days prior to 
first administration of study treatment  
2. Prior exposure to a BTK or BCL-2 inhibitor.  
3. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ibrutinib or venetoclax. 
4. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for 
tumor lysis syndrome. 
5. History of other malignancies, except:  
 Malignancy treated with curative intent and with no known active disease present for 
≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by 
treating physician. 
 Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
 Adequately treated carcinoma in situ without evidence of disease.  


30 
 
v 14 July 2022 
6. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or 
chronic administration [>14 days] of > 20 mg/day of prednisone) within 28 days of the first 
dose of study drug. 
7. Undergone an allogeneic stem cell transplant within the past 1 year. 
8.  Current or history of graft versus host disease 
9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
10. Recent infection requiring systemic treatment that was completed ≤14 days before the first 
dose of study drug. 
11. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade ≤1, or to 
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. 
12. Known bleeding disorders (e.g., von Willebrand’s disease) or hemophilia. 
13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
14. Known HIV infection 
15. Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).  
 Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, 
hepatitis C antibody, must have a negative polymerase chain reaction (PCR) result for 
the respective disease before enrollment.  Those who are PCR positive will be 
excluded. 
16. Any uncontrolled active systemic infection. 
17. Major surgery within 4 weeks of first dose of study drug. 
18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk. 
19. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to randomization. 
20. Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 
21. Concomitant use of warfarin or other Vitamin K antagonists. 
22. Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior 
to the first dose of ibrutinib or subjects who require continuous treatment with a strong 
CYP3A inhibitor (See Appendix VI) 
23. High-grade transformation confirmed by biopsy. 
24. Malabsorption syndrome or other condition precluding enteral route of administration. 
25. Known CNS involvement by lymphoma 


31 
 
v 14 July 2022 
26. Erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome 
27. Lactating or pregnant. 
28. Unwilling or unable to participate in all required study evaluations and procedures. 
29. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations). 
30. Currently active, clinically significant hepatic impairment (≥ moderate hepatic impairment 
according to the Child Pugh classification (class B or C)) (see Appendix X) 
 
3.3 Inclusion of Women and Minorities  
 Both men and women of all races and ethnic groups are eligible for this trial.  
o Inclusion of Women and Minorities:  
o It is the intent of Lombardi Comprehensive Cancer Center to enroll patients 
regardless of gender or race. Both men and women of all races and ethnic groups are 
eligible for this study. In the development of this protocol, the possibility of inherent 
gender or racial/ethnic differences in treatment response has been considered. 
 
4. 
REQUIRED DATA 
4.1. 
  Screening Phase 
To be completed within 14 DAYS before Cycle 1 Day 1: 
 All blood work 
To be completed within 28 DAYS before Cycle 1 Day 1 
 Any radiologic study (e.g., PET, CT, or MRI) that is utilized for tumor measurement 
 History and physical 
 
 
 


32 
 
v 14 July 2022 
4.2. 
    Schedule of Events 
                                                  Table 1: Schedule of Events 
 
All scheduled visits during Cycle 1 can occur +/- 1 day.  
All scheduled visits during Cycles 2-12 can occur +/- 3 days if necessary. 
For patients who continue on therapy after Cycle 12, scheduled visits and associated testing will 
occur every 2 cycles (instead of every cycle) with even numbered cycles only (i.e. Cycle 14, 16, 
etc.) All scheduled visits for patients receiving treatment after Cycle 12 can occur +/- 7 days if 
necessary. 
 
As the bone marrow biopsy and aspirate are not needed to determine eligibility for trial 
enrollment, this test has been removed from the screening phase of the study. The bone marrow 
procedures must be performed after the patient has been provided an official identification 
subject number, but before the administration of the first dose of study drugs on Cycle 1 Day 1. 
The bone marrow biopsy at enrollment may be waived per investigator discretion. If a patient 
achieves a complete response by imaging, a bone marrow biopsy should be performed to confirm 
a complete response. 
 
 
Prior to  
Cycle 1 Day 
Cycle 1  
D1, 8, 15, 22 
Cycle 2-12 
Day1 
Even Numbered 
Cycles after C12 
At time of 
restaging* 
Follow-
up** 
TESTS & OBSERVATIONS 
 
 
 
 
 
 
History and progress notes 
X 
X 
A 
X 
X 
X 
Medication History 
X 
X 
A 
X 
X 
 
Physical examination 
X 
X 
A 
X 
X 
X 
Pulse, blood pressure 
X 
X 
A 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight/body surface area 
X 
X 
A 
 
 
 
Performance status 
X 
X 
A 
X 
X 
X 
Tumor measurements 
X 
B 
B 
B 
B 
B 
Solicited baseline abnormalities/ 
adverse events assessment 
X 
 
X 
X 
 
 
 
LABORATORY STUDIES 
 
 
 
 
 
 
CBC, differential, platelets 
X 
X 
A 
X 
X 
X 
CMP, CrCl (estimated) 
X 
X 
A 
X 
X 
X 
Uric acid, LDH, Mg, Phos, Ca 
X 
X 
A 
C 
C 
C 
β2-microglobulin 
X 
 
 
 
 
 
Serum or urine βHCG‡ 
X 
 
A 
 
 
 
HBsAg, HBsAb, HB core Ab 
X 
 
 
 
 
 
HCV antibody, HIV 
X 
 
 
 
 
 
PT/INR, PTT 
X 
 
 
 
 
 
EKG 
X 
C 
C 
C 
C 
C 
Pharmacokinetics 
 
X 
 
 
 
 
CORRELATIVE STUDIES 
 
 
 
 
 
 
Caris Life Sciences MI Tumor Seek 
D 
 
 
 
 
E 


33 
 
v 14 July 2022 
BCL-2 Protein Assessment 
D 
 
 
 
 
E 
Tumor cell cultures 
D 
 
 
 
 
 
STAGING 
 
 
 
 
 
 
PET-CT 
X 
 
 
 
X 
F 
CT/MRI (neck/chest/abd/pelvis) 
X 
 
 
 
 
X 
Bone marrow aspirate & biopsy 
G 
 
 
 
H 
 
Histologic review 
X 
 
 
 
 
I 
 
* 
Restage during week 12 (cycle 3), week 24 (cycle 6), and during week 52 (cycle 13). 
** After week 52 of cycle 13, follow up every 6 months for 2 years, then every 12 months until disease 
progression or for a maximum of 10 years from study entry. If the patient ends treatment for any 
reason other than disease progression, follow up every 6 months until disease progression or for a 
maximum of 10 years from study entry. If disease progresses, follow up annually for a maximum of 
10 years from study entry.  
 
In the phase II portion of the study, patients who achieve a complete remission and electively 
discontinue therapy after 24 cycles will have a more frequent follow up schedule of every 3 months 
for a 1 year after discontinuation. Follow up consists of physical exam, labs, and imaging. After 1 
year, they then resume follow up every 6 months for 2 years, then every 12 months until disease 
progression or for a maximum of 10 years from study entry. Patients may resume therapy for 
progression of disease or at the discretion of the investigator within one year of discontinuing therapy. 
If the patient resumes therapy within this time frame, study assessments should be performed as per 
Cycle 2 and beyond with the original restaging schedule. Patients will continue therapy until 
progression of disease or unacceptable toxicity.  
‡ 
For women of childbearing potential. 
A May be performed within 48 hours of Day 1   
B If accessible to physical examination, record measurements. 
C     PRN 
D   To be performed on bone marrow sample after patient determined eligible and enrolled in study, but 
prior to administration of study drugs on Cycle 1 Day 1. If bone marrow not sufficiently involved 
with lymphoma, patient should be referred for a biopsy for the correlative studies or recent biopsy of 
another affected area may be submitted. Lack of marrow involvement does not impact patient 
eligibility.  (Section 10). 
E    At the time of progression or relapse 
F    In the phase II portion of the study, patients who achieve a complete remission may discontinue 
therapy after 24 cycles.  These patients must undergo a PET-CT during Cycle 24 to confirm they are 
in a complete remission prior to discontinuation.   
G   The bone marrow biopsy must be performed prior to administration of study drugs on Cycle 1 Day 1. 
The results are not needed for treatment unless the only indication for treatment is lymphomatous 
involvement of the bone marrow. Obtain 10 cc of aspirate (5 cc in EDTA tube, 5 cc in yellow citrate 
tube) and three centimeters of core. One centimeter of core and 5 cc of aspirate in an EDTA tube will 
be submitted to pathology for standard assessment for lymphomatous involvement. One centimeter 
of core and 5 cc aspirate in yellow tube will be submitted to HTSR. One centimeter of core will be 
submitted to Caris Life Sciences.  See Appendix XII regarding sample submission. The bone marrow 
biopsy may be waived at investigator discretion.  
H     If initially positive, repeat only in patients who are in CR by all other criteria. If marrow is negative 
on one restaging biopsy, no subsequent bone marrow exam need be performed unless lymphoma has 
progressed clinically at another site. If bone marrow is still positive on restaging biopsy, it should be 
repeated at yearly intervals until determined to be negative. If not performed at enrollment, patients 
should undergo a bone marrow biopsy if imaging indicates a CR. 


34 
 
v 14 July 2022 
I      At time of progression or relapse, a biopsy of suspected area of involvement is recommended.  
 
5. 
 STUDY DESIGN 
5.1. 
Overview of Study Design 
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the 
maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory 
grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.  
5.2.     Treatment Plan 
5.2.1 Phase I Study Treatment Plan 
Patients will be treated with combination therapy of ibrutinib and venetoclax according to their 
assigned dose level cohort. Dose escalation is described in Table 2 and the paragraph below.  
Each cycle is 28-days. Patients will be monitored for dose limiting toxicity (DLT) weekly during 
Cycle 1. Patients will receive the combination until progression or unacceptable toxicity. Patients 
will be followed during therapy through progression until next line of therapy. Questions 
regarding treatment should be directed to the Study Chair.  
 
Table 2: Dose Level Cohorts 
Dose Levels 
Dose Level 
Ibrutinib  
Venetoclax  
0 
420 mg 
400 mg 
1 
560 mg 
400 mg 
2 
560 mg 
600 mg 
*Dose Level 0 is the starting level dose 
The MTD finding procedure starts at DL0. Three patients will initially be entered at this dose 
level.  
 If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. 
 If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. 
 If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. 
If no DLT is observed from the additional 3 patients, then dose escalation will continue to 
the next upper dose level. If any DLT is observed from the 3 additional patients, then the 


35 
 
v 14 July 2022 
previously lower dose will be chosen as the MTD and the dose finding procedure will be 
terminated. 
Dose escalation will be continued as per Table 2 until a dose with no more than 1/6 DLTs is 
found and is chosen as the MTD. Once the MTD is determined, there will be a 17-patient phase 
II study at this dose level. 
The original design of this study included a Dose Level 3 of Ibrutinib 560 mg and Venetoclax 
800 mg. After examining the pharmacokinetic data at Dose Level 2, which showed a 
significantly increased systemic plasma exposure to ibrutinib, it was determined not to proceed 
with Dose Level 3. One patient had initiated therapy at Dose Level 3 before the decision was 
made for closure. 
5.2.2 Phase II Study Treatment Plan 
Patients will be enrolled at the recommended phase II dose. Duration of therapy will depend on 
depth of response. Patients who achieve a complete remission may discontinue therapy after 24 
cycles. These patients must undergo a PET-CT during Cycle 24 to confirm they are still in a 
complete remission prior to discontinuation.  Patients who achieve a partial response will 
continue therapy until progression or unacceptable toxicity. Patients will be followed throughout 
the duration of therapy through progression until next line of therapy. Patients who achieve a 
complete remission and discontinue therapy after 24 cycles will be monitored closely per Table 1 
and may be reinitiated on treatment within one year of discontinuation for either progression of 
disease or at the discretion of the treating physician. 
Ibrutinib (capsules) and venetoclax (tablets) should be administered orally once daily at the same 
time. The capsules and tablets are to be taken at the same time each day with 8 ounces 
(approximately 240 mL) of water.  The capsules and tablets should be swallowed intact and 
subjects should not attempt to open capsules or tablets or dissolve them in water. The first dose 
will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an 
outpatient basis.  All subjects must be trained to self-administer therapy orally 30 minutes after 
the completion of breakfast or the subject’s first meal of the day. If a dose is not taken at the 
scheduled time, it can be taken as soon as possible on the same day with a return to the normal 
schedule the following day.  Subject should not take extra capsules or tablets to make up the 
missed dose.  
At study entry, patients will receive a Medication Calendar, and will be instructed on how to use 
the Medication Calendar. Study drugs will be dispensed to subjects in bottles at each visit.  At 
monthly visits, the patient will bring the Medication Calendar to the clinic.  All bottles of study 
medication (full, partial, and empty) should be brought to the clinic to compare with the 
Medication Calendar.  The Medication Calendar for the previous month will be reviewed, and 
new Medication Calendar will be given to the patient ( APPENDIX V). Unused study drugs 


36 
 
v 14 July 2022 
dispensed during previous visits must be returned to the site. Returned capsules and tablets must 
not be re-dispensed to anyone. 
5.3. 
   Prophylaxis and Management of Tumor Lysis Syndrome 
5.3.1. 
Prophylaxis for Tumor Lysis Syndrome 
TLS is a risk for patients with NHL who are treated with high cell-killing agents. Risk is highest 
for those with bulky disease, elevated pretreatment lactate dehydrogenase (LDH) levels, elevated 
leukocyte count, and dehydration. Patients with bulky disease, defined as any lymph node ≥ 8 cm 
on the screening CT scan, and/or lymphocytosis due to circulating lymphoma cells, are 
considered at higher risk of TLS and must be hospitalized for more intensive monitoring during 
the initial dose of study drugs. Patients who do not present with bulky disease are not considered 
at higher risk for TLS and do not require hospitalization, but may be hospitalized per discussion 
with the investigator and Medical Monitor.  
All patients must receive prophylaxis for TLS prior to the initiation of the first dose of the study 
drugs. Prophylaxis will include the following: 
 Appropriate hydration, consisting of a fluid intake of approximately 2-3L/day starting 24-
48 hours days prior to start of the study drugs and continued for at least 24 hours after the 
first does (for patients for whom volume overload is considered a significant risk, 
hospitalization should be considered). 
 Administration of an agent to reduce uric acid, such as allopurinol 300 mg/day, orally 
beginning 72 hours prior to the first study drugs dose. Rasburicase IV should be 
administered (unless medically contraindicated) for those patients with elevated uric acid 
levels prior to treatment which is, defined as a value above the local laboratory ULN or 
476 μmol/L. Agents should be given until normalization of serum uric acid and other 
laboratory evidence of TLS (e.g. elevated serum LDH levels). 
 Laboratory results should be reviewed, and electrolyte values should not demonstrate any 
clinically significant abnormalities prior to the first dose of study drugs or the patient 
should receive additional prophylactic treatment and hydration prior to the initiation of 
dosing. 
 Patients at higher risk of TLS will be hospitalized for initial study drugs dose. 
 For patients at particularly high risk for TLS, as judged by the investigator, consideration 
may be given to starting at a lower dose of study drugs and increasing study drugs dose in 
a stepwise fashion in discussion with the Medical Monitor. 
On the day of initial visit with administration of study drugs, serial vital sign assessments will be 
performed, and serum chemistry and hematology samples will be drawn prior to the dose of 


37 
 
v 14 July 2022 
study drugs and at 8 and 24 hours following the dose. The serum chemistry and hematology 
samples will be immediately sent to the laboratory and the investigator or designee must 
promptly review the results. Laboratory results from pre-dose samples must be reviewed prior to 
study drugs administration unless laboratory results from within the prior 24 hours have already 
been reviewed and do not require intervention. Laboratory values obtained prior to the dose of 
study drugs are to be used to determine whether a patient developed a change related to TLS. 
Laboratory results from the 24-hour post-dose assessments must be reviewed prior to receiving 
the dose of study drugs for that day.  
Patients who develop electrolyte changes suggestive of TLS should undergo aggressive 
management and further monitoring per Appendix VII. Definitions of Laboratory and Clinical 
Evidence of Tumor Lysis Syndrome are listed in Appendix VIII. In addition: 
 The next day’s dose of venetoclax should be held. If electrolyte changes are resolved 
within 24-48 hours of the last dose, venetoclax should be resumed at the same dose. 
 For any electrolyte changes requiring more than 48 hours to resolve, venetoclax should 
be resumed at a dose of 100 mg less than the last dose. 
 For any events of clinical TLS, venetoclax should be resumed at a dose of 100 mg less 
than the last dose following resolution of the TLS. 
 
5.3.2. 
Hospitalization  
Patients at higher risk for TLS (any lymph node ≥ 8 cm and/or circulating lymphoma cells) must 
be hospitalized for the initial dose of study drugs. Hospitalization should also be considered for 
patients with creatinine clearance <80 mL/min, in discussion with the study chair, Dr. Ujjani. 
Hospitalization will begin the evening prior to the first dose of study drugs and continue for 24 
hours after. Upon admission, serum chemistry and hematology laboratory samples should be 
drawn, and IV hydration should be started with a target of 150-200 cc/hr or as clinically 
appropriate. Laboratory results should be reviewed, and electrolyte values should not 
demonstrate clinically significant abnormalities prior to the first dose of study drugs, or the 
patient should receive additional prophylactic treatment and hydration prior to the initiation of 
dosing. A nephrologist (or acute dialysis service) must be consulted/contracted on hospital 
admission (per institutional standards) to ensure emergency dialysis is available and the 
appropriate staff is aware and prepared to handle any necessary intervention for TLS. Telemetry 
should also be considered.  
Serial vital sign assessments will be performed, and TLS laboratory samples will be drawn prior 
to the first dose of study drugs at 8, 12, and 24 hours post-dose, additionally, hematology 
samples will be drawn at 8 and 24 hours post-dose. These samples are to be immediately sent to 
the laboratory and the investigator or designee must promptly review the results. Laboratory 
values obtained prior to the dose of study drugs are to be used to determine whether a patient 


38 
 
v 14 July 2022 
developed a change related to TLS. Patients are still considered eligible to initiate therapy on 
Cycle 1 Day 1 if their hematologic parameters have dropped below eligibility requirements due 
to aggressive intravenous hydration. Laboratory results from the 24-hour post-dose sample must 
be reviewed prior to receiving the dose of study drugs for that day. Patients who develop 
electrolyte changes suggestive of TLS should undergo aggressive management and further 
monitoring per Appendix VII. Reintroduction of venetoclax in these patients should be 
performed as described in Section 5.3.1.  
5.4. 
      Pharmacokinetics 
5.4.1. 
Objective 
Steady-state plasma concentrations of ibrutinib, PCI-45227, and venetoclax after therapy 
administration will be determined on all patients enrolled during Phase I portion of the 
study on Cycle 1 Day 1. 
5.4.2. 
Methods 
Blood specimens for ibrutinib  
Pharmacokinetic venous blood samples for ibrutinib (3 mL) will be collected pre- and 
post-administration (Section 5.4.3) in a green top tube. Blood specimens will be processed 
promptly, and plasma separated, frozen and stored. Plasma will be split into 2 cryovials 
(0.5 mL each). The tubes will be ultimately transported to Frontage Laboratories, Inc. See 
Appendix X for further details. 
Frontage Laboratories, Inc., 
ATTENTION: Joseph Falcone/Stacy Seal 
Sample Coordinator 
700 Pennsylvania Drive 
Exton, PA 19341 
Phone: 484-202-6619 or 484-202-6603 
 
Blood specimens for venetoclax 
The blood samples for venetoclax will be collected in 3 mL evacuated potassium EDTA 
(K2 EDTA)-containing collection tubes pre- and post-administration (Section 5.4.3).   
Sufficient blood will be collected to provide approximately 1 mL plasma from each 
sample. Immediately after collection, the blood samples will be inverted several times to 
ensure good mixing of the blood and anticoagulant, and will be placed in an ice bath or 
cryoblock until centrifuged.  The blood samples for venetoclax will be centrifuged at 
approximately 1100 – 1600 × g for 10 – 15 minutes using a refrigerated centrifuge (2° to 
8°C) to separate the plasma within 1 hour of collection. The plasma samples will be 
transferred using plastic pipettes into screw-capped polypropylene tubes (Greiner # 
122263-2DG) labeled with the drug name (Venetoclax), type of sample (plasma), the 
protocol number, the subject number, the study period and/or study day, and the planned 


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v 14 July 2022 
time of sampling relative to dosing. The plasma samples will be placed in a freezer within 
2 hours of collection and maintained and at –20°C or colder until transferred to AbbVie. 
Abbvie, Inc. 
Attn:  Sample Receiving 
Dept. R43F, Bldg. AP13A, Room 2310 
c/o:  AbbVie Delivery Services 
1150 S. Northpoint Blvd. 
Waukegan, IL  USA 60085 
Phone: (847) 937-0889 
Fax: (847) 938-9898 
Email: sample.receiving@abbvie.com 
 
Measurement of plasma concentrations 
Plasma concentrations of ibrutinib, PCI-45227, and venetoclax will be determined using 
validated liquid chromatography followed by tandem mass spectrometry (HPLC-MS/MS) 
methods.  
Pharmacokinetic parameter estimation 
The plasma concentration-time profiles will be analyzed using non-compartmental 
analysis. The following pharmacokinetic parameters will be calculated, whenever possible: 
area under the plasma concentration-time curve from time 0 to 24 hours (AUC(0-24)), area 
under the plasma concentration-time curve from time 0 to infinity (AUC(0-inf)), peak 
concentration (Cmax), time to reach the maximum concentration (Tmax), elimination half-
life (T1/2), accumulation factor R to the PK parameters (e.g., Cmax and AUC), and 
metabolite-to-parent AUC ratio. Additional parameters including CL/F and Vd/F for 
ibrutinib may be calculated as appropriate. 
5.4.3. 
Schedule 
                     
Table 3: Pharmacokinetic Sampling Schedule 
Cycle 
Day  
Predoseb 
Time after ibrutinib and venetoclax dosinga 
1h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
6 h (± 1 h) 
1 
1 
X 
X 
X 
X 
X 
1 
2 
X 
 
 
 
 
1 
15 
X 
X 
X 
X 
X 
a. 
Record actual time of sample collection. 
a. 
Ibrutinib will be dosed at the same time as venetoclax. 
b. 
Samples for ibrutinib and venetoclax on Cycle 1 Day 15 should be collected approximately 24 (± 2 
h) hours after previous study dose and before administration of study drugs 


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v 14 July 2022 
Refer to the instructions on collecting and processing PK samples (Section 5.4.2.).  On the 
day of the sampling visit, the clinical staff will instruct the subject to not take ibrutinib and 
venetoclax before arrival at the clinic.  Study drug intake will be observed and recorded by 
clinic staff.  The actual time (versus requested time) that each PK sample is drawn must be 
recorded in the using a 24-hour format.   
6. 
MODIFICATIONS AND MANAGEMENT OF TOXICITY 
6.1.  Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any Serious Adverse Event criterion 
must be reported as a Serious Adverse Event in the appropriate time frame and documented as 
clinical sequelae to an overdose. There is no specific antidote for ibrutinib or venetoclax. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1400 mg/day) of ibrutinib. In a separate study 1 healthy subject who received 
a dose of 1,680 mg experienced reversible Grade 4 hepatic enzyme increases (AST and ALT). 
Refer to the IB for additional details about this case. Subjects who ingest more than the 
recommended dosage should be closely monitored and given appropriate supportive treatment. 
 
Refer to Section 13.3 for further information regarding special reporting situations as a result of 
overdose.  
6.2.  Dose Modification for Adverse Reactions 
The dose of study drugs should be modified according to the dose modification guidelines in 
Table 4 if any of the following toxicities occur: 
 Grade > 3 non-hematologic toxicity  
 Grade 4 hematologic toxicity, except grade 4 neutropenia < 7 days  
 Grade 3 thrombocytopenia (<50,000/µL) in the presence of clinically significant bleeding 
 Grade > 3 neutropenia with infection or fever 
 Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy.  
 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation. (See section 7.2.4) 
If the dose of ibrutinib or venetoclax is reduced, at the investigator’s discretion, the dose of 
ibrutinib or venetoclax may be re-escalated after 2 cycles of a dose reduction in the absence of a 
recurrence of the toxicity that led to the reduction. Dose changes must be recorded in the Dose 
Administration eCRF. 


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v 14 July 2022 
In patients with persistent and/or problematic Grade 1/2 non-hematologic adverse events such as 
fatigue, diarrhea, or nausea, the dose of study drugs can be reduced by one dose level at the 
discretion of the study investigator. The dose of study drugs may be re-escalated after 2 cycles of 
a dose reduction at discretion of the study investigator. If there is a recurrence of the prior 
toxicity, the patient will return to and remain on the lower dose. Dose changes must be recorded 
in the Dose Administration eCRF.  
 
Table 4. Ibrutinib and Venetoclax Dose Modifications  
 
Occurrence Action to be Taken  
First 
Withhold study drugs until recovery to Grade ≤1 or baseline; may restart at original 
dose level 
Second 
Withhold study drugs until recovery to Grade ≤1 or baseline; Ibrutinib should be 
reduced by 140 mg per day and Venetoclax should be reduced by 100 mg  
Third 
Withhold study drugs until recovery to Grade ≤1 or baseline; Ibrutinib should be 
reduced by 140 mg per day and Venetoclax should be reduced by 100 mg  
Fourth 
Discontinue study drug 
 
**See Section 7 regarding permissible concomitant medications, include growth factor 
support and CYP3A inhibitors. 
6.2.1.1. 
Leukocytosis/Leukostasis 
A high number of circulating malignant cells (>400,000/mcL) may confer increased risk of 
leukostasis; these subjects should be closely monitored. Administer supportive care such as 
hydration and/or leukapheresis as indicated. Ibrutinib may be temporarily held, and investigator 
should be contacted. Venetoclax should be continued in the setting of leukocytosis/leukostasis.  
6.2.1.2. 
Dose Modification for Subjects with Hepatic Impairment 
Subjects 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 Error! 
Reference source not found.. Ibrutinib is metabolized in the liver. In the population PK analysis 
(1,202 subjects), 179 subjects (14.9%) had mild hepatic impairment according to National 
Cancer Institute criteria and 12 subjects (1.0%) had moderate hepatic impairment. These subjects 
did not show a significantly higher ibrutinib exposure compared with subjects with normal 
hepatic function. In a hepatic impairment study, data showed an increase in ibrutinib exposure. 
For subjects with mild liver impairment (Child-Pugh class A), the recommended dose is 280mg 
daily. For subjects with moderate liver impairment (Child-Pugh class B), the recommended dose 
is 140mg daily. Monitor subjects for signs of ibrutinib toxicity and follow dose modification 
guidance as needed. It is not recommended to administer ibrutinib to subjects with severe hepatic 
impairment Subjects with clinically significant chronic hepatic impairment at the time of 


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v 14 July 2022 
Screening (Child- Pugh class C) are excluded from study participation. Concomitant use of 
strong CYP inhibitors is not permitted in subjects with chronic hepatic impairment. Refer to 
Appendix D for Child-Pugh classification. Please refer to Table 3 for dose modifications due to 
hepatic impairment.  
Table 5. 
Dose Modification Guidance for Hepatic Impaired Subjects 
 
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. 
 
7. 
CONCOMITANT MEDICATIONS/PROCEDURES 
7.1. Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell 
growth factors (erythropoietin) is permitted while on therapy per institutional policy and in 
accordance with the ASCO guidelines. [31] Transfusions may be given in accordance with 
institutional policy.  
Short courses (≤14 days) of steroid treatment for non-cancer related medical reasons (e.g., joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that do 
not exceed 100mg per day of prednisone or equivalent are permitted. 
If clinically indicated, antimicrobial prophylaxis can be considered.  Consider drug-drug 
interactions before initiating an agent. (Appendix V) Although there is a potential for drug-drug 
interactions, there is likely to be limited potential clinical effects, therefore Bactrim 


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v 14 July 2022 
(trimethoprim sulfamethoxazole) can be considered for Pneumocystis prophylaxis, with close 
clinical monitoring. 
After consultation with the investigator the following may be considered; localized hormonal or 
bone sparing treatment for non-B-cell malignancies, and localized radiotherapy for medical 
conditions other than the underlying B-cell malignancies.   
The following may be considered: localized hormonal or bone sparing treatment for non-B-cell 
malignancies, and localized radiotherapy for medical conditions other than the underlying B-cell 
malignancies.   
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 100 
mg per day of prednisone or equivalent. 
7.2.   Medications to be used with caution 
7.2.1. CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4. Concomitant use of ibrutinib with drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure, and strong CYP3A 
inhibitors should be avoided. Avoid grapefruit and Seville oranges during ibrutinib treatment as 
these contain moderate inhibitors of CYP3A. Dose adjustment of ibrutinib due to concomitant 
use of CYP3A inhibitors should follow Table 6. 
 
 
 
 
 
 
 
Table 6. 
Ibrutinib Dose Modification Guidance for Co-Administration with CYP3A 
Inhibitors 


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v 14 July 2022 
Patient Population 
Co-administered Drug 
Recommended Ibrutinib Dose for the 
Duration of the Inhibitor Usea 
B-Cell 
Malignancies 
Mild CYP3A inhibitors 
420 mg or 560 mg once daily per 
indication. No dose adjustment required. 
Moderate CYP3A inhibitors 
280 mg once daily. 
Voriconazole 200mg twice daily 
Posaconazole suspension 100mg 
once daily, 100 mg twice daily, or 
200 mg twice daily 
140 mg once daily. 
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 in Appendix VI. For further 
information, please refer to the current version of the IB and examples of inhibitors, inducers, 
and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This 
website is continually revised and should be checked frequently for updates. 
Venetoclax should be administered using caution with weak CYP3A4 inducers and inhibitors.  If 
a moderate CYP3A inhibitor must be used, venetoclax should be dose reduced by at least 50%. 
Venetoclax can be resumed at the normal dose 3 days after discontinuance of the moderate 
CYP3A inhibitor.  
This website is continually revised and should be checked frequently for updates. For the most 
comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please refer to the 
current version of the IB.  


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v 14 July 2022 
7.2.2. Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib or 
Venetoclax 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp) but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose. There is no clinical data available; therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin, 
should be taken at least 6 hours before or after ibrutinib or venetoclax. If a P-gp inhibitor must be 
used with venetoclax, venetoclax should be dose reduced by at least 50%. 
7.2.3. QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered.  
7.2.4. Antiplatelet Agents and Anticoagulants 
Use ibrutinib with caution in subjects requiring 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 subjects 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 Error! Reference source not found.). Subjects with congenital bleeding 
diathesis have not been studied. 
7.3. 
  Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving ibrutinib treatment.   
Corticosteroids for the treatment of the underlying disease are prohibited.  Corticosteroids for the 
treatment of non-cancer related reasons for longer than 14 days and/or at doses >100mg of 
prednisone or its equivalent are prohibited.   
Due to drug-drug interactions, strong CYP3A inhibitors and inducers should not be administered 
with venetoclax or ibrutinib. (See Appendix V). 
Live-virus vaccines should not be given within 28 days prior to the initiation of study treatment, 
at any time during study treatment, or in the 30 days following last dose of study treatment.  
7.4.  Guidelines for Ibrutinib and Venetoclax Management with Surgeries or Procedure 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:   


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v 14 July 2022 
 Minor Surgical Procedures 
For minor procedures (such as a central line placement, skin or needle biopsy, lumbar 
puncture [other than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib should 
be held for at least 3 days prior to the procedure and should not be restarted for at least 3 days 
after the procedure. For bone marrow biopsies that are performed while the subject is on 
ibrutinib, it is not necessary to hold ibrutinib for these procedures.  Venetoclax can be 
continued as per physician discretion for planned or emergency procedures.  
 Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention (except for emergency procedures) and 
should be held at least 7 days after the procedure and restarted at the discretion of the 
investigator when the surgical site is reasonably healed without serosanguinous drainage or 
the need for drainage tubes. Venetoclax can be continued as per physician discretion for 
planned or emergency procedures.  
8. 
DEFINITION OF DOSE LIMITING TOXICITY  
Assessment of DLT will be defined as any non-hematologic or hematologic toxicity listed below 
that occurs during the first cycle of treatment. Toxicities will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. 
Patients will be included in the DLT assessment as long as they have received at least 85% of 
planned doses of each drug or have experienced a DLT any time after the 1st dose. For each 
patient who did not receive >85% of therapy, another patient will be enrolled at that dose level.   
8.1.  Non-hematologic toxicity  
Non-hematologic toxicity will be defined as any of the following: 
 
Any Grade 3 or 4 non-hematologic toxicity except 
o Grade 3 fever without neutropenia  
o Grade 3 fatigue 
o Anorexia 
o Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral 
nutrition, or requiring prolonged hospitalization 
 Failure of any Grade 3 or 4 fever without neutropenia, fatigue, anorexia, nausea, 
vomiting, or diarrhea to resolve or recover to baseline level after delaying the next dose 
by more than 2 weeks 
 Any treatment-related death  


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v 14 July 2022 
8.2.  Hematologic Toxicity 
All subjects, regardless of baseline hematologic status (i.e. neutrophil and platelet counts), will 
be included in the DLT assessment. Hematologic toxicity will be defined as any of the following: 
 
Any Grade 4 hematologic toxicity, except for Grade 4 neutropenia < 5 days 
 
Grade 4 neutropenia > 5 days 
 Grade 3 or 4 neutropenia complicated by fever ≥ 38.5°C or infection   
 Grade 4 thrombocytopenia (must be repeated same day by a separate peripheral blood 
draw to confirm toxicity), that is considered a treatment emergent adverse event 
 Grade 3 thrombocytopenia with clinically significant bleeding 
 Grade 2 thrombocytopenia with clinically significant bleeding felt to be drug related 
 Grade 4 anemia unexplained by underlying disease 
9. 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
9.1. Ibrutinib  
   Availability 
Ibrutinib is supplied as hard gelatin capsules containing micronized ibrutinib and the following 
excipients: microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and may 
contain magnesium stearate. Capsules are available 140 mg strength size 0, gray, hard gelatin 
capsule. Capsules are packaged in high-density polyethylene (HDPE) bottles with an induction 
seal and a child resistant screw top cap. Each bottle contains 120 capsules.  
   Storage and Stability 
Ibrutinib Hard Gelatin Capsules should be stored at 15 – 25°C. Shelf life surveillance of the 
intact bottles is ongoing. 
   Administration 
Ibrutinib is taken orally, around the same time each day with 8 ounces (approximately 240 mL) 
of water. The capsules should be swallowed intact. 
The capsules should be swallowed intact and subjects should not attempt to open capsules or 
dissolve them in water. The use of strong CYP3A inhibitors/inducers, and grapefruit and 
Seville oranges should be avoided for the duration of the study (see Appendix V). 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The subject should not take extra 
capsules to make up the missed dose. 
9.2. Venetoclax 
   Availability 
The venetoclax tablets will be packaged in high-density polyethylene (HDPE) plastic bottles or 
blister packs to accommodate the study design.  Each container will be labeled per local 


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v 14 July 2022 
regulatory requirements. Venetoclax is available in tablets of 100 mg consisting of light yellow 
to dark yellow powder. 
   Storage and Stability 
   The clinical supply should be stored at 15° to 25°C (59° to 77°F). 
   Administration 
The tablets are to be taken around the same time each day with 8 ounces (approximately 
240 mL) of water.  The tablets should be swallowed intact and subjects should not attempt to 
open tablets or dissolve them in water. All subjects will be trained to self-administer 
venetoclax orally QD 30 minutes after the completion of breakfast or the subject’s first meal of 
the day. 
 
Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
10. CORRELATIVE SCIENCE COMPANION STUDY 
10.1. Next-Generation Sequencing  
Next generation sequencing via the MI TumorSeek™ will be performed on bone marrow 
aspirate samples from eligible patients, prior to initiation of targeted therapy. MI TumorSeek™ 
is a 596 gene Next-Generation Sequencing Cancer Service available through Caris Life 
Sciences. Patients will undergo a bone marrow core biopsy and aspirate prior to initiation of 
therapy.  One 1-cm core biopsy will be submitted to Caris Life Sciences in 50 mL of 10 % 
neutral buffered formalin overnight. If the patient is found to have greater than 20% 
involvement with FL in their bone marrow sample by standard hematopathology review, MI 
TumorSeek™ analysis will be performed on the submitted sample through Caris Life Sciences. 
If the patient lacks greater than 20% lymphomatous involvement of their bone marrow, they 
will be recommended to undergo a biopsy of an affected lymph node or other disease-involved 
area as determined by pretreatment staging PET-CT. The MI TumorSeek™ assay will be 
repeated on new tissue samples from patients who initially achieve a partial or complete 
remission and subsequently progress. Special focus will be placed on BTK and BCL-2, 
including variants of unknown significance, as well as PI3K, as idelalisib is an FDA approved 
PI3K inhibitor the patient may have received previously or will subsequently receive.  
10.2. BCL-2 Family Proteins 
Levels of expression of various BCL-2 family member proteins will be assessed on tumor 
samples from patients prior to treatment, on bone marrow biopsy samples after achieving a 
complete response, and tumor samples at progression. Assessments will be performed on bone 
marrow biopsy core samples of patients with lymphomatous involvement. One centimeter of 
the core biopsy will be submitted to the Lombardi Comprehensive Cancer Center 


49 
 
v 14 July 2022 
Histopathology and Tissue Shared Resource (HTSR) for processing. The presence of tumor 
will be assessed by H&E. Sections will be stained by the HTSR for BCL-2 family proteins 
including BCL-2, MCL-1, BIM, and BCL-XL. The stained slides will be subsequently 
transported to the Department of Pathology for H-score assessment of individual BCL-2 family 
member proteins.  Samples will be reviewed independently by two hematopathologists (Metin 
Ozdemirli, MD; Bhaskar Kallakury, MD). If the bone marrow is not involved, the patient may 
be recommended to undergo a biopsy of an affected lymph node or other disease-involved area 
as determined by pretreatment staging PET-CT. Alternatively, if tissue is already available 
from a recent biopsy of an affected area, it may be submitted. These patients will only undergo 
a follow up biopsy if they experience a progression on study. 
10.3. Tumor Cell Cultures 
The cell culture studies will be conducted in the laboratory of Dr. Michael Johnson, who has 
recently established similar primary co-culture models with other B-cell malignancies.  Bone 
marrow aspirates will be assessed for tumor cell content as described above and processed by 
ficoll-gradient centrifugation.  Five milliliters of aspirate will be collected in a yellow citrate 
tube. Depending on tumor cell percentage, the cells may be enriched by depletion of CD3, 
CD14, and CD16 positive cells with magnetic beads or used directly after assessment of 
viability and cell number. A variety of co-culture systems will be tested initially including 
culture with the follicular dendritic cell-like cell line HK, the immortalized mesenchymal 
stromal cell line HS-5, and primary bone marrow-derived mesenchymal stromal cells. [28-30] 
The tumor cells will be plated in IDEM, or -MEM supplemented with 10%FBS on mono-
layers of un-modified or irradiated co-culture cells plated in wells.  Tumor cell viability and 
proliferation will be assessed at various periods after culture by EdU-Click-IT-Alexa Fluor 
labeling assay and colorimetric vital dye assay.  Drug sensitivity assays will be done in a 
similar fashion by treating wells of co-cultured cells with various concentrations of venetoclax 
and ibrutinib alone and in combination for 24 hours followed by staining the cells with CD19 to 
mark the tumor cells and Calcine AM to assess viability, followed by quantification using a 
custom MetaMorph macro. 
11. SUBJECT COMPLETION AND WITHDRAWAL 
11.1. Completion 
The investigator will conduct the study in compliance with the protocol and complete the study 
within the timeframe specified in the contract.   Continuation of this study beyond this date must 
be mutually agreed upon in writing by both the investigator and the sponsor.  The investigator 
will provide a final report to the IEC/IRB following conclusion of the study. The investigator 
must retain any records related to the study according to local requirements.  The end-of-study is 
defined as the date of the last subject’s last visit. 


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11.2. Withdrawal from Study Treatment 
Each subject has the right to withdraw from the study at any time.  In addition, the investigator 
will discontinue a subject from the study at any time if the investigator considers it necessary for 
any reason including: 
 The investigator believes it is in the best interest of the subject; 
 The subject’s response to therapy is unsatisfactory, as evidenced by progression of 
disease while on study drug; 
 The subject requires radiotherapy, cancer-related surgery as a result of tumor progression, 
or alternate anti-neoplastic agents during the study period; 
 Noncompliance with the protocol; 
 Unacceptable adverse event(s), or  
 General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
If, at any time the constraints of this protocol are detrimental to the patient’s health and/or patient 
no longer wishes to continue protocol therapy, protocol therapy shall be discontinued.  In this 
event: 
 Notify the Study Chair 
 Document the reason(s) for discontinuation of therapy in the study record. 
 Follow the patient for relapse, progression, survival, and secondary malignancies or new 
primaries. 
12. STATISTICAL METHODS AND ANALYSIS 
This is a phase I/II study in which patients will be enrolled in a standard 3+3 design.  Once the 
maximum tolerated dose is determined, there will be a 17-patient phase II study. 
12.1. Phase I study 
The maximum tolerated dose (MTD) finding procedure uses the traditional 3+3 cohort method, 
starting from dose level 0. A dose level will be chosen as the MTD if it has 6 patients, and 
number of observed DLT is 0 or 1. The MTD is also known as the recommended phase II dose. 
Three patients will be enrolled at Dose Level 0 (DL0). Patients will be assessed for DLTs 
during Cycle 1.  
Three patients will initially be entered at DL0.  
 If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. 
 If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. 
 If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. 
If no DLT is observed from the additional 3 patients, then dose escalation will continue to 


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v 14 July 2022 
the next upper dose level. If any DLT is observed from the 3 additional patients, then the 
previously lower dose will be chosen as the MTD and the dose finding procedure will be 
terminated. 
Dose escalation will be continued as per Table 2 until a dose with no more than 1/6 DLTs is 
found and is chosen as the MTD.  
 
12.2. Phase II Study  
Once the MTD, also the known as the recommended phase II doses are determined, the phase 
II portion of the study will open to potentially 17 patients with relapsed or refractory follicular 
lymphoma at this dose level.  A Simon’s Minimax 2-stage design will be used to test the null 
hypothesis that the response rate is at most 30% against an alternative response rate of 60% (a 
desirable rate). This design assumes that current individual therapies for this group of patients 
would have response rate about 30% and it is hoped that the Ibrutinib and Venetoclax would 
improve the response rate to 60% or more. In Stage 1, 10 patients will be enrolled. The study 
will proceed to Stage 2 if there are 3 or more responders, otherwise the study will be stopped 
for futility. In Stage 2, an additional 7 patients will be enrolled for a total of 17 patients and we 
would accept Ibrutinib and Venetoclax for further studies if there are at least 9 responders out 
of 17 patients. This design would have 80% statistical power for detecting the advantage in 
response rate for Ibrutinib and Venetoclax at a statistical significance level of 5% (one-sided). 
If the combination of Ibrutinib and Venetoclax is actually not effective, there is a 0.04 
probability of concluding that it is (targeted value is 0.05). If the combination is actually 
effective, there is a 0.199 probability of concluding that is not (the targeted value is 0.2). 
The 17 patients for the phase II portion will include the FL patients who are treated at the MTD 
level in phase I and who satisfy the phase II enrollment criteria.  
Descriptive statistics (mean, median, n, min, max, std, etc.) will be used to summarize patients' 
demographics as well as prognostic information. Complete response rate and overall response 
rate will be estimated for each dose level as per the revised Lugano Response Criteria for Non-
Hodgkin Lymphoma with their 90% exact Binomial confidence intervals (Appendix VI). [24] 
Progression-free survival (defined as time between enrollment and disease progression or 
death) and overall survival (defined as time between enrollment and death) with their 95% 
confidence intervals will be estimated by Kaplan-Meier method for the whole number of 
patients in this study and at the MTD. 
12.3.      Toxicity Evaluation 
Ineligible patients will be replaced by new eligible patients during both phases of the study and 
will be excluded in the data analysis. Ineligible patients are defined as patients who were 
initially believed to be eligible, but with full screening have been found to be ineligible. 
Toxicity (attribute and grade) will be summarized for each dose level as per the NCI Common 


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v 14 July 2022 
Terminology Criteria for Adverse Events (CTCAE Version 4.03) for all patients who receive at 
least one dose of study treatment.  
12.4.     Target Accrual and Study Duration 
The real sample size of this study is variable. The minimum required sample size is 6, but this 
number may change based on the number of DLTs experienced by patients during the phase I 
portion of the study. The maximum samples size will be 35  patients (= 3 dose levels x 6 
patients + 17 patients for expansion). The patient accrual will be closed as soon as the MTD is 
found and the phase II expansion is completed. We will have conference calls every 2 weeks 
with all sites with patients enrolled to discuss toxicity in individual cases.  The safety data of 
all patients will be reviewed during the biweekly conference calls, and the stopping rule for the 
3+3 cohort scheme will be applied.   
The estimated accrual rate is about 2 patients per month. As a result, it will take about 13 
months to find and expand the MTD. However, observation of PFS will require longer follow-
up. A maximum of 10 years of follow-up is required for all patients. Once the targeted number 
of patients has been accrued to this study, a notice suspending accrual will be issued to the 
Group via email broadcast announcing permanent termination of patient accrual within 14 
days. 
12.5. Correlative Science Statistical Considerations  
12.5.1. 
Mutations of Resistance 
The frequency table will be used to summarize patients’ clinical outcome status (partial or 
complete remission and progression). Fisher's Exact test will be used to assess the relationship 
between the clinical outcomes and the occurrence of new mutations or alterations in the genome.   
12.5.2. 
BCL-2 Family Proteins 
Descriptive statistics (including mean, median, std, min, max) will be used to summarize the H-
score assessment of individual BCL-2 family member proteins. The H-score will then be 
categorized, and Fisher's Exact test will be used to explore its relationship with varying 
expression of BCL-2 family member proteins. 
 
12.5.3. Tumor Cell Cultures 
Evaluate for possible correlations between in vitro sensitivity, patient response, the pattern of 
BCL-2 family member expression, and the spectrum of gene mutations identified by NGS. 
13. ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide.  


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13.1. Definitions  
13.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational study drug, whether or not considered related to the 
study drug. 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an adverse event term.  As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events may include, but are not limited to: 
 
Subjective or objective symptoms provided by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
 
Any AEs experienced by the subject through the completion of final study procedures. 
 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period  
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
 
Pre-existing condition:  A pre-existing condition (documented on the medical history CRF) 
is not considered an AE unless the severity, frequency, or character of the event worsens 
during the study period. 
 
Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after enrollment 


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in the study for a condition that has not changed from its baseline level.  Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due to 
long travel distances are also not SAEs. 
 
Diagnostic Testing and Procedures:  Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
 
Asymptomatic Treatment Related Lymphocytosis: This event should also not be 
considered an AE.  Subjects with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures 
13.1.2. 
Serious Adverse Events 
A serious adverse event based on 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 IND 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. 
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form. For deaths related to disease progression (coded to 
malignant neoplasm progression), the date and cause of death will be recorded on the appropriate 
case report form, however, the event will be considered expected for the purpose of determining 
expedited reporting requirements to regulatory authorities. If the cause of death is unknown at 
the time of reporting, "unexplained death" should be recorded on the eCRF. If the cause of death 


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later becomes available "unexplained death" should be replaced by the established cause of 
death. 
 
For deaths related to disease progression (coded to malignant neoplasm progression), the date 
and cause of death will be recorded on the appropriate case report form, but the event will not be 
expedited as an individual case safety report (ICSR) to regulatory authorities. 
 
13.1.3. 
Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4 
(CTCAE v4.03) will be used for grading the severity (intensity) of adverse events. The CTCAE 
version 4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each 
referenced AE.  Should a subject experience any AE not listed in the CTCAE version 4.03, the 
following grading system should be used to assess severity: 
 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities 
 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
 
Grade 5 (Death related to AE) – experiences which result in subject death 
13.1.4. 
Causality (Attribution)  
The Investigator is to assess the causal relation (i.e., whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence cannot 
be established with the onset of the AE and administration of the 
investigational product; or, a causal relationship is considered 
biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 


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Possibly Related: 
There is a clinically plausible time sequence between onset of the AE 
and administration of the investigational product, but the AE could also 
be attributed to concurrent or underlying disease, or the use of other 
drugs or procedures.  Possibly related should be used when the 
investigational product is one of several biologically plausible AE 
causes. 
Related: 
The AE is clearly related to use of the investigational product. 
13.2.  Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically mentioned as 
occurring with the study drug under investigation. 
13.3. 
Special Reporting Situations 
Special reporting situation on a study may require expedited reporting and/or safety evaluation 
include, but are not limited to: 
 Overdose of any study drug 
 Suspected abuse/misuse of a study drug 
 Inadvertent or accidental exposure to a study drug 
 Medication error involving a product (with or without subject exposure to the study drug, 
e.g., name confusion) 
Occurrence of any special reporting situations should be recorded in the eCRF. If any special 
reporting situation meets the criteria of an AE, it should be recorded on the AEs eCRF. If the AE 
is considered serious, it should be recorded on the AEs eCRF as serious and should be reported 
on the Serious Adverse Event Report Form. The Serious Adverse Event Report Form should be 
sent via email or fax to Pharmacyclics Drug Safety or designee within 15 days of awareness 
13.4.  Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators  
13.4.1. 
Assessment of Adverse Events 


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Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation time points during the study. All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, detected 
through physical examination, clinically significant laboratory test, or other means, will be 
recorded.  Each recorded adverse event or serious adverse event will be described by its duration 
(i.e., start and end dates), severity, regulatory seriousness criteria (if applicable), suspected 
relationship to the investigational product, and any actions taken. 
13.4.2. 
Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be captured from the time signed and dated ICF is 
obtained until 30 days following the last dose of study drug.  
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug. Resolution information after 30 days should be 
provided.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document. All records will need to 
capture the details of the duration and the severity of each episode, the action taken with respect 
to the study drug, investigator’s evaluation of its relationship to the study drug, and the event 
outcome. Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection").  
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  
If a death occurs within 30 days after the last dose of study drug, the death must be reported as a 
serious adverse event.  
13.4.3. 
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 must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 months 
after the last dose of study drug. Any female subjects receiving study drug(s) who become 


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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.   
 
Pharmacyclics 
All Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs), and Special 
Reporting Situations (SRSs) (initial and follow-up information) should be reported to the 
Pharmacyclics Drug Safety team. All notifications should be sent via email (preferred method) or 
fax to the following inbox: AEintakeCT@pcyc.com/1-408-215-3500 
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study drug must be reported. Any occurrence of pregnancy must 
be reported to Pharmacyclics Drug Safety, per SAE reporting timelines. All pregnancies will be 
followed for outcome, which is defined as elective termination of the pregnancy, miscarriage, or 
delivery of the fetus. Pregnancies with an outcome of live birth, the newborn infant will be 
followed until 30 days old and this must be reported to Pharmacyclics Drug Safety, per SAE 
reporting timelines. Any congenital anomaly/birth defect noted in the infant must be reported as 
a serious adverse event. 
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 all serious adverse events experienced by a study subject receiving an 
AbbVie product within 24 hours of learning of the event regardless of the relationship of the 
event to the AbbVie product.  Principal Investigator shall make available to AbbVie promptly 
such records as may be necessary and pertinent to investigate any such event, if specifically 
requested by AbbVie; and in addition, report all non-serious adverse events of tumor lysis 
syndrome for studies involving ABT-199. 
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. 
13.4.4. 
Other Malignancies 


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All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for overall survival. If 
observed, enter data in the corresponding eCRF.  
13.4.5. 
Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the Sponsor. These events (regardless of seriousness) will be reported on 
the Serious Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, 
or designee, within 15 days of awareness.   
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 v4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to above. 
Tumor lysis syndrome 
Tumor lysis syndrome is an important identified risk for Venetoclax, especially in CLL 
indications. For active surveillance and continual characterization of the safety concern, both 
non-serious and serious events of TLS are requested to AbbVie. 
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. 
13.5.    Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events and AESIs (initial and follow-up information) will be reported on 
FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB 
Reporting Form and sent via email (AEintakeCT@pcyc.com) or fax ((408) 215-3500) to 
Pharmacyclics Drug Safety within 15 days of the event. Pharmacyclics may request follow-up 
and other additional information from the Sponsor Investigator.  
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 


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 
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) 
 
14. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS   
14.1. Regulatory and Ethical Compliance 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent and all other forms of subject information related 
to the study (e.g., advertisements used to recruit subjects) and any other necessary documents 
be reviewed by an Institutional Review Board (IRB). The IRB will review the ethical, 
scientific and medical appropriateness of the study before it is conducted. IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site. 
 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guideline governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  
Any amendments to the protocol will require IRB approval prior to implementation of any 
changes made to the study design. The investigator will be required to submit, maintain and 
archive study essential documents according to ICH GCP. Any serious adverse events that 
meet the reporting criteria, as dictated by local regulations, will be reported to both responsible 
Ethics Committees and Regulatory Agencies, as required by local regulations. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IRB of any 
changes that affect the conduct of the study and/or increase the risk to subjects. 
 
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form must be 
sent to Pharmacyclics for review and approval prior to submission to the IRB.  Written 
verification of IRB approval will be obtained before any amendment is implemented. 
14.2. Enrollment  
Enrollment must occur prior to the initiation of therapy. Enrollment to the optional correlative 
science companion studies will be performed at the time enrollment occurs to the treatment 
study. Enrollment to both the treatment study and the correlative studies will not be completed 
if eligibility requirements are not met for both trials. The multicenter clinical trial project 


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manager must be contacted by the site regarding each potential patient (email: LCCC-Multi-
Site-Office@georgetown.edu).  Eligibility will be confirmed by Lombardi CCC quality 
assurance office (email: LCCCQAO@georgetown.edu).  
14.3. Informed Consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts.  Human protection 
committee approval of this protocol and a consent form is required. 
The investigator or his/her representative will explain the nature of the study to the subject and 
answer all questions regarding this study.  Prior to any study-related screening procedures 
being performed on the subject, the informed consent statement will be reviewed and signed 
and dated by the subject, the person who administered the informed consent, and any other 
signatories according to local requirements.  A copy of the informed consent form will be 
given to the subject and the original will be placed in the subject’s medical record.  An entry 
must also be made in the subject’s dated source documents to confirm that informed consent 
was obtained prior to any study-related procedure and the subject received a signed copy.  
14.4. Case Report Forms and Record Maintenance 
The investigator will document subject data in his/her own subject files.  These subject files 
will serve as source data for the study.  All eCRF data required by this protocol will be 
recorded by investigative site personnel in the RAVE system.  All data entered into eCRF will 
be supported by source determination. 
The investigator or an authorized member of the investigator’s staff will make any necessary 
corrections to the eCRF.  All change information, including the date and person performing the 
corrections, will be available via the audit trail, which is part of the EDC system.  For any 
correction, a reason for alteration will be provided. The eCRFs will be reviewed periodically 
for completeness, legibility, and acceptability. The principal investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to 
eCRFs as evidence thereof.  
14.5. Publication of Study Results 
Per the IST Agreement, the Investigator is required to submit to Pharmacyclics a copy of a 
planned publication (abstract, poster, oral presentation or manuscript) prior to the submission 
thereof for publication or disclosure.  Pharmacyclics may provide scientific comments and 
suggestions understanding that the Investigator has sole editorial responsibility and retains the 
authority to make the final determination on whether or not to incorporate Pharmacyclics 
comments or requests for additional information. 


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14.6. Study Discontinuation 
Per the IST Contract, the Investigator reserves the right to terminate the study at any time.  
Should this be necessary, both the Investigator will arrange discontinuation procedures in 
partnership with Pharmacyclics.  In terminating the study, the Investigator will assure that 
adequate consideration is given to the protection of the subjects’ interests.  Pharmacyclics may 
terminate the study for reasons including, but not limited to: evidence that the PI or an involved 
investigator is unqualified to conduct research or fulfill sponsor responsibilities (e.g., is listed 
on a debarment or ineligible investigator list); failure to meet timelines or achieve agreed upon 
milestones; a known or perceived risk to patient well-being is identified; or breach of contract. 
Additional grounds for termination are outlined in the IST Agreement. 
14.7    Data and Safety Monitoring  
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and 
safety monitoring of this multi-site trial.  As this study is an investigator-initiated study Phase 
I/II study utilizing a non-FDA approved drug for which the PI holds the IND it is considered a 
high-risk study which requires real-time monitoring by the PI and study team and review every 
4 months by the LCCC Data and Safety Monitoring Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety 
monitoring at their weekly institution-based disease group meetings and on monthly disease 
group teleconferences.  
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the 
IRB retains the authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and 
Safety Monitoring Committee every 4 months from the time the first patient is enrolled on the 
study. Results of the DSMC meetings will be forwarded to the IRB with recommendations 
regarding need for study closure. 
DSMC recommendations should be based not only on results for the trial being monitored as     
well as on data available to the DSMC from other studies.  It is the responsibility of the PI to 
ensure that the DSMC is kept apprised of non-confidential results from related studies that 
become available.  It is the responsibility of the DSMC to determine the extent to which this 
information is relevant to its decisions related to the specific trial being monitored. 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible.  In the unlikely event that the trial PI does 
not concur with the DSMC recommendations, then the LCCC Associate Director of Clinical 
Research must be informed of the reason for the disagreement.  The trial PI, DSMC Chair, and 
the LCCC AD for Clinical Research will be responsible for reaching a mutually acceptable 
decision about the study and providing details of that decision to the IRB.  Confidentiality must 


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be preserved during these discussions.  However, in some cases, relevant data may be shared 
with other selected trial investigators and staff to seek advice to assist in reaching a mutually 
acceptable decision. 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy 
the DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the 
trial be closed for any reason, the recommendation will be reviewed by the Associate Director 
for Clinical Research at G-LCCC.  Authority to close a trial for safety reasons lies with the IRB, 
with the above described input from DSMC and the AD for Clinical Research.   
 


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2. Rummel M, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP 
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an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 
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3. Flinn I, van der Jagt R, Kahl B, et al.  Radomized trial of bendamustine-rituximab or R-
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4. Kaminski M, Zelenetz A, Press O, et al.  Pivotal study of iodine-131 tositumomab for 
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5. Gopal A, Kahl B, de Vos S, et al.  PI3Kdelta inhibition by idelalisib in patients with 
relapsed indolent lymphoma.  N Engl J Med 2014;379(11):1008-18. 
6. Bishop GA, Haxhinasto SA, Stunz LL, et al. Antigen-specific B-lymphocyte activation.  
Crit Rev Immunol 2003;23:165–197.   
7. Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: The dark side of B-cell 
differentiation.  Nat Rev Immunol 2002;2:920–932.   
8. Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B cell development 
and function: a genetic perspective. Immunol Rev 2000;175:120-127. 
9. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's 
tyrosine kinase. ChemMedChem 2007;2:58-61. 
10. Bartlett N, LaPlant B, Qi J, et al. Ibrutinib monotherapy in relapsed/ refractory follicular 
lymphoma: Preliminary results of a phase 2 consortium trial. Blood (ASH Annual 
Meetings) 2014; Abstract 800. 
11. Advani R, Buggy J, Sharman J, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) 
has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin 
Oncol 2013;31(1):88-94. 
12. Younes A, Flinn I, Berdeja J, et al. Combining Ibrutinib with R-CHOP: Updated Results 
From a Phase Ib Study in Treatment-Naïve Patients with CD20-Positive B-cell NHL. 
Blood (ASH Annual Meetings) 2013 122: Abstract 852. 
13. Hanahan D, Weinberg RA. The hallmarks of cancer.  Cell.  2000;100(1):57-70. 
14. Fesik SW.  Promoting apoptosis as a strategy for cancer drug discovery.  Nat Rev Cancer.  
2005;5(11):876-85. 
15. Mardsen VS, Strasser A.  Control of apoptosis in the immune system:  Bcl-2, BH3-only 
proteins and more.  Annu Rev Immunol.  2003;21:71-105. 


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16. Adams JM, Cory S.  Life or death decisions by the Bcl-2 protein family.  Trends Biochem 
Sci.  2001;26(1):61-6. 
17. Davids M, et al. Phase I study of VENETOCLAX in patients with relapsed/refractory 
NHL: responses observed in the DLBCL and FL at the higher cohort doses. J Clin Oncol 
(ASCO Annual Meeting Abstracts) 2014;32(15): Abstract 8522. 
18. Brett LK, et al. Drug Screening Reveals That Ibrutinib (PCI-32765) Exhibits Synergy With 
BCL-2 and Proteasome Inhibitors In Models Of Mantle Cell Lymphoma and CLL. Blood 
(ASH Annual Meeting Abstracts) 2013 122: Abstract 3080. 
19. Kuo HP, Chang BY. Combination Of Ibrutinib and BCL-2 or SYK Inhibitors In Ibrutinib 
Resistant ABC-Subtype Of Diffuse Large B-Cell Lymphoma. Blood (ASH Annual 
Meeting Abstracts) 2014; Abstract 505. 
20. Woyach J, Furman R, Liu T, et al. Resistance Mechanisms for the Bruton's Tyrosine Kinase 
Inhibitor Ibrutinib. N Engl J Med 2014; 370:2286-2294. 
21. Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition 
overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional 
genomics in mantle cell lymphoma. Cancer Discov 2014 Sep;4(9):1022-35. 
22. Vogler M, Butterworth M, Majid A, et al. Concurrent up-regulation of BCL-XL and 
BCL2A1 induces approximately 1000-fold resistance to ABT-737 in CLL. Blood 
2009;113(18):4403-4413.  
23. Thijssen R, Geest CR, de Rooij MFM, et al. Possible mechanisms of resistance to the novel 
BH3-mimetic ABT-199 in in vitro lymph node models of CLL–the role of Abl and Btk. 
Blood 2013;122(21). Abstract 4188. 
24. Bodo J, Zhao X, Smith MR, Hsi ED. Activity of ABT-199 and acquired resistance in FL 
cells. Blood 2014;124(21). Abstract 3635. 
25. Tahir S, Smith M, Hessler P, et al. Mechanisms of resistance to ABT-199 in leukemia and 
lymphoma cell lines. AACR Precision Medicine Series 2014; Abstract B30. 
26. Ame-Thomas P, Tarte K. The yin and the yang of FL cell niches: role of microenvironment 
heterogeneity and plasticity. Semin Cancer Biol. 2014 Feb;24:23-32. 
27. Goval JJ, Thielen C, Bourguignon C, Greimers R, Dejardin E, Choi YS, Boniver J, de LL. 
The prevention of spontaneous apoptosis of FL B cells by a follicular dendritic cell line: 
involvement of caspase-3, caspase-8 and c-FLIP. Haematologica 2008 Aug;93(8):1169-
77. 
28. Guilloton F, Caron G, Menard C, Pangault C, Ame-Thomas P, Dulong J, De VJ, Rossille 
D, Henry C, Lamy T, et al. Mesenchymal stromal cells orchestrate FL cell niche through 
the CCL2-dependent recruitment and polarization of monocytes. Blood 2012 Mar 
15;119(11):2556-67. 
29. Roecklein BA, Torok-Storb B. Functionally distinct human marrow stromal cell lines 
immortalized by transduction with the human papilloma virus E6/E7 genes. Blood 1995 
Feb 15;85(4):997-1005. 


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30. Kagami Y, Jung J, Choi YS, Osumi K, Nakamura S, Morishima Y, Seto M. Establishment 
of a FL cell line (FLK-1) dependent on follicular dendritic cell-like cell line HK. Leukemia 
2001 Jan;15(1):148-56. 
31. Smith TJ, Bohlke K, Lyman G, et al. Recommendations for the Use of WBC Growth 
Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin 
Oncol. 2015.62.3488; published online on July 13, 2015. 
32. Cheson B, Fisher R, Barrington S, Cavalli F, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I REFERENCE SAFETY INFORMATION FOR IBRUTINIB 
 


68 
 
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69 
 
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APPENDIX II FOLLICULAR LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX (FLIPI) 
 
Follicular Lymphoma International Prognostic Index (FLIPI) 
(abstracted from Solal-Céligny et al. Blood. 2004; 104(5):1258-65) [9] 
 
 
 
      Number of 
Risk Group 
Risk Factors* 
Low Risk 
0-1 
Intermediate Risk 
2 
High Risk 
≥ 3 
 
* Risk Factors include: 
• 
Age > 60 
• 
Ann Arbor Stage III-IV 
• 
Number of nodal sites > 4 
• 
Serum LDH > upper limit of normal 
• 
Hemoglobin < 12 g/dL 
 
 
 
Follicular Lymphoma International Prognostic Index 2 (FLIPI2) 
(abstracted from Federico et al. JCO. 2009) [11] 
 
 
 
       Number of 
Risk Group 
Risk Factors* 
Low Risk 
0 
Intermediate Risk 
1-2 
High Risk 
3-5 
 
 
* Risk Factors include: 
• 
Age > 60 
• 
Bone marrow involvement 
• 
Longest diameter of the largest involved node > 6 cm 
• 
2-microglobulin > upper limit of normal 
• 
Hemoglobin < 12 g/dL 
 
 
 
 


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v 14 July 2022 
APPENDIX III ECOG PERFORMANCE SCALE 
 
 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
 
 
 
 
APPENDIX IV   COCKCROFT- GAULT FORMULA FOR ESTIMATED CREATININE CLEARANCE 
 
 
For Serum Creatinine Concentration (SrCr) in mg/dLa 
 
CrCl(mL/min) 
(140 - age) (weight)b 
 
(72) (SrCr) 
 
FOR FEMALES, USE 85% OF CALCULATED CRCL VALUE. 
 
a 
Age in years and weight in kilograms 
b 
Use actual weight 
 
 


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v 14 July 2022 
 APPENDIX V        MEDICATION CALENDAR 
 
PATIENT MEDICATION DIARY  
 
Today’s date ______________________________ 
Agents: Ibrutinib and Venetoclax  
Patient Name__________________ (initials acceptable) Patient Study ID ________ 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 4 week-period while you take ibrutinib and venetoclax. 
2. You will take ibrutinib and venetoclax drugs every day.  
3. Record the date, the number of capsules and tablets you took, and when you took them. Record doses 
as soon as you take them; do not batch entries together at a later time. 
4. If you have any comments or notice any side effects, please record them in the Comments column. If 
you make a mistake while you write, please cross it out with one line, put your initials next to it, and 
then write the corrected information next to your initials.  Example: 10:30 am SB 9:30 am 
5.    If you miss a dose of ibrutinib and/or venetoclax, you should take it as soon as you remember, as long 
as it is on the same day. You should not take two doses of the same drug on the same day. 
6. Please return this form to your physician when you go for your next appointment. 
 
 
Day 
 
Date 
Time of daily 
dose 
# of capsules taken 
of Ibrutinib 
# of tablets taken of 
Venetoclax 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10  
 
 
 
 
11  
 
 
 
 
12  
 
 
 
 
13  
 
 
 
 
14  
 
 
 
 
15  
 
 
 
 
16  
 
 
 
 


73 
 
v 14 July 2022 
17  
 
 
 
 
Day 
Date 
Time of daily 
dose 
# of capsules taken 
of Ibrutinib 
# of tablets taken of 
Venetoclax 
Comments 
18  
 
 
 
 
19  
 
 
 
 
20  
 
 
 
 
21  
 
 
 
 
22  
 
 
 
 
23  
 
 
 
 
24  
 
 
 
 
25  
 
 
 
 
26  
 
 
 
 
27  
 
 
 
 
28  
 
 
 
 
 
 
Physician’s Office will complete this section: 
 
1. Date patient started protocol 
treatment___________________________________________________ 
 
2. Date patient was removed from study 
____________________________________________________ 
 
3. Patient’s dose cohort 
____________________________________________________________________ 
 
4. Total number of capsules and tablets taken this month (each size) 
_________________________________________ 
 
5. Physician/Nurse/Data Manager’s Signature 
_________________________________________________ 
 
Patient’s signature 
______________________________________________________________________________ 
 
 


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v 14 July 2022 
APPENDIX VI DRUGS TO BE AVOIDED OR USED WITH CAUTION  
PROHIBITED MEDICATIONS 
Warfarin (Coumadin) 
Biologic agents 
Anticancer therapy 
Other investigational agents 
Steroid therapy for anti-
neoplastic intent 
 
CYP3A Strong Inhibitors 
Atazanavir 
Clarithromycin 
Itraconazole 
Fluvoxamine 
Nefazodone 
Nelfinavir 
Ritonavir 
Saquinavir 
Telithromycin 
Voriconazole 
Ketoconazole 
Boceprevir 
Cobicistat 
Conivaptan 
Indinavir 
Lopinavir 
Mibefradil 
Posaconazole 
Telaprevir 
Troleandomycin 
 
CYP3A Moderate Inhibitors 
Fluconazole 
Aprepitant 
Erythromycin 
Diltiazem  
Verapamil 
Amprenavir 
Atazanavir 
Ciprofloxacin 
Crizotinib 
Darunavir 
Dronedarone 
Fosamprenavir 
Imatinib 
Grapefruit juice 
Seville orange juice 
 
CYP3A Strong Inducers 
Avasimibe 
Carbamazepine  
Mitotane 
Modafinil 
Phenobarbital 
Phenytoin  
Rifabutin 
Rifampin  
St. John’s Wort 
 
CYP3A Moderate Inducers 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Nafcillin 
Oxcarbazepine 
Troglitazone 
MEDICATIONS TO USE WITH CAUTION 
CYP3A Weak Inducers  
Armodafinil 
Clobazam 
Pioglitazone 
Glucocorticoids such as 
prednisone 
Rufinamide 
Nevirapine 
Pioglitazone 
Vemurafenib 
 
 
CYP3A Weak inhibitors 
Alprazolam 
Amlodipine 
Atorvastatin 
Cimetidine 
Ranitidine 
Amiodarone 
Bicalutamide 
Cilostazol 
Cyclosporine 
Fluvoxamine 
Fluoxetine 
Ginkgo 
Goldenseal 
Isoniazid 
Nilotinib 
Oral contraceptives 
Pazopanib 
Ranitidine 
Ranolazine 
Suboxone 
Tipranavir 
Ticagrelor 
Zileuton 
 
Note that this is not an exhaustive list. Further information can be found at the following websites: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/  
and 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeli
ng/ucm080499.htm.  
 
 


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v 14 July 2022 
APPENDIX VII  LUGANO REVISED RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA 32 
Site 
PET-CT- Based Response 
CT-Based Response  
Complete 
Response 
Complete metabolic response 
Complete radiologic response (all of the 
following): 
Lymph nodes & 
extralymphatic 
sites 
Score 1, 2, or 3 with or without a 
residual mass on 5-point scale 
Target nodes/nodal masses must regress ≤ 
1.5cm in longest transverse diameter of a 
lesion (LDi); no extralymphatic sites of 
disease 
Non-measured 
lesion 
NA 
Absent 
Organ 
enlargement 
NA 
Regress to normal 
New Lesions 
None 
None 
Bone Marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if indeterminate, 
and flow cytometry IHC negative 
Partial 
Response 
Partial metabolic response 
Partial remission (all of the following): 
Lymph nodes & 
extralymphatic 
sites 
Score of 4 or 5 with reduced uptake 
compared with baseline and residual 
mass(es) of any size. No new or 
progressive lesions. At interim these 
findings suggest responding disease. At 
end of treatment these findings indicate 
residual disease. 
≥50% decrease in SPD of up to 6 target 
measurable node & extranodal sites. When a 
lesion is too small to measure on CT, assign 
5x5mm as the default value; when no longer 
visible, 0x0 mm. For a node >5x5mm, but 
smaller than normal, use actual measure for 
calculation. 
Non-measured 
lesion 
NA 
Absent/normal, regressed but no increase 
Organ 
enlargement 
NA 
Spleen must have regressed by >50% in 
length beyond normal 
New lesions 
None 
None 
Bone Marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan. 
NA 
Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, 
longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission 
tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular 


76 
 
v 14 July 2022 
to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions; NA, Not 
applicable 
Stable disease 
No metabolic response 
Stable Disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change 
in FDG uptake from baseline at interim 
or end of treatment 
< 50% decrease from baseline in SPD of up 
to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive 
disease are met 
Non-measured 
lesion 
NA 
No increase consistent with progression 
Organ 
enlargement 
NA 
No increase consistent with progression 
New lesions 
None 
None 
Bone Marrow 
No change from baseline 
NA 
Progressive 
Disease 
Progressive metabolic disease 
One of the following: 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in 
intensity of uptake from baseline and/or 
nadir with evidence of new or enlarging 
FDG avid nodes.  
PPD progression: An individual node/lesion 
must be: 
 
LDi > 1.5 cm and  
 
Increase by ≥ 50% from PPD nadir 
and 
 
Increase in LDi or SDi from nadir 
- 0.5 cm for lesions ≤ 2 cm 
- 1.0 cm for lesions > 2 cm 
Extranodal 
lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment 
 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline. If no 
prior splenomegaly, must increase 
by at least 2 cm from baseline 
 
New or recurrent splenomegaly 
Non-measured 
lesions 
None 
New or clear progression of preexisting 
non-measured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(e.g., infection, inflammation). If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; 
if < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone Marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 
 
 
 
*PET 5-point scale  
1-No uptake above background 
2-Uptake ≤ mediastinum 
3-Uptake > mediastinum but ≤ liver 
4-Uptake moderately > liver 
5-Uptake markedly higher than liver and/or new lesions  
X-New areas of uptake unlikely to be related to lymphoma 


77 
 
v 14 July 2022 
APPENDIX VIII  RECOMMENDATIONS FOR INITIAL MANAGEMENT OF ELECTROLYTE 
ABNORMALITIES AND PREVENTION OF TUMOR LYSIS SYNDROME 
 
Within the first 24 hours after either the first dose or dose increase, if any laboratory criteria 
below are met, the patient should be hospitalized for monitoring and the investigator notified. No 
additional study drugs doses should be administered until resolution. A rapidly rising serum 
potassium level is a medical emergency. 
 
Nephrology (or acute dialysis service) must be consulted/contacted on admission (per 
institutional standards to ensure emergency dialysis is available). 
 
Intravenous (IV) fluids (e.g. D5 ½ normal saline) should be initiated at a rate of at least 1 
mL/kg/h rounded to the nearest 10 mL (target 150 to 200 mL/h; not < 50 mL/h). Modification of 
fluid rate should also be considered for individuals with specific medical needs. 
 
Monitor for symptoms or signs of tumor lysis syndrome (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, phosphorous, uric acid, calcium and creatinine within 1 hour. 
 
Vital signs should be taken at time of all blood draws or any intervention 
 
The management recommendations below focus on the minimum initial response required. If a 
diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary 
management will be as per institutional protocols. 
 
 
 


78 
 
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79 
 
v 14 July 2022 
APPENDIX IX DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS SYNDROME 
 
Metabolic 
Abnormality 
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome 
Criteria for Classification of 
Clinical Tumor Lysis Syndrome 
Hyperuricemia 
Uric acid > 8.0 mg/dL (475.8 µmol/liter) 
in adults or above the upper limit of the 
normal range for age in children 
 
Hyperphosphatemia 
Phosphorus > 4.5 mg/dL 
(1.5 mmol/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 
(1.75 mmol/liter) or ionized calcium 
< 1.12 (0.3 mmol/liter)† 
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(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 
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 defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per liter) or a 
period of oliguria lasting 6 hours or more.  By definition, if acute kidney injury is present, the patient has clinical tumor lysis 
syndrome.  Data about acute kidney injury 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. 
 
 
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54 
 
 
 
 


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v 14 July 2022 
APPENDIX X CHILDS PUGH CLASSIFICATION    
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. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R. “Transection of the oesophagus for 
bleeding oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 
 
 
 
 


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APPENDIX XI IBRUTINIB PK SAMPLE COLLECTION 
 
Collect the PK blood samples according to the time points described in the protocol. 
 
USE 1 x 2-mL GREEN TOP SODIUM HEPARIN TUBE FOR EACH PK COLLECTION. 
 
1. Allow tube to fill COMPLETELY, as far as the vacuum will allow. 
2. Mix the tube immediately upon completion to avoid clotting by inverting gently 5 times. 
    DO NOT SHAKE. 
3. Place the blood samples on melting ice until centrifugation 
4. Place the sample in a refrigerated centrifuge (0-4°C). 
 
NOTE:  When necessary use a refrigerated centrifuge bucket in cases where a refrigerated centrifuge is not 
available.  Maintain cold temperature during the plasma preparation process. 
 
5. Centrifuge tube within 60 minutes of collection at 4°C for 15 minutes at 2500 rpm. 
6. Transfer plasma with pipette equally into two 2-mL cryovials (approximately 0.5 mL of  
    plasma in each tube). 
7. Enter the Subject ID number on the sample labels. 
8. Store plasma samples in a freezer at -80°C or below, within approximately 60 minutes of  
    blood collection. 
9. Ship samples FROZEN in batches (after collection from each subject is completed) to Frontage Laboratories, Inc. 
 
NOTE:  Every effort should be made to collect the full 2 mL blood sample at each time point.  In the event that less 
than 1 mL of blood is collected, the sample will be processed as described above except that the plasma will not be 
divided into two tubes.  All deviations will be recorded on the PK worksheet. This single plasma sample should be 
frozen, stored and shipped with the primary set of samples. 
 
 
 
  
PK Sample Shipping Instructions 
 
PK SPECIMENS to be batch shipped (FROZEN) after collection from each subject. Please include: 
 
• 
One primary set of samples for each subject 
• 
One back-up set of samples for each subject (unless only single plasma sample available) 
 
Samples should be shipped on dry ice Monday through Wednesday only. 
 
As much as possible, a complete set of primary samples (all timepoints) for a subject should be batched and shipped 
together in the same shipment. 
 
Ship the back-up set after the confirmation of receipt of the primary set by Frontage Laboratories, Inc. 
 
Do NOT ship back-up aliquots of plasma in the same shipment as the primary samples from the same subject. 


82 
 
v 14 July 2022 
 
Contact FEDEX customer service to determine the latest pickup time for your site and the scheduling deadline. 
Record the FEDEX Tracking number from the top of each airbill for your records and tracking purposes. 
 
Note:  A Shipping Notification fax should be send prior to shipping.   
Electronic packaging slip must be sent to SM@frontagelab.com 
 
SHIPPING ADDRESS 
 
Joseph Falcone 
Sample Coordinator 
Frontage Laboratories, Inc. 
700 Pennsylvania Drive 
Exton, PA 19341 
P: 484-348-4790 
F: 610-232-0101 
 
 


83 
 
v 14 July 2022 
APPENDIX XII CORRELATIVE STUDY SAMPLE SUBMISSION 
A. PATIENTS ENROLLED AT MEDSTAR GEORGETOWN UNIVERSITY HOSPITAL 
Georgetown HTSR contacts: 
Anju Duttargi - (202) 687- 0641, ad1155@georgetown.edu 
Dylan Kutz  - Lab: 202-687-1924, dk1120@georgetown.edu 
 
Checklist for procedure: 
1) 
One bone marrow biopsy kit 
2) 
Caris Life Sciences Fresh Tissue Shipper Kit (Will include a formalin container) 
3) 
1 EDTA tube 
4) 
1 Yellow-top  (ACD) tube 
5) 
Two standard pathology formalin containers 
 
Correlative samples to be collected per protocol from Bone Marrow Biopsy (See Table 1): 
1) 
Collect 10 cc of bone marrow aspirate in heparinized syringe 
a. 
Place 5 cc of aspirate in yellow-top tube  
b. 
Place 5 cc of aspirate in EDTA tube 
2) 
Three 1-cm cores of bone marrow should be obtained. A core sample should be 
placed in both of the standard formalin containers and in the one from the Caris 
Life Sciences Fresh Tissue Shipper Kit. 
 
Local Pathology:  
The EDTA tube and 1 cm core in standard formalin container should be sent to local pathology 
department for standard assessment to evaluate for presence and extent of lymphomatous 
involvement. Please send the bone marrow biopsy pathology report to the multicenter trials 
project manager as soon as available.  
 
Caris Lab:  
The core sample in the Caris Life Sciences Fresh Tissue Shipper Kit should be shipped directly 
to Caris.  Fill out forms included in kit. 
 


84 
 
v 14 July 2022 
If the patient lacks greater than 20% lymphomatous involvement of their bone marrow, they will 
be recommended to undergo a biopsy of an affected lymph node or other disease-involved area. 
This sample will need to be submitted to Caris Life Sciences. Please use the Caris Life Sciences 
Block Shipper kit to submit the sample. If the patient has recently undergone a biopsy of another 
affected area, this sample may be submitted instead after approval by Dr. Ujjani.  
 
Georgetown HTSR: The yellow-top tube and other 1 cm core which was placed in the standard 
formalin container should be given to HTSR at Georgetown. The yellow-top tube should be sent 
at room temperature. It does not need to be spun or otherwise prepared.  
Prior to shipment, each specimen container must be labeled with 
- 
subject ID 
- 
site/institution 
- 
collection date 
- 
specimen type 
 
When possible, samples should be collected Mon- Thurs to avoid weekend or holiday-related 
delays. Notify HTSR of specimen submission at least 1 business day prior to the date samples 
will submitted. 
 
 


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B. PATIENTS ENROLLED AT NON-GEORGETOWN SITES 
Checklist for procedure: 
1) One bone marrow biopsy kit  
2) Caris Life Sciences Fresh Tissue Shipper Kit (Will include a formalin container) 
3) 1 EDTA tube 
4) 1 Yellow-top (ACD) tube 
5) Two standard pathology formalin containers 
6) Pre-labeled histology cassettes with Telfa paper inside for biopsy collection 
 
Correlative samples to be collected per protocol from Bone Marrow Biopsy (See Table 1): 
1) Collect 10 cc of bone marrow aspirate in heparinized syringe 
a. Place 5 cc of aspirate in yellow-top tube 
b.  Place 5 cc of aspirate in EDTA tube 
2) Three 1-centimeter bone marrow cores should be obtained  
a. One core should be placed into one of the standard formalin containers  
b. One core should be placed in between the two sheets of Tefla paper inside the 
histology cassette. The cassette should be closed and placed into the other 
standard formalin container. 
c. One core should be placed in the formalin container from the Caris Life Sciences 
Fresh Tissue Shipper Kit.  
 
Local Pathology:  
The EDTA tube and 1 cm core in standard formalin container (without the histology cassette) 
should be sent to local pathology department for standard assessment to evaluate for presence 
and extent of lymphomatous involvement. Please send the bone marrow biopsy pathology 
report to the multicenter trials project manager as soon as available. 
 
Caris Lab:  
The core samples in the Caris Life Sciences Fresh Tissue Shipper Kit should be shipped directly 
to Caris.  Fill out forms included in kit. 


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If the patient lacks greater than 20% lymphomatous involvement of their bone marrow, they will 
be recommended to undergo a biopsy of an affected lymph node or other disease-involved area. 
This sample will need to be submitted to Caris Life Sciences. Please use the Caris Life Sciences 
Block Shipper kit to submit the sample. If the patient has recently undergone a biopsy of another 
affected area, this sample may be submitted after approval by Dr. Ujjani. 
 
Georgetown HTSR:  
The yellow-top tube and other 1 cm core which was placed into the histology cassette in the 
standard formalin container should be shipped to the HTSR at Georgetown. The yellow-top tube 
should be sent at room temperature. It does not need to be spun or otherwise prepared. The core 
biopsy should be kept in formalin and should NOT be paraffin embedded prior to shipping.   
Prior to shipment, each specimen container must be labeled with 
- 
subject ID 
- 
site/institution 
- 
collection date 
- 
specimen type 
 
When possible, samples should be shipped Mon- Thurs to avoid weekend or holiday-related 
delays. FedEx Priority Overnight shipment is strongly recommended. 
 
Notify HTSR of specimen shipment at least 1 business day prior to the date samples will be 
shipped and include the tracking number. 
 
Georgetown HTSR Shipping Address:  
 
c/o Anju Duttargi 
LR-10C Pre-Clinical Science Bldg 
3900 Reservoir Road NW 
Washington, DC 20007 
Phone: (202) 687-1924 
Email: HTSR@georgetown.edu / ad1155@georgetown.edu 
 


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HTSR Contacts:                  ** Include all contacts on shipment notification emails. ** 
a. 
Anju Duttargi– HTSR Assistant Director, Operations & Tissue Banking 
(202) 687- 0641, ad1155@georgetown.edu 
b. 
Dylan Kutz  -- HTSR Lab Coordinator  
Lab: 202-687-1924, dk1120@georgetown.edu