Conditions: Relapsed Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 10
Healthy volunteers: no

Brief summary:
A Study of Venetoclax Plus Ibrutinib and Rituximab in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL).

Our hypothesis is that the combination therapy of BTK (Bruton's tyrosine kinase) Inhibitor Ibrutinib plus Venetoclax and Rituximab in relapsed or refractory DLBCL will have an increased activity with acceptable toxicity. Furthermore, this new novel therapeutic combination will be safe and well tolerated among this patient population.

Detailed description:
This is a Phase 1b, single-arm, open-label, single-center study of venetoclax (ABT-199) in combination with ibrutinib and rituximab in Subjects with Relapsed/Refractory DLBCL. The trial consists of a dose-escalation of venetoclax in combination with standard doses of ibrutinib and rituximab. For the dose escalation part of the study, a standard 3+3 design will be utilized. Once the MTD has been established, the dose escalation part will be followed by a dose expansion part in a cohort with a maximum of 24 subjects with DLBCL. The purpose of the dose expansion part is to investigate the efficacy of the combination. Between the dose-escalation and dose-expansion, the maximum number of subjects will be 30.

Cycle length will be 28 days. Venetoclax will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.

Arms:
arm 1: Cycle length will be 28 days. 400mg ABT-199 will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used. arm 2: Cycle length will be 28 days. 800mg ABT-199 will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.

Interventions: intervention 1: 400mg ABT-199 intervention 2: Ibrutinib intervention 3: Rituximab intervention 4: 800mg ABT-199
Intervention descriptions: intervention 1: Oral dose daily until disease progression intervention 2: Oral dose daily until disease progression intervention 3: Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1 intervention 4: Oral dose daily until disease progression

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
This is a John Theurer Cancer Center at HackensackUMC document that contains 
confidential information.  It is intended solely for the recipient clinical investigator(s) 
and must not be disclosed to any other party.  This material may be used only for 
evaluating or conducting clinical investigations; any other proposed use requires 
written consent from John Theurer Cancer Center at HackensackUMC. 
 
Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
1 
 
PROTOCOL 
TITLE: 
Phase Ib Dose Finding Study of ABT-199 (A-1195425.0) 
Plus Ibrutinib (PCI-32765) and Rituximab in Patients with 
Relapsed/Refractory Diffuse Large B-cell NHL (DLBCL) 
 
STUDY NUMBER: 
54179060LYM1004/ML30063 
VERSION NUMBER: 
3 
TEST PRODUCTS: 
Venetoclax (GDC-0199, ABT-199, RO5537382); Ibrutinib 
(PCI-32765), Rituximab 
 
INVESTIGATOR: 
Andre Goy, M.D. 
John Theurer Cancer Center at Hackensack UMC 
92 Second Street Hackensack, NJ 07601 
Telephone:  551-996-4469 
Fax: 551-996-0787 
E-mail:  Goy.Andre@hackensackmeridian.org 
SUB-INVESTIGATORS: 
Martin Gutierrez, M.D. 
Tatyana Feldman, M.D. 
Alan Skarbnik, M.D. 
Lori Leslie, M.D. 
Ann McNeill, APN, RN 
SPONSOR: 
 
SUPPORT PROVIDED 
BY: 
John Theurer Cancer Center at Hackensack University 
Medical Center 
Genentech, Inc. (funding support) / Abbvie (drug) 
Janssen Scientific Affairs, LLC (ibrutinib and funding 
support) 
PROTOCOL DATE: 
12 October 2018 
 


 
Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
2 
 
PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
Phase Ib Dose Finding Study of ABT-199 (A-1195425.0) 
Plus Ibrutinib (PCI-32765) and Rituximab in Patients with 
Relapsed/Refractory Diffuse Large B-cell NHL (DLBCL) 
 
Protocol #  
 
 
54179060LYM1004/ML30063 
 
Protocol Version Date:  12 October 2018 
 
Investigator: 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct 
of this study and to ensure its conduct in compliance with the 
protocol, informed consent, IRB/EC procedures, the 
Declaration of Helsinki, ICH Good Clinical Practices 
guidelines, and the applicable parts of the United States Code 
of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 
 
 
 


TABLE OF CONTENTS 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .....................................................................................................12 
1.1 
DIFFUSE LARGE B-CELL LYMPHOMA .....................................12 
1.1.1 
Current Management .........................................................................12 
1.2 
Venetoclax .........................................................................................13 
1.2.1 
Background ........................................................................................13 
1.2.2 
Nonclinical Activity and Pharmacokinetic Profile ............................14 
1.2.3 
Nonclinical Toxicology .....................................................................14 
1.2.4 
Clinical Experience ...........................................................................16 
1.2.5 
Risks Associated with Venetoclax ....................................................24 
1.2.5.1 Tumor Lysis Syndrome .....................................................................24 
1.2.5.5 Effects on Fertility ...............................................................................25 
1.2.5.8 Drug Interactions .................................................................................26 
1.3 
Ibrutinib (PCI-32765) ........................................................................26 
1.3.1 
Background ........................................................................................26 
1.3.2 
Nonclinical and Clinical Data ...........................................................28 
1.3.3 
Pharmacology ....................................................................................28 
1.3.4 
Toxicology .........................................................................................28 
1.3.4.1 Carcinogenesis, Mutagenesis, Impairment of Fertility .....................28 
1.3.5 
Summary of Clinical Safety of Ibrutinib ...........................................28 
1.3.5.1 Monotherapy Studies.........................................................................28 
1.3.5.2 Combination Therapy Studies ...........................................................29 
1.3.5.3 Treatment Discontinuations ..............................................................30 
1.3.5.4 Treatment-Related Lymphocytosis ...................................................30 
1.3.5.5 Hemorrhagic Events ..........................................................................31 
1.3.5.6 Infections ...........................................................................................31 
1.3.5.7 Cytopenias .........................................................................................31 
1.3.5.8 Cardiac Arrythmias ...........................................................................31 
1.3.5.9 Hypertension .....................................................................................32 
1.3.5.10 Tumor Lysis Syndrome ...................................................................32 
1.3.5.11 Embryo-Fetal Toxicity ....................................................................32 
1.3.5.12 Other Malignancies .........................................................................32 


TABLE OF CONTENTS 
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1.4 
Summary of Rituximab .....................................................................32 
1.5 
Study Rationale .................................................................................32 
1.5.1 
Rationale for Dose .............................................................................33 
1.5.2 
Hypothesis .........................................................................................33 
2. 
OBJECTIVES ............................................................................................................33 
2.1 
Primary ..............................................................................................34 
2.2 
Secondary ..........................................................................................34 
3. 
OVERALL STUDY DESIGN ..................................................................................34 
4. 
STUDY POPULATION ............................................................................................35 
4.1 
Inclusion Criteria ...............................................................................35 
4.2 
Exclusion Criteria ..............................................................................36 
4.2.1 
Justification for inclusion and exclusion criteria ...............................37 
4.2.2 
Criteria for discontinuation ................................................................37 
5. 
TREATMENT ...........................................................................................................38 
5.1 
Definitions of Dose-limiting toxicities ..............................................38 
5.2 
Study Drug Administration ...............................................................39 
6. 
TREATMENT PLAN ...............................................................................................39 
7. 
STUDY MEDICATION ...........................................................................................41 
7.1 
VENETOCLAX ................................................................................41 
7.1.1 
Administration ...................................................................................41 
7.1.2 
Concomitant Therapies ......................................................................42 
7.1.3 
Prophylaxis and Management of Tumor Lysis 
Syndrome 42 
7.1.4 
Guidelines for Dosage Modification and Treatment 
Interruption or Discontinuation..............................................................................44 
7.1.5 
Infections Prophylaxis .......................................................................46 
7.1.6 
Excluded Therapy ..............................................................................47 
7.2 
Ibrutinib .............................................................................................47 
7.2.1 
Formulation, Packaging, and Storage of Ibrutinib ............................47 
7.2.2 
Dose and Administration of Ibrutinib ................................................48 
7.2.3 
Dose Hold, Reduction or Discontinuation of Ibrutinib .....................48 


TABLE OF CONTENTS 
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7.2.4 
Dose Modification of Ibrutinib ..........................................................48 
7.2.4.1 Dose modifications for adverse events: ............................................48 
7.2.4.2 Dose modifications for use with CYP3A inhibitors..........................49 
7.2.4.3 Dose modifications for use in hepatic impairment............................50 
7.2.5 
Prohibitions and Restrictions .............................................................50 
7.2.6 
Tumor Lysis Syndrome .....................................................................51 
7.3 
Potential for Drug-Drug Interactions .................................................51 
7.4 
Rituximab ..........................................................................................51 
7.4.1 
Rituximab Administration .................................................................51 
7.5 
Drug compliance ...............................................................................51 
7.6 
Disposal, destruction, and accountability ..........................................52 
8. 
CONCOMITANT MEDICATIONS/PROCEDURES ..............................................52 
8.1 
Concomitant Medications ..................................................................52 
8.1.1 
Permitted Concomitant Medications .................................................52 
8.1.2 
Medications to be used with Caution ................................................52 
8.1.2.1 CYP3A4/5 Inhibiting/Inducing Drugs ..............................................52 
8.1.2.2 Drugs that may Have Their Plasma Concentrations 
Altered by Ibrutinib..........................................................................................53 
8.1.2.3 Concomitant Use of QT Prolonging Agents .....................................53 
8.1.2.4 Concomitant Use of Antiplatelet Agents and 
Anticoagulants .................................................................................................53 
8.1.3 
Prohibited Concomitant Medications ................................................54 
9. 
CRITERIA FOR PATIENT DISCONTINUATION ................................................54 
9.1 
General Criteria for discontinuation ..................................................55 
10. CLINICAL AND LABORATORY EVALUATIONS .............................................55 
10.1 
Pretreatment Evaluations ...................................................................55 
10.2 
Evaluations during Treatment ...........................................................55 
10.3 
Post-Treatment Evaluations ...............................................................55 
11. EVALUATION OF RESPONSE ..............................................................................56 
12. STATISTICAL CONSIDERATIONS ......................................................................56 
13. REPORTING OF ADVERSE EVENTS ...................................................................59 


TABLE OF CONTENTS 
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13.1 
Assessment of Safety .........................................................................59 
13.1.1 
Adverse Events ..................................................................................60 
13.1.2 
Serious Adverse Events .....................................................................60 
13.2 
Methods and Timing for Assessing and Recording 
Safety Variables .................................................................................61 
13.2.1 
Adverse Event Reporting Period .......................................................61 
13.2.2 
Assessment of Adverse Events ..........................................................62 
13.3 
Procedures for Eliciting, Recording, and Reporting 
Adverse Events ..................................................................................63 
13.3.1 
Eliciting Adverse Events ...................................................................63 
13.3.2 
Specific Instructions for Recording Adverse Events .........................63 
13.3.2.1 Diagnosis versus Signs and Symptoms ...........................................63 
13.3.2.2 Deaths ..............................................................................................63 
13.3.2.3 Preexisting Medical Conditions ......................................................63 
13.3.2.4 Hospitalizations for Medical or Surgical Procedures ......................63 
13.3.2.5 Post-Study Adverse Events .............................................................64 
13.4 
Adverse Events of Special Interest ....................................................64 
13.4.1 
Venetoclax .........................................................................................64 
13.4.2 
Ibrutinib .............................................................................................64 
13.4.3 
Adverse Drug Reaction (ADR) .........................................................65 
13.4.4 
Pregnancy ..........................................................................................65 
13.4.5 
Product Quality Complaint (PQC) ....................................................66 
13.5 
Recording of Adverse Events ............................................................66 
13.6 
Maintenance of Safety Information ...................................................67 
13.7 
Monitoring .........................................................................................67 
13.8 
JTCC at hackensackumc reporting: Notifying the 
FDA ...................................................................................................67 
13.8.1 
Additional reporting requirements ....................................................68 
13.8.2 
Transmission Methods: .....................................................................69 
13.9 
Management of Adverse Events, Serious Adverse 
Events and Special Reporting Situations ...........................................70 
13.9.1 
Procedures for Reporting Adverse Events (AE), 
Serious Adverse Events (SAE), Pregnancies, Special Reporting 
Situation, and Product Quality Complaints (PQCs) to Janssen 
Scientific Affairs ....................................................................................................70 


TABLE OF CONTENTS 
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13.9.2 
Procedures for Reporting Adverse Events (AE), 
Serious Adverse Events (SAE), Pregnancies, Special Reporting 
Situation, and Product Quality Complaints (PQCs) to Genentech ........................72 
13.10 
MedWatch 3500A Reporting Guidelines ..........................................79 
13.10.1.1 Follow-up Information ..................................................................79 
13.11 
Study Close-Out ................................................................................79 
14. STUDY ADMINISTRATION AND INVESTIGATOR 
RESPONSIBILITIES ................................................................................................81 
14.1 
Ethics and good clinical practice .......................................................81 
14.2 
Institutional Review Board/Independent Ethics 
Committee .........................................................................................81 
14.3 
Informed consent ...............................................................................81 
14.4 
Amendments to the protocol .............................................................82 
14.5 
Publication of results .........................................................................82 
14.6 
Data Handling and Record Keeping ..................................................83 
14.6.1 
Confidentiality ...................................................................................83 
14.6.2 
Source Documents .............................................................................83 
14.6.3 
Case Report Forms ............................................................................83 
14.6.4 
Retention of Records .........................................................................83 
14.6.5 
Data Safety Monitoring .....................................................................84 
15. REFERENCES ..........................................................................................................85 
 
LIST OF TABLES 
 
 
Table 1 
Dose Modifications for Hematologic Toxicity Venetoclax 
Monotherapy ............................................................................................45 
Table 2 
Venetoclax Dose Modifications for Non-Hematologic Toxicity ............46 
Table 3 
Venetoclax Dose Reduction ....................................................................46 
Table 4 
Ibrutinib Dose Modifications  .................................................................49 
Table 5 
Recommended Ibrutinib Dose Modifications for use with CYP3A 
Inhibitors  .................................................................................................49 
 


TABLE OF CONTENTS 
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LIST OF APPENDICES 
Appendix 1 
Study Flowchart  ......................................................................................85 
Appendix 2 
Calculation of Creatinine Clearance Using the Cockcroft-Gault  
Formula  .................................................................................................. 88 
Appendix 3 
Genentech Safety Reporting Fax Cover Sheet  .....................................  89 
Appendix 4 
Inhibitors and Inducers of CYP3A  .......................................................  90 
Appendix 5 
Recommendations for Initial Management of Electrolyte    
Imbalances and Prevention of Tumor Lysis Syndrome  ........................ 91 
Appendix 6 
The Lugano Classification for Response Assessment of Non-
Hodgkin Lymphoma ................................................................................95 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ABC 
activated B cell 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
anti-HBc 
antibody to hepatitis B core antigen 
aPTT 
activated partial thromboplastin time 
BM 
bone marrow 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentrationtime curve 
BSA 
body surface area 
CDC 
complement-dependent cytotoxicity 
CHOP 
cyclophosphamide, doxorubicin, vincristine, prednisone 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration observed 
CNS 
central nervous system 
CR 
complete response or complete remission 
CRu 
unconfirmed complete response 
CSR 
Clinical Study Report 
D 
Day 
DFS 
disease-free survival 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
F 
phenylalanine 
FACS 
fluorescent-activated cell sorter 
FcR 
leukocyte receptors for the Fc portion of IgG 
FDA 
Food and Drug Administration 
18F-FDG 
18F-fleurodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded  
FISH 
fluorescence in situ hybridization 
GCB 
germinal center B cell 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GCSF 
granulocyte-colony stimulating factor 
GEP 
gene expression profiling 
HD 
high dose 
HTLV 
human T-cell leukemia virus 
ICH 
International Conference on Harmonisation 
Ig 
immunoglobulin  
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
IMC 
Internal Monitoring Committee 
IV 
Intravenous 
IL 
interleukin  
IPI 
International Prognostic Index 
IVRS 
interactive voice response system 
LD 
low dose 
LVEF 
left ventricular ejection fraction 
LVS. D 
left ventricular systolic dysfunction 
MAD 
MTD 
maximum administered dose 
maximum tolerated dose 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NONMEM 
Non-Linear Mixed Effect Model 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease  
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic 
PET 
positron emission tomography 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response or partial remission 
R-CHOP 
rituximab in combination with cyclophosphamide, doxorubicin, vincristine, 
prednisone 
SAE 
serious adverse event 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
SD 
stable disease 
SDI 
shorter duration of infusion 
SLL 
small lymphocytic lymphoma 
SOC 
Scientific Oversight Committee 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
U.S. 
United States 
V 
valine  
WHO 
World Health Organization 


 
 
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1. 
INTRODUCTION 
1.1 
DIFFUSE LARGE B-CELL LYMPHOMA 
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma 
(NHL), representing about 30% of all NHL 2007 (Shankland, 2012). The American Cancer Society 
estimates an incidence of NHL of about 66,000 new cases; hence approximately 20,000 new cases 
of DLBCL are diagnosed annually in the US and about a similar number in Europe. NHL is the 
most common blood cancer and its incidence has increased 4% a year between 1975 and 1991, and 
to a lesser degree (0·3% yearly) from 1992 to 2007 (Weisenburger 1994; Shankland, 2012). 
 
1.1.1 
Current Management 
The landmark GELA (98-05) study established the role of rituximab in combination with CHOP in 
aggressive CD20 positive lymphoma. This phase III trial randomized CHOP versus R-CHOP in 
197 patients ≥ 60 years old with de novo DLBCL (Coiffier 2002).  Patients who received R-CHOP 
showed a higher CR rate (from 35-45% to 65-75% range) and superior 5y PFS (30% vs 54%) as 
well as an improvement in 5 year OS (from 45% to 58%). The benefit of rituximab was confirmed 
by several other studies both in the US (Vose 2001; Habermann 2006), Canada (Sehn, 2005) and 
Europe including in patients less than 60y (Pfreundschuh 2006). The US large ECOG3404 study 
showed no benefit of rituximab maintenance after induction in patients who had received R-CHOP 
(Habermann 2006). The long-term follow-up of the GELA study LNH-98-05 confirmed the benefit 
of R-CHOP with a 10-year PFS of 36.5% compared with 20% for CHOP alone, and 10-year OS of 
43.5% compared with 27.6% (Feugier 2005). The benefit was seen in all ages including very elderly 
(70 and 80y +) while the most significant prognostic factors included elevated B2 microglobulin, 
bulky disease and bone marrow (BM) involvement at baseline (Coiffier, 2010). R-CHOPq21 days 
became the standard of care in both elderly and younger patients as well.  
 
Diffuse large B cell lymphoma is a heterogeneous disease not only clinically, but also 
morphologically and molecularly. Recent progress has been made in terms of understanding and 
categorizing the molecular heterogeneity of DLBCL. In a retrospective analysis of a large series of 
patients with DLBCL, the Leukemia and Lymphoma Molecular Profiling Project used 
deoxyribonucleic acid (DNA) microarray to identify distinct gene-expression profiles on the basis 
of hierarchical clustering (Rosenwald 2002). Two principal independent gene-expression 
subgroups were identified: germinal-center B-cell-like (GCB) and activated B-cell-like (ABC). 
Following standard chemotherapy, the GCB and ABC subgroups were not only prognostically 
distinct in direct comparison (with superior outcome in the GCB subgroup), but this prognostic 
distinction was also independent of the IPI. Therefore, it may be possible to distinguish prognostic 
subgroups of DLBCL on a molecular as well as clinical basis.  Recent studies indicate that chronic 
active BCR signaling is a pathogenic mechanism in ABC DLBCL and this chronic activation 
engages the classic NF-κB pathway; in contrast GCB DLBCL pathogenesis is independent of this 
pathway (Lenz 2010). This difference in the molecular mechanism of pathogenesis (ie, constitutive 
activation of NF-κB in ABC DLBCL) may explain why the ABC subtype is less sensitive to 
chemotherapy and remains less curable than the GCB subtype. 
 


 
 
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Bruton’s Tyrosine Kinase (Btk) plays an essential role in the chronic active BCR signaling cascade 
in which engages NF-κB activation in wild-type CARD11 ABC DLBCL. In vitro data targeting 
this pathway in ABC DLBCL cells was recently reported by Davis and colleagues (Davis 2010).  
At this time the standard of care for relapsed and refractory patients with chemosensitive disease 
to second-line therapy is to proceed on to HDT and stem cell transplant (SCT), although no 
preferred regimen has been identified. 
 
For those patients with relapsed and refractory DLBCL not eligible for HDT/SCT, both the U.S. 
National Comprehensive Cancer Network (NCCN) and the European Society for Medical 
Oncology (ESMO) recommend inclusion in a clinical trial whenever possible. According to the 
NCCN 2013 guidelines, if no appropriate clinical trials are available multiple immunotherapy and 
chemotherapy regimens with or without rituximab can be considered. Under the same 
circumstances the ESMO treatment guidelines state that multiple salvage chemotherapy regimens, 
including R-GEMOX (rituximab, gemcitabine and oxaliplatin) may be used (Tilly 2012). 
 
 
1.2 
VENETOCLAX   
1.2.1 
Background 
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway.  The Bcl-2 
oncogene was first identified in FL, where the t(14;18) chromosomal translocation results in 
significant overexpression of Bcl-2 protein in B cells.  The Bcl-2 family of genes encodes a group 
of closely related proteins that exhibit pro- or anti-apoptotic activity and share up to four Bcl-2 
homology domains (Korsmeyer 1999; Cory and Adams 2002; Borner 2003; Cory et al. 2003).  Bcl-
2 overexpression is a major contributor to the pathogenesis of several lymphoid malignancies and 
is overexpressed in acute and chronic leukemias. 
In CLL cells, the microRNAs (miRNAs) miR15a and miR16-1 that negatively regulate the 
transcription of Bcl-2 are deleted or down-regulated, resulting in uncontrolled expression of Bcl-2 
(Calin et al. 2008).  Although Bcl-2 expression levels are variable across patients, high expression 
of Bcl-2 (compared with normal white blood cells) is observed in CLL cells in  95% of CLL 
patients (unpublished data from Phase II study of ABT4710n [navitoclax]). 
Bcl-2 overexpression represents one common mechanism for evading apoptosis.  However, CLL 
cells may concurrently express high levels of Bcl-2 prebound to pro-death proteins such as Bim, 
thus priming these cells for death such that treatment with a BH3 mimetic like venetoclax (ABT-
199) will rapidly drive them into apoptosis (Del Gaizo Moore et al. 2007, Del Gaizo Moore and 
Letai 2008).  Nonclinical data in NHL cell lines support a model analogous to CLL, where higher 
levels of Bcl-2 expression correlate strongly with greater sensitivity to venetoclax (unpublished 
data, Abbott Inc.).  CLL and many NHL cells are therefore dependent on high levels of Bcl-2 for 
survival, making them potentially attractive targets for venetoclax.  Furthermore, this sensitivity to 
Bcl-2 inhibition may provide the possibility for a chemotherapy-sparing option for CLL patients. 


 
 
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1.2.2 
Nonclinical Activity and Pharmacokinetic Profile 
Venetoclax (synonymous with ABT-199, GDC-0199, and referred to as venetoclax throughout the 
protocol) is a highly selective, orally available small-molecule Bcl-2 family protein inhibitor that 
binds with high affinity (dissociation constant [Ki]  0.10 nM) to Bcl-2 and with lower affinity to 
other Bcl-2 family proteins Bcl-XL and Bcl-w ( 480-fold and  2000-fold lower affinity than to 
Bcl-2, respectively).  Overexpression of anti-apoptotic Bcl-2 family proteins is associated with 
resistance to chemotherapy, and antagonism of the action of these proteins might overcome 
resistance and enhance response to therapy.  Anti-apoptotic 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 FLs, mantle cell lymphomas, diffuse large B-cell lymphomas, and 
acute myeloid leukemias.  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 were wild-type cell lines. 
Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines derived 
from acute lymphoblastic leukemia and NHL. 
The pharmacokinetic (PK) profile of venetoclax was evaluated in multiple animal species.  In mice, 
rats, monkeys, and dogs, low plasma clearance and low volumes of distribution characterized the 
venetoclax PK profile.  Half-lives ranged from 2.2 hours in monkeys to 12 hours in dogs.  Food 
had a marked effect on the oral bioavailability in dogs. 
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma proteins 
( 99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, heart, lungs, small 
intestine, and white fat, but was poorly distributed in testes, brain, muscle, and bone.  Liver 
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. 
In vitro, venetoclax is metabolized by CYP3A4 and is a moderate inhibitor of CYP2C8 and a potent 
inhibitor of CYP2C9.  It is not a potent inhibitor of CYP3A4, CYP1A2, CYP2B6, CYP2C19, or 
CYP2D6 (IC50  30 M) and does not induce CYP3A4 or CYP1A2 at concentrations up to 10 M. 
See the venetoclax Investigator’s Brochure for a detailed discussion of the nonclinical activity of 
venetoclax. 
1.2.3 
Nonclinical Toxicology 
Venetoclax has been assessed in repeated-dose general toxicology studies and in genetic, 
developmental/reproductive, and safety pharmacology studies. 


 
 
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Repeated-dose oral toxicity studies with venetoclax were conducted in mice and dogs.  Good 
Laboratory Practice (GLP)-compliant, definitive toxicity studies consisted of Investigational New 
Drug (IND)-enabling studies in mice and dogs with 4 weeks of dosing followed by a 4-week (dose-
free) recovery period; a 2-week toxicity study in dogs that focused on lymphocyte recovery over 
an extended (18 weeks) recovery period; and chronic toxicity studies in mice (6 months) and dogs 
(9 months).  No recovery periods were included in the chronic toxicity studies.  The maximum 
venetoclax plasma exposures (mean area under the concentration-time curve from 0 to 24 hours 
[AUC0-24h]) achieved in the 4-week studies were 92 g  hr/mL (at 600 mg/kg/day) in mice and 
572 g  hr/mL (at 150 mg/kg/day) in dogs.  In the chronic toxicity studies, AUCs reached 34.1 
h  h/mL (at 300 mg/kg/day) in mice and 139 h  h/mL (at 20 mg/kg/day) in dogs. 
The primary toxicities associated with venetoclax administration included effects on the 
hematologic system (decreased lymphocytes and erythrocytes) in mice and dogs, the male dog 
reproductive system (testicular germ cell depletion), and embryofetal toxicity in mice. 
In mice and dogs, venetoclax produced robust decreases in lymphocytes in the peripheral blood (of 
up to 75% in mice and up to 81% in dogs) and in lymphoid tissues.  In dogs, the recovery of 
lymphocyte counts (total lymphocytes, CD4 and CD8 T cells and mature B cells) was 
prolonged, requiring up to 18 weeks after completion of 2 weeks of dosing.  B cells were the most 
sensitive lymphocyte subtype based on the magnitude of decrease and/or the length of time required 
for recovery (i.e., 25% 111% of individual baseline; mean reversal to 54% of baseline average).  
Tcell subsets reversed more readily and showed more dose-dependence in recovery time and 
extent.  Decreases of lymphocytes in lymphoid tissues were reversible in mice and reversible to 
partially reversible in dogs.  Venetoclax-related decreases in lymphocytes in blood and lymphoid 
tissues are considered pharmacologically mediated and non-adverse. 
Venetoclax effects on red blood cell mass parameters principally consisted of dose-related 
decreases of hematocrit and hemoglobin in mice and dogs; these effects were adverse only at the 
highest dosages in the 4-week mouse and dog studies and were reversible. 
No effects of venetoclax have been identified in female reproductive tissues in mice or dogs in 
general toxicology studies.  However, in dogs venetoclax produced adverse, non-reversible, non-
dose-related microscopic findings of testicular germ cell depletion at all dosages tested; there were 
no testicular effects in mice.  The translatability of the testicular findings in dogs to humans is 
unknown, but this change may be related to Venetoclax pharmacology, as one or more members of 
the Bcl-2 family of proteins play a role in spermatogenesis (Olderied et al. 2001; Sugiyama et al. 
2001; Yan et al. 2003). 
Venetoclax resulted in increased post-implantation loss and decreased fetal body weights in the 
mouse embryofetal development study at the highest dosage administered (150 mg/kg/day); the no-
observed-adverse-effect level (NOAEL) was defined at the mid-dose of 50 mg/kg/day.  Venetoclax 
was not teratogenic, and there were no other effects on development or fertility. 


 
 
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Venetoclax produced loss of hair pigmentation in dogs (reversibility has not been assessed).  
Evidence from Bcl-2 knockout mouse (Bcl-2-/-) studies indicates that hair hypopigmentation is 
consistent with the pharmacological effect of Bcl-2 functional loss, and occurs due to loss of hair 
follicle melanocytes dependent on Bcl-2 for survival.  A dedicated physical examination of the skin 
and extensive ophthalmic examinations determined that pigmentation of the skin and in the eye 
(particularly, the iris and fundus) of the dog appears unaffected. 
Other effects of venetoclax included single-cell necrosis in various epithelial tissues in dogs (i.e., 
gallbladder, stomach, exocrine pancreas, and epididymides), which was of minimal magnitude and 
produced no loss of mucosal integrity, and increased pigment in Kupffer cells or macrophages in 
the liver and gallbladder of dogs.  None of the effects were considered to be adverse, and all were 
reversible. 
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax. 
Venetoclax was tested in a battery of safety pharmacology assays and produced no effects in central 
nervous system/neurobehavioral or respiratory studies in mice at oral doses up to 600 mg/kg.  In 
dogs, mild reductions in cardiac contractility and cardiac output were observed at plasma 
concentrations of  16 g/mL; these concentrations exceeded the concentration of venetoclax in 
humans (3.39 g/mL at the 900 mg dose).  No effects on blood pressure, heart rate, or 
electrocardiogram (ECG) parameters were observed in dogs at a maximum drug concentration of 
46 g/mL. 
See the venetoclax Investigator’s Brochure for details on nonclinical studies. 
1.2.4 
Clinical Experience 
 
NHL Studies 
As of 28 November 2015, four Phase 1/2 studies are ongoing in the NHL indication as 
described below.  
Study M12-175 Arm B 
A complete study description for NHL subjects in Arm B of Study M12 -175 is provided 
above in Section 8.3.1.1.1 of the Investigator’s Brochure. 
 
Preliminary Safety Summary (Arm B) 
Most subjects (97.2%) in Study M12-175, Arm B experienced at least 
1 treatment-emergent adverse event. An overview of adverse events, grade ≥ 3 adverse 
events, and serious adverse events reported in Study M12-175 Arm B in (please refer to Table 30 
(Section 8.3.2.1.4) of the Investigator’s Brochure. 
 
The most common adverse events in Arm B (NHL subjects) were nausea (48.1%), 
diarrhea (44.3%), fatigue (40.6%), and vomiting and decreased appetite (20.8% each). 
Adverse events grade 3 and above were reported for 54.7% subjects. The most common 


 
 
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events grade 3 or above were anemia (16.0%) and neutropenia (12.3%). Serious adverse 
events were reported in 34.0% subjects. The most common serious adverse events were 
malignant neoplasm progression (8.5%) and diarrhea, influenza, and hyponatremia (2.8% 
each). 
 
A total of 17 (16.0%) subjects experienced adverse events that led to discontinuation of 
venetoclax. The most common adverse events leading to discontinuation was malignant 
neoplasm progress (6 [5.7%] subjects) and nausea (2 [1.9%] subjects). All other events 
leading to discontinuation were reported in 1 subject each. A total of 9 (8.5%) subjects 
experienced adverse events that led to death, including 8 events of malignant neoplasm 
progression and 1 event of respiratory failure. All fatal events were considered to have no 
reasonable possibility of being related to venetoclax. 
Preliminary Efficacy Summary (Arm B) 
Efficacy data for Arm B of Study M12-175 was not reported in the interim clinical study 
report as it was for Arm A (Section 8.3.1.1.1 of the Investigator’s Brochure). 
As of 15 September 2015, a total of 106 subjects with R/R NHL (Arm B) were enrolled in 
Arm B (70 in the Dose-Escalation Cohorts and 36 in the Safety Expansion Cohort) and 
evaluated for objective response following the International Working Group criteria 
(subjects with Waldenstrom's Macroglobulinemia [WM] were evaluated using the 
International Workshop [IW]-WM criteria). The investigator-assessed ORR for all 
FL subjects and DBLBCL subjects excluding DLBCL-Richter's transformation subjects 
(across dose-escalation and safety expansion) was 37.9% and 17.6%, respectively; CR 
was achieved by 4 subjects in each group (13.8% and 11.8%, respectively). 
Study M12-630 
Study M12-630, titled "A Phase 1 Study Evaluating the Safety and Pharmacokinetics of 
ABT-199 in Combination with Bendamustine/Rituximab (BR) in Subjects with Relapsed 
or Refractory Non-Hodgkin's Lymphoma," is an ongoing, open-label, dose-escalation 
study. The primary objectives are to assess the safety profile, characterize 
pharmacokinetics, and determine the MTD and RPTD of venetoclax when administered in 
combination with BR in subjects with relapsed or refractory NHL. The secondary 
objectives are to evaluate preliminary efficacy data regarding PFS, ORR, TTP, OS, and 
DOR. Biomarkers and pharmacogenetics are evaluated as exploratory objectives. 
This study is a dose-escalation study with a total enrollment of 60 subjects. This study is 
evaluating the safety and pharmacokinetic profile of venetoclax in 60 subjects when 
administered in combination with BR following a dose-escalation scheme, with the 
objective of defining the DLT and the MTD. This portion consists of 3 Arms with 
different lengths of venetoclax daily dosing following a 28-day cycle (3 consecutive days 
in Arm A [3/28], 7 consecutive days in Arm B [7/28], and continuous dosing [28/28] in 
Arm C). Each arm may escalate to the MTD with a minimum of 3 subjects at each dose 
level. Venetoclax dose is escalated in 50 mg increments until a dose of 100 mg is 
achieved and in larger increments thereafter unless study subject data indicate smaller 
increments are required. Rituximab is administered via IV infusion at 375 mg/m2 once 


 
 
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per cycle, and bendamustine via IV at 90 mg/m2 twice per cycle for up to 6 cycles. To 
mitigate the risk for TLS observed, subjects receive tumor lysis prophylaxis prior to and 
during treatment in Cycle 1 (and subsequent cycles, if needed). 
Subjects may discontinue BR treatment but continue venetoclax monotherapy for up to 
2 years following the date of the last subject enrolled on study provided they complete BR 
dosing in Cycle 1, continue to tolerate the drug, have no evidence of disease progression, 
and do not meet any criteria for subject discontinuation. 
A total of 58 subjects received at least 1 dose of venetoclax and had data available in 
Study M12-630. Preliminary dose-escalation, safety, and efficacy results for these 
subjects are described below. 
Determination of DLTs During Dose Escalation 
In Arm A (3/28 day dosing), subjects were dosed at 50 and 100 mg designated cohort 
doses. In Arm B (7/28 day dosing), subjects were dosed at 100 mg designated cohort 
doses. There were no DLTs in Arms A and B. In Arm C (28/28 day dosing), subjects 
were dosed at 100 mg and 200 mg designated cohort doses. In the 200 mg dose cohort in 
Arm C (Cohort 5), 2 of 3 subjects experienced DLTs: grade 3 serious adverse event of 
febrile neutropenia and grade 4 adverse event of nonserious thrombocytopenia, 
respectively. The event of febrile neutropenia was considered by the investigator to have 
a reasonable possibility of being related to venetoclax. Following these DLTs, the next 
cohort opened to enrollment in the previous arm, Arm B (7/28 Day 200 mg dosing), as 
allowed per protocol, and was completed with no DLT. A protocol amendment was filed 
on 03 February 2014 to strongly encourage G-CSF prophylaxis during venetoclax 
administration, particularly in heavily pretreated subjects, in order to avoid toxicity due to 
the BR backbone regimen and revise the DLT definition to distinguish between toxicities 
due to the combination and those commonly observed with the BR backbone regimen. 
Dose escalation continued in Arm B to 400 mg (Cohort 6) with no DLT events. Cohort 8 
was in Arm C (28/28 days) at the 400 mg designated cohort dose when 1 subject 
experienced a grade 4 serious adverse event of Stevens Johnson Syndrome with primary 
reasonable possibility due to allopurinol; however, it is a DLT because it was reasonable 
possibility due to venetoclax and bendamustine. The cohort expanded to 8 subjects with 
no further DLT event. Dose escalation continued with Cohort 9 at 600 mg in Arm C. 
One subject experienced a DLT of grade 4 thrombocytopenia with an investigator opinion 
as primary reasonable possibility to bendamustine and reasonable possibility to 
venetoclax + rituximab. Dose escalation continued with Cohort 10 at 800 mg in Arm C 
and Cohort 11 at 1200 mg in Arm C with no further DLT events. 
Preliminary Safety Summary 
Most subjects (98.3%) in Study M12-630 experienced at least 1 treatment-emergent 
adverse event. An overview of adverse events, grade ≥ 3 adverse events, and serious 
adverse events reported in Study M12-630 are presented below in Table 34 
(Section 8.3.2.2.4) in the Investigator’s Brochure. 
The most common adverse events were nausea (63.8%), neutropenia (55.2%), diarrhea 
(50.0%), thrombocytopenia (46.6%), vomiting and fatigue (37.9% each), lymphocyte 


 
 
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count decreased (36.2%), and anemia, constipation, and hyperglycemia (32.8% each). 
Forty-six (79.3%) subjects experienced adverse events grade 3 or above. The most 
common adverse events grade 3 and above were neutropenia (48.3%), lymphocyte count 
decreased (34.5%), and thrombocytopenia (20.7%). Serious adverse events were reported 
for 21 (36.2%) subjects and included the following: febrile neutropenia and malignant 
neoplasm progression (4 subjects, 6.9%), and diarrhea, nausea, vomiting, and dyspnoea 
(2 subjects, 3.4% each). All other events were reported for 1 subject each. 
Adverse events leading to discontinuation were reported for 9 (15.5%) subjects. 
Four subjects experienced fatal events 2 events of malignant neoplasm progression and 
1 event each of disease progression and respiratory failure). None of these events were 
considered to have a reasonable possibility of being related to venetoclax. 
 
Preliminary Efficacy Summary 
Preliminary efficacy data for Study M12-630 are available for 48 subjects with R/R NHL 
as of 17 September 2015. Median time on study was 5.3 months (range: 0.1 to 
38.1 months). The ORR was 67.4% (31 of 48 evaluable subjects), with CR in 13 subjects 
(28.3%) and PR in 18 subjects (39.1%). Three additional subjects (6.5%) experienced 
stable disease. 
Study GO27878 (CAVALLI) 
Study GO27878, titled " A Phase Ib/II, Open-Label Study Evaluating the Safety and 
Pharmacokinetics of GDC-0199 (ABT-199) in Combination with Rituximab (R) or 
Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone 
(CHOP) in Patients with B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL," is an 
ongoing, open-label, dose-finding study. The study is being conducted in 2 phases, as 
summarized below. The primary objectives are to: 1) estimate the MTD and RPTD of 
venetoclax in combination with rituximab or obinutuzumab and standard doses of CHOP 
(i.e., R-CHOP and G-CHOP, respectively) in subjects with B-cell NHL, either previously 
untreated or R/R after a maximum of one prior therapy; and 2) assess the 
safety/tolerability of venetoclax combined with R-CHOP or G-CHOP and the preliminary 
efficacy of venetoclax + R-CHOP (by PET-defined CR) in treatment-naive subjects with 
DLBCL. Secondary objectives are to: 1) characterize the pharmacokinetics of venetoclax 
when administered in combination with R-CHOP or G-CHOP, and the pharmacokinetics 
of rituximab, obinutuzumab, and CHOP components when administered in combination 
with venetoclax in the previously untreated or R/R setting; and 2) assess the preliminary 
efficacy of venetoclax in combination with R-CHOP (by CT-defined CR rate, OR rate, 
response duration, PFS, and OS) in subjects with previously untreated DLBCL and the 
preliminary efficacy of venetoclax in combination with G-CHOP (by OR rate, CR rate, 
PFS). Exploratory objectives are assessment of biomarkers that might predict response 
and resistance to treatment, subgroup analyses of efficacy (e.g., DLBCL genotypic 
subtypes, high Bcl-2 [Bcl-2-positive] expression), MRD as a prognostic marker in 
DLBCL, and prognostic significance of PET in this setting. 
In the dose-finding Phase 1 portion of the study, 2 parallel treatment arms of up to 
4 cohorts each explore doses of venetoclax ranging from 200 to 800 mg in combination 


 
 
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with R-CHOP and G-CHOP. The MTD was not reached, and in Phase 2 a RPTD of 
800 mg for Arm A is used in subjects with previously untreated DLBCL. Subjects are 
treated for a total of 8 cycles (6 to 8 cycles of CHOP and 8 cycles of venetoclax + 
rituximab or venetoclax + obinutuzumab). Each cycle consists of 21 days. 
For each cycle, subjects receive either rituximab infusion (375 mg/m2) on Day 1 or 
obinutuzumab infusion (1000 mg) on Days 1, 8, and 15 (Cycle 1) or on Day 1 (Cycles 2 
through 8), followed by CHOP, all with standard premedication. Oral dosing with begins 3 days 
later and continues on a daily basis through Cycle 8 Day 21. 
Venetoclax is administered before the infusion of rituximab or obinutuzumab on Day 1 of 
Cycles 2 through 8, and before CHOP on Day 1 of Cycles 2 through 6. Due to 
observations of greater than expected hematologic toxicity (in the setting of mandatory 
G-CSF prophylaxis) the dosing regimen was modified after cohort 1 (200 mg of 
venetoclax) from the daily dosing of venetoclax to a non-continuous 10 day dosing of 
venetoclax. For the subsequent cohorts (400 mg, 600 mg, and 800 mg) venetoclax is 
administered at Cycle 1 Days 4 through 10, and Cycle 2 through 8 Days 1 through 10. 
In order to mitigate the risk for TLS, CHOP is initiated before venetoclax and all subjects 
receive TLS prophylaxis before the first dose of venetoclax, with those at higher TLS risk 
hospitalized for the initial dose. 
The planned enrollment for the study is 24 to 48 subjects in Phase 1 and 180 to 
200 subjects in Phase 2. As of 28 November 2015, 46 and 8 subjects have been enrolled 
in the Phase 1 and Phase 2 portions of the study, respectively. 
Two patients in Arm A experienced DLTs; one DLT occurred at the 200 mg dose in 
Cohort 1 (grade 3 neutropenia) and the other DLT occurred at the 600 mg dose in 
Cohort 3 (grade 4 LTLS). For the latter DLT, the severity grade of 4 was assigned by the 
investigator although the subject had laboratory abnormalities only, was not symptomatic, 
and had stable cardiac and renal function and vital signs. Three patients in Arm B 
experienced DLTs; 2 DLTs occurred at the 200 mg dose in cohort 1 (grade 3 pneumonia 
and grade 3 infection). The third DLT occurred at the 600 mg dose in cohort 3 (grade 4 
sepsis). 
 
Preliminary Safety Summary 
As of 28 November 2015, 54 subjects have been enrolled in Study GO27878 and 
49 subjects had data available. Most subjects (95.9%) across all cohorts in 
Study GO27878 experienced at least 1 treatment-emergent adverse event. An overview of 
adverse events, grade ≥ 3 adverse events, and serious adverse events reported in 
Study GO27878 are presented below in Table 34 (Section 8.3.2.2.4) in the Investigator’s 
Brochure. 
The most common adverse events across cohorts in Study GO27878 were nausea 
(44.9%), diarrhea (38.8%), fatigue and neutropenia (36.7%), constipation (34.7%), 
vomiting (28.6%), and thrombocytopenia (26.5%). Serious adverse events have been 
reported for 26 (53.1%) of subjects in the study. The most common SAE was febrile 
neutropenia in 10 (20.4%) subjects. Eleven (22.4%) experienced adverse events that led 
to withdrawal from any treatment. The most common events leading to study drug 
discontinuation were thrombocytopenia and peripheral neuropathy in 2 subjects each; all 


 
 
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other events leading to study drug discontinuation occurred in 1 subject each. No events 
resulted in death. 
One case under the preferred term of drug-induced liver injury was reported in 
Study GO27878. Subject 10102 (female, 39 years of age) had a slight elevation in liver 
function test (2 × ULN) on Cycle 3 Day 7. On Cycle 4 Day 1, liver function tests were 
7 to 8 × ULN with normal bilirubin. Venetoclax and other NHL treatments were 
discontinued because of this event. All viral studies were normal, however, the subject 
was taking concomitant duloxetine for depression. A liver biopsy demonstrated relatively 
nonspecific features consistent with drug-induced hepatitis. Her liver function tests 
continued to be abnormal during the subsequent 8 months following discontinuation of all 
cancer treatments. Duloxetine was then discontinued and her liver function tests as of 
July 2015 remained mildly elevated. The investigator considered this event to be related 
to venetoclax, obinutuzumab, cyclophosphamide, doxorubicin, vincristine and prednisone. 
In the investigator's opinion, other etiological factors reported for the event included 
concomitant medication. 
Study BO29337 (CONTRALTO) 
Study BO29337, titled "A Phase II, open-label study evaluating the safety and efficacy of 
GDC-0199 (ABT-199) plus bendamustine plus rituximab (BR) in combination with BR 
alone or GDC-0199 plus rituximab (R) in patients with relapsed and refractory follicular non-
Hodgkin's lymphoma" is an ongoing, open-label efficacy study. The primary 
efficacy objectives are to 1) evaluate the efficacy of venetoclax + BR compared with BR 
alone in subjects with R/R FL and 2) evaluate the efficacy of venetoclax + rituximab in 
subjects with R/R FL. Efficacy endpoints will be PET-defined compete response at the 
time of the primary assessment (6 to 8 weeks after Cycle 6 Day 1) as defined by an IRC. 
The secondary efficacy objective is to make a preliminary assessment of efficacy as 
measured by investigator assessed CR (6 to 8 weeks after Cycle 6 Day 1) and CR at the 
Year 1 assessment. The safety objectives are to explore the safety of venetoclax at a dose 
of 600 mg in combination with BR in the 6-patient Run-In in order to allow expansion of 
800 mg in the randomized cohort; to evaluate safety of venetoclax + BR compared with 
BR alone in patients with R/R FL; and to evaluate the safety of venetoclax in combination 
with rituximab. The pharmacokinetic objective is to characterize the pharmacokinetics of 
venetoclax in combination with rituximab or BR in patients with R/R FL. Exploratory 
objectives include: a preliminary assessment of potential biomarkers that might predict 
disease response; assessment of the conversion rate, defines as the proportion of patient 
with a PR or SD at the primary response assessment who convert to a PCR/PR or PR at 
any time during subsequent extended therapy; and assessment of MRD negativity in bone 
marrow or peripheral blood. 
This open-label, international, multicenter, Phase 2 study will investigate the efficacy and 
safety of venetoclax in combination with BR (venetoclax + BR) compared with BR alone 
in patients with R/R FL, comparing 2 chemotherapy-containing regimens 
(Chemotherapy-Containing Cohort). In addition, an exploratory analysis of the safety and 
efficacy of venetoclax in combination with rituximab (venetoclax + R), a 
chemotherapy-free regimen, will be performed (Chemotherapy-Free Cohort). Assignment 
to the Chemotherapy-Containing or Chemotherapy-Free Cohort for a given patient will be 


 
 
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at the discretion of the investigator. 
The Chemotherapy-Containing Cohort will enroll and then randomize subjects during 
2 study periods: a Safety Run-In Period, consisting of a safety cohort of at least 
6 subjects, followed by a Randomization Period consisting of approximately 100 subjects. 
The first 6 patients enrolled in the Chemotherapy-Containing Cohort (or more if required) 
will comprise the Safety Run-In group for Treatment Arm B, dosing venetoclax at 600 mg in 
combination with BR per the Schedule of Assessments for Arm B. Subjects in the 
Safety Run-In group will be monitored for safety events impacting on decision guidelines 
for a period of 28 days, with safety data from these 6 patients evaluated by an Internal 
Monitoring Committee and Scientific Oversight Committee. Once a dose has been 
chosen from the Safety Run-In Period, randomization to the two treatment arms of the 
Chemotherapy-Containing Cohort (Arms B and C) will begin and approximately 
100 subjects will be randomized in 1:1 fashion to 1 of the 2 chemotherapy-containing 
treatment arms. 
Subjects will receive study treatment for approximately 24 – 52 weeks, depending on 
treatment arm. All subjects will be assessed for response to treatment by the investigator 
with the use of standard criteria according to the Lugano Classification: Revised Criteria 
for Response Assessment at screening and at the following timepoints: Interim Response 
Assessment (Cycle 3 between Day 22 and Day 28); Primary Response Assessment (6 to 
8 weeks following Cycle 6 Day 1; Year 1 Assessment (52 weeks up to 4 weeks after 
Cycle 1 Day 1 of treatment). Following completion of therapy, subjects who have not 
progressed will be followed clinically every 3 months until the end of Year 2 from 
initiation of multi-agent therapy (Cycle 1 Day 1). Subjects will then be followed every 
6 months until disease progression, study withdrawal, end of study, or death, whichever 
comes first. 
 
Preliminary Safety Summary 
As of 28 November 2015, 103 subjects have safety data available, including 9 subjects in 
the Run-in phase, 52 subjects in Arm A (venetoclax + rituximab), 21 subjects in Arm B 
(venetoclax + BR), and 21 subjects in Arm C (BR). Most subjects (83.3%) across all 
cohorts in Study BO29337 experienced at least 1 treatment-emergent adverse event. An 
overview of adverse events, grade ≥ 3 adverse events, and serious adverse events reported in 
Study BO29337 are presented below in Table 34 (Section 8.3.2.2.4) in the Investigator’s 
Brochure. 
The most common adverse events across cohorts for Study BO29337 were nausea 
(28.7%), diarrhea (26.9%), and neutropenia (21.3%). In general, the types of events were 
similar across cohorts; however, subjects in Arm C (BR) experienced fewer adverse 
events that those subjects in Arm A or Arm B. Serious adverse events were reported in 
18 (16.7%) subjects, including 3 subjects in the Run-in phase, 12 subjects in Arm A, 
3 subjects in Arm B, and no subjects in Arm C. Serious adverse events occurring in 
2 subjects each were: blood lactate dehydrogenase increased and tumor lysis syndrome. 
All other events occurred in 1 subject each. Six (5.6%) subjects experienced adverse 
events that led to study drug discontinuation. Nausea occurred in 2 subjects each; all other 
events occurred in 1 subject each. Fatal events were reported in 2 subjects in Arm A: 
1 event of pulmonary hemorrhage and1 event of colitis. Neither event was considered 
related to venetoclax. 
 


 
 
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In the NHL oncology program, safety data are available for 215 subjects who received 
venetoclax in combination with other therapies in Studies M12-630, GO27878, and 
BO29337. An overview of adverse events reported in the venetoclax combination NHL 
studies is provided in Table 34 in the Investigator’s Brochure. 
 
A summary of the treatment-emergent adverse events reported in ≥ 10% subjects treated 
with venetoclax in combination with other therapies in the NHL oncology program is 
presented by study in Table 35 in the Investigator’s Brochure. Most subjects receiving venetoclax 
in combination with BR in Study M12-630 (98.3%) or in Study BO29337 (83.3%) and 
approximately two-thirds of subjects receiving venetoclax in combination with R-CHOP or G-
CHOP in Study GO27878 (65.9%) reported at least 1 adverse event. The most common adverse 
events in Studies M12-630 and BO29337 were nausea (63.8% and 28.7%, respectively), 
diarrhea (50.0% and 26.9%, respectively), and neutropenia (55.2% and 21.3%, 
respectively). The most common adverse events in Study GO27878 were fatigue (36.7%) 
and infusion related reaction (28.6%). 
 
A summary of adverse events NCI CTCAE grade 3 and above reported in 2% or more of 
the subjects treated with venetoclax in combination with other therapies in the NHL 
oncology program is presented in Table 36 in the Investigator’s Brochure. 
 
A summary of serious adverse events reported in > 1 subject and reported in more than 
1 subject treated with venetoclax in combination with other therapies in the NHL 
oncology program is presented in Table 37 in the Investigator’s Brochure. 
 
Overall Safety Summary for NHL 
As of November 28, 2015 a total of 346 NHL subjects have been treated in venetoclax 
oncology clinical program: 131 subjects received venetoclax as a single agent and 
215 subjects received venetoclax in combination with other agents including rituximab, 
obinutuzumab and bendamustine, R-CHOP or G-CHOP. The safety summaries for NHL 
patients treated in monotherapy or combination studies is described separately in 
Section 8.3.2.1.4 and Section 8.3.2.2.4 in the Investigator’s Brochure, respectively. 
Overall for NHL, when treated with venetoclax as a single agent or in combination with 
other therapies, most subjects experience at least one adverse event with most common 
being nausea, diarrhea; neutropenia and infusion related reactions commonly occur in 
combination studies. Approximately half of subjects in NHL clinical trials experience 
≥ grade 3 adverse events with most common being neutropenia, anemia and 
thrombocytopenia. The frequency of thrombocytopenia and anemia are slightly higher in 
NHL combination trials, however the numbers are small. The frequency of serious 
adverse events of neutropenia/ferbile neutropenia is low (< 2%) in NHL monotherapy 
studies; however, the frequency of febrile neutropenia serious adverse events in NHL 
combination studies can be higher. There were no serious adverse events of anemia or 
thrombocytopenia in NHL monotherapy studies and no serious adverse events of anemia 
or thrombocytopenia in more than 1 subjects were reported in combination trials. Of the 
fatal events in NHL program, majority are the adverse events of malignant neoplasm 


 
 
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progression. Many of the adverse events reported in the current NHL studies are 
consistent with underlying disease or concomitant medical conditions, as well as other 
combination agents used to treat NHL patients. TLS, neutropenia, and infections are 
consistent with the expected safety profile of venetoclax based on expected on-target 
effects of Bcl-2 inhibition; the important identified and potential risks for venetoclax in 
NHL program remain the same as in CLL population and are described below, as well as 
in Section 9.2 (Guidance to Investigator) in the Investigator’s Brochure. 
The incidence of TLS in NHL studies is low with reported 2 cases (1.9%) of TLS in 
monotherapy Study M12-175 (Arm B), 2 cases of TLS (1.9%) in combination 
Study BO29337 (venetoclax + BR) and 3 cases of TLS (6.1%) in combination 
Study GO27878 (venetoclax + R-CHOP or G-CHOP). Tumor lysis syndrome remains as 
important identified risk for NHL program. The guidance for TLS prophylaxis can be 
found in Section 9.2.2.1 (Guidance to investigator) and in NHL study protocols. 
Neutropenia has a similar frequency in NHL clinical program as in CLL with higher 
frequency in NHL combination studies. Serious adverse events of neutropenia and febrile 
neutropenia, albeit in small numbers, occurred in higher frequency in combination studies 
and remains as an important identified risk. Infections, including serious, were observed 
in NHL clnical program, with similar incidence in monotherapy and combination studies. 
There were no deaths due to infections in NHL program. Infections remain as potential 
risk for NHL clinical program. 
 
See the venetoclax Investigator’s Brochure for more details on these and additional studies. 
1.2.5 
Risks Associated with Venetoclax 
. Risks identified for venetoclax include: TLS, cytopenias (i.e., neutropenia, thrombocytopenia, or 
lymphopenia), infections, as well as drug interactions with CYP3A4 inhibitors or inducers (see 
section 9.2.2 of the 2016 IB).  
1.2.5.1 
Tumor Lysis Syndrome 
 
The available data suggest that in non-CLL subjects the risk of TLS is low. Since the data 
set is small, the risk of TLS is being closely monitored in non-CLL indications. In 
general, before initiating venetoclax, subjects risk for developing TLS should be assessed. 
Prophylaxis with hydration and uric-acid reducing agents is recommended. Clinical 
chemistries should be corrected. Monitor with clinical chemistries and manage promptly, 
as clinically indicated.  
 
1.2.5.2 Neutropenia 
Neutropenia is an important identified risk for venetoclax, specifically in CLL. 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 some combination studies. 
Serious adverse events of neutropenia or neutropenia events that lead to discontinuations 


 
 
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are few across the entire venetoclax oncology program. For the oncology studies, 
neutropenia management guidelines are provided in the protocol. Granulocyte colony 
stimulating factors can be used for supportive measures, however the guidance for their 
use in non-CLL indications, especially in AML, is per routine local oncology practice, as 
well as protocol-specific. 
 
1.2.5.3 Infections 
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 and are similar across all indications. Infections are 
closely monitored in venetoclax program across all indications. In the oncology studies, 
recommendations are included in the protocol regarding the need for anti-infective 
prophylaxis per standard of care (e.g., National Comprehensive Cancer Network 
guidelines [NCCN] for oncology subjects).1 
 
1.2.5.4 Other Hematological Effects 
Anemia has been reported in the oncology studies with slightly higher frequency in some 
studies in which venetoclax is combined with other chemotherapeutic agents; however, 
most of the events were nonserious and confounded by disease factors and prior therapies. 
The dataset in non-CLL indications is small. 
Thrombocytopenia adverse events 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 nonserious and assessment 
of these events is confounded by the subjects' underlying disease state, prior therapies and 
preexisting thrombocytopenia, including autoimmune thrombocytopenia in several 
subjects. The dataset in non-CLL indications is small. 
Lymphopenia has been observed in preclinical studies. While opportunistic infections 
have been reported in the clinical program, data is confounded by subjects underlying 
disease and prior therapies. In the oncology studies, anti-infective prophylaxis should be 
implemented as clinically indicated, including appropriate prophylaxis for viral, fungal, 
bacterial, or Pneumocystis carinii pneumonia infections. 
1.2.5.5 Effects on Fertility 
Based on nonclinical studies, there is a 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. Male 
subjects are excluded from the initial SLE studies and healthy volunteer studies. 
1.2.5.6 Treatment-Emergent Malignancies (Second Primary 


 
 
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Malignancies) 
Events of second primary malignancies have been reported across the oncology program. 
No pattern has been was observed. As venetoclax is being evaluated in subjects with R/R 
disease who had previously been treated with various cytotoxic agents, second primary 
malignancies are closely monitored. 
 
1.2.5.7 Food Effect 
Administration with a low-fat meal increased venetoclax exposure by approximately 
3.4-fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 
5.3-fold compared to fasting conditions. Venetoclax should be administered with a meal. 
1.2.5.8 Drug Interactions 
Concomitant Use with Other Medications 
Venetoclax should not be used with strong CYP3A inhibitors (e.g., ketoconazole, 
ritonavir, clarithromycin, itraconazole, voriconazole) at initiation and during ramp-up 
phase. Concomitant use of venetoclax with moderate CYP3A inhibitors 
(e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil), or strong CYP3A 
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort), or moderate CYP3A 
inducers (e.g., bosentan, efavirenz, etavirine) should be avoided. For patients who have 
completed the ramp-up phase and are on a steady daily dose of venetoclax, concomitant 
use of strong and moderate CYP3A inhibitors may be allowed with venetoclax dose 
reductions.  
Venetoclax should be administered using caution with weak inhibitors or inducers of 
CYP3A, substrates or inhibitors of P-gp, BCRP, or OATP1B1/B3. If venetoclax is 
co-administered with warfarin, the international normalized ratio (INR) should be 
monitored closely. 
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. 
1.3 
IBRUTINIB (PCI-32765)  
1.3.1 
Background 
Ibrutinib (PCI-32765) is a first-in-class, potent, orally administered covalently-binding inhibitor of 
Bruton’s tyrosine kinase (BTK). Inhibition of BTK blocks downstream B-cell receptor (BCR) 
signaling pathways, prevents B-cell proliferation, induces cell apoptosis and demobilization from 
microenvironment. In vitro, ibrutinib inhibits purified BTK and selected members of the kinase 
family with 10-fold specificity compared with non-BTK kinases. The U.S. Food and Drug 
Administration (FDA) approved Ibrutinib (IMBRUVICA™) for the treatment of patients with 
mantle cell lymphoma (MCL) who have received at least one prior therapy and is currently under 
investigation in various Phase 3 studies, including MCL, CLL/SLL and other B cell malignancies. 
Ibrutinib is also approved for the treatment of patients with CLL who have received at least one 
prior therapy, patients with del(17p) CLL, and patients with Waldenstrom’s macroglobulinemia. 
This combination with venentoclax and rituximab is investigational.  


 
 
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B-cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokines release. B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (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 (Hendriks, 2014). 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 (Shaffer, 2002). Several lines of 
evidence suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies (Rickert, 2013).  
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 (NK) cells, 
but the selective effect of BTK mutations suggests that its primary functional role is in antigen 
receptor signaling in B-cells (Satterthwaite, 2000). 
Ibrutinib has demonstrated single agent activity in the treatment of relapsed or refractory de novo 
DLBCL in Study PCYC-1106-CA. Study PCYC-1106-CA is a Phase 2, open-label, 
nonrandomized, multicenter study in patients with relapsed or refractory de novo DLBCL receiving 
560 mg/day of ibrutinib. Data are currently available on 70 patients from this trial who have 
relapsed or refractory disease with 29 ABC subtype, 20 GCB subtype, 16 Type 3 subtype and 5 
subjects subtype unknown. The ORR in these 70 patients was 25% (17/70) with 9% of patients 
achieving a complete response (CR) and 16% of patients achieving a partial response (PR). Of the 
patients with ABC subtype, the ORR was 41% (12/29) with 17% CR and 24% PR. Of the patients 
with GCB subtype the ORR was 5% (1/20) with the one responder achieving a PR. The median OS 
was 9.76 months for those with ABC subtype and 3.35 months for those with GCB subtype (De 
Vos 2013). 
 
Ibrutinib has robust activity as a single agent in subjects with relapsed or refractory DLBCL, with 
higher response rates in subjects with the ABC subtype and lower response rates in subjects with 
the GCB subtype. The effect of a prior response to chemotherapy on subsequent response to 
ibrutinib was assessed. More subjects in the ABC DLBCL subset who were chemo-sensitive had a 
response (78.6%) compared with the chemo-sensitive non-ABC DLBCL subset (25.0%). Fewer 
subjects with ABC DLBCL who were chemo-refractory (defined as failure to achieve a response 
to the last prior chemotherapy regimen, ie, a regimen with at least 2 chemotherapeutic agents) had 
a response (16%), but the response was still favorable as compared with the chemo-refractory non-
ABC DLBCL subset (0/25 subjects, 0%). Based on these results, ibrutinib appears to be more active 
in subjects with chemo-sensitive DLBCL. Therefore use of ibrutinib in earlier lines of therapy and 
in the non-GCB subtype of DLBCL may have the greatest clinical effect. Despite results previously 
described, clearly there is a need for novel combinations to improve outcomes in 
relapsed/refractory DLBCL. 


 
 
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1.3.2 
Nonclinical and Clinical Data 
 
Ibrutinib is a first-in-class, potent, orally administered covalent inhibitor of Bruton’s tyrosine 
kinase (BTK) currently under investigation in various B-cell malignancies (Hendriks, 2014; 
Ponader, 2012).  
 
For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the Investigator's Brochure and United States Package Insert (USPI). 
 
1.3.3 
Pharmacology 
Ibrutinib was designed as a selective and covalent inhibitor of BTK. 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 for BTK 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 (Herman, 2011).  
 
For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the Investigator's Brochure. 
 
1.3.4 
Toxicology 
 
1.3.4.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
Carcinogenicity studies have not been conducted with ibrutinib. 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. 
 
1.3.5 
Summary of Clinical Safety of Ibrutinib 
Safety data are available for 636 subjects treated in 5 monotherapy and 3 combination therapy 
studies, as discussed below (Investigator’s Brochure Version 8, dated 24 Jun 2014).  
 
1.3.5.1 
Monotherapy Studies 
The PCYC1104 clinical trial included 111 previously treated MCL patients treated with ibrutinib 
560 mg daily and the median treatment duration was 8.3 months. The most commonly occurring 
adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, 
musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, 
dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite. 
 


 
 
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The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, 
abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of 
renal failure have occurred with ibrutinib therapy. Increases in creatinine 1.5 to 3 times the upper 
limit of normal occurred in 9% of patients. 
 
The following data reflect exposure to ibrutinib in an open label clinical trial (PCYC1102) that 
included 48 patients with previously treated CLL and a randomized clinical trial (PCYC1112 
(RESONATE)) that included 391 randomized patients with previously treated CLL or SLL. The 
most commonly occurring adverse reactions in these studies (≥ 20%) were thrombocytopenia, 
neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, 
rash, nausea, and pyrexia. Approximately five percent of patients receiving ibrutinib in these 
studies discontinued treatment due to adverse events. These included infections, subdural 
hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% 
of patients. 
 
 
1.3.5.2 
Combination Therapy Studies 
The safety of ibrutinib administered as combination therapy to 130 subjects was evaluated in 3 
clinical studies. In Study PCYC-1108-CA, ibrutinib is administered in combination with either the 
FCR (fludarabine, cyclophosphamide, and rituximab) or the BR (bendamustine and rituximab) 
regimen chemotherapy. In Study PCYC-1109-CA, ibrutinib is administered in combination with 
the monoclonal antibody ofatumumab in patients with relapsed and refractory CLL. In Study PCI-
32765DBL1002, ibrutinib is administered in combination with standard R-CHOP (rituximab with 
cyclophosphamide, doxorubicin, vincristine, and prednisone). Across these combination studies, 
the most common adverse event has been diarrhea (47.7%), nausea (33.1%), infusion related 
reaction (29.2%), and fatigue (26.2%). Neutropenia (24.6%) has been the most common 
hematologic toxicity, followed by anemia (20.0%) and thrombocytopenia (19.2%). 
 
Adverse events that were Grades 3 or 4 or higher in severity were reported in 57.7% of subjects. 
The most common have been hematologic: neutropenia (21.5%), anemia and thrombocytopenia 
(7.7% each), and febrile neutropenia (6.2%). Pneumonia (7.7%) was the most frequently reported 
non-hematologic Grade 3 or higher adverse event. 
 
Overall, 36.2% of treated subjects have experienced at least 1 serious adverse event. The only event 
reported as related occurring in more than 2 subjects has been pneumonia. The most commonly 
reported serious adverse events were febrile neutropenia and pneumonia (6.2% each), cellulitis 
(3.8%), atrial fibrillation (3.1%), and dehydration and dyspnea (2.3% each). 
 
Results from an ongoing Phase 1 study designed to determine the maximum tolerated dose, dose 
limiting toxicity, and preliminary efficacy of BR in combination with ibrutinib in 20 patients with 
relapsed/refractory NHL are available. Patients with at least 1 prior therapy or previously untreated 
but not candidates for autologous SCT were eligible. Bendamustine 90 mg/m2 on Days 1 and 2 
with rituximab 375 mg/m2 on Day 1 were administered with escalating doses of ibrutinib (280 mg 


 
 
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or 560 mg) on Days 1 to 28 every 28 days for 6 cycles. Responding patients could continue ibrutinib 
alone after Cycle 6 until disease progression or unacceptable toxicity. 
 
Nine of the 20 patients had MCL (2 previously untreated; 7 received 1 to 5 prior therapies). The 
overall response rate was 100% (4 CRs and 1 PR) for the 5 patients with MCL who were evaluable 
for response to treatment. No DLTs were reported. Grade 3/4 adverse events (N=20) included 
lymphopenia (15 subjects), neutropenia (5 subjects), rash (3 subjects), and anemia, 
thrombocytopenia, nausea and vomiting (2 subjects each event). The combination of ibrutinib with 
BR was well-tolerated without unexpected toxicity and with preliminary activity in patients with 
previously untreated and relapsed MCL. Blum et al demonstrated that ibrutinib can be safely 
combined with BR in this phase I combination study in relapsed or refractory NHL and that it 
enhanced BR’s clinical activity with an ORR in 5 evaluable MCL patients of 100% (80% CR, 20% 
PR) (Blum, 2012). 
 
1.3.5.3 
Treatment Discontinuations 
As of 6 April 2013, 71/636 subjects discontinued treatment due to an adverse event, across the 
monotherapy and combination therapy ibrutinib studies (excluding Study PCYC-1103-CA); 62 
subjects receiving monotherapy population and 9 subjects receiving combination therapy. The most 
frequently reported adverse events that led to treatment discontinuations were pneumonia (13 
subjects), respiratory failure (4 subjects), and cardiac arrest and Richter’s Syndrome (3 subjects 
each). In an open label study of 111 previously treated MCL patients, 10 patients (9%) discontinued 
treatment due to adverse reactions in the trial. The most frequent adverse reaction leading to 
treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose 
reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 
400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. 
However, some of these cases were in the setting of disease progression. Forty percent of patients 
had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction 
of hyperuricemia was reported for 15% of patients.  
 
In CLL studies, 1 and 2, approximately five percent of patients receiving ibrutinib in discontinued 
treatment due to adverse events. These included infections, subdural hematomas and diarrhea. 
Adverse events leading to dose reduction occurred in approximately 6% of patients. 
 
 
1.3.5.4 
Treatment-Related Lymphocytosis 
Similar to other agents targeting BCR signaling, transient lymphocytosis is a pharmacodynamic 
effect of ibrutinib, in which the inhibition of BTK-mediated cellular homing and adhesion results 
in a mobilization of tumor cells to the peripheral blood (Woyach, 2014; Wodarz, 2014). Upon 
initiation of treatment, a transient phase of increase in lymphocyte counts (ie, ≥50% increase from 
baseline and above absolute count 5,000/μL), often associated with reduction of lymphadenopathy 
has been observed in most subjects (75%) with relapsed/refractory CLL/SLL and some subjects 
(33%) with relapsed/refractory MCL treated with ibrutinib monotherapy.  This observed transient 
lymphocytosis is usually not associated with an adverse event and should not be considered 


 
 
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progressive disease in the absence of other clinical findings. Lymphocytosis in subjects with 
CLL/SLL on ibrutinib monotherapy typically occurs during the first month of ibrutinib therapy and 
resolves by a median of 23 weeks (range 1-104+ weeks. Similar observation was seen in MCL 
though usually to a lesser degree and shorter duration (Wang, 2013).  In MCL registration trial, 
onset of isolated lymphocytosis occurred during the first few weeks of ibrutinib therapy and 
resolves by a median of 8 weeks. Available data in subjects with DLBCL that have been treated 
with ibrutinib in multiple Phase 1 and Phase 2 studies, revealed no evidence of treatment related 
lymphocytosis. 
 
1.3.5.5 
Hemorrhagic Events 
Fatal bleeding events have occurred in patients treated with ibrutinib. Grade 3 or higher bleeding 
events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) 
have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to 
ibrutinib in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred 
in 44% of patients treated with ibrutinib. 
 
The mechanism for the bleeding events is not well understood. Ibrutinib may increase the risk of 
hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk 
of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of 
surgery and the risk of bleeding  
 
 
1.3.5.6 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. Grade 3 or greater infections 
occurred in 24% of 1,011 patients exposed to ibrutinib in clinical trials.  Cases of progressive 
multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have 
occurred in patients treated with ibrutinib. Monitor patients for fever and infections and evaluate 
promptly. 
 
1.3.5.7 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia 
(8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell 
malignancies treated with single agent ibrutinib. 
Monitor complete blood counts monthly. 
 
1.3.5.8 
Cardiac Arrhythmias 
Fatal and serious cardiac arrhythmias have occurred with ibrutinib. Grade 3 or greater ventricular 
tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial 
flutter occurred in 4% of 1,011 patients exposed to ibrutinib in clinical trials. These events have 
occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a 
previous history of cardiac arrhythmias. Periodically monitor patients clinically for cardiac 
arrhythmias. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or 


 
 
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new onset dyspnea should have an ECG performed. If cardiac arrhythmia persists, consider the 
risks and benefits of ibrutinib treatment and dose modification 
 
1.3.5.9 
Hypertension 
Hypertension has occurred in 12% of 1,011 patients treated with ibrutinib in clinical trials with a 
median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset 
hypertension or hypertension that is not adequately controlled after starting ibrutinib. Adjust 
existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
 
1.3.5.10 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Monitor patients closely and take 
appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). 
 
1.3.5.11 
Embryo-Fetal Toxicity 
Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant 
woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with 
MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 
mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower 
exposures. Advise women to avoid becoming pregnant while taking ibrutinib. If this drug is used 
during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to a fetus 
 
 
1.3.5.12 
Other Malignancies 
Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients 
treated with ibrutinib in clinical trials. The most frequent second primary malignancy was non-
melanoma skin cancer (6%).  
  
1.4 
SUMMARY OF RITUXIMAB 
Rituximab is a CD20-directed cytolytic antibody indicated for the treatment of relapsed/refractory 
and previously untreated CD20-positive follicular lymphoma (FL) and previously untreated CD20-
positive diffuse large B-cell (DLBCL). It has also been approved as maintenance therapy for up to 
2 years after initial treatment, for patients with previously untreated FL who have a PR or a CR to 
rituximab in combination with chemotherapy. (RITUXAN® Prescribing Information 2012) 
(MabThera (rituximab) product info).  
 
1.5 
STUDY RATIONALE 
In a high-risk SLL/CLL population, the combination of Ibrutinib (PCI-32765) and rituximab 
showed in a heavily pretreated group of patients an ORR of 85%, and as described above BCL-2 
inhibition has significant activity in MCL and DLBCL. Based on data by Griner 2014, a high-
throughput combinatorial screening revealed a strong cooperation between ibrutinib and BCL2 
family inhibitors in killing ABC like DLBCL cells. Greater synergy was observed between 
ibrutinib and venetoclax than with navitoclax (which targets BCL2) in all ABC DLBCL cell lines 


 
 
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tested.  This provides a rationale for our hypothesis of the combination of Ibrutinib and BCL-2 
Inhibition 
(venetoxlax 
(ABT-199))/rituximab 
in 
patients 
with 
newly 
diagnosed 
or 
relapsed/refractory DLBCL.  With this study, we will test the efficacy in both GC DLBCL and non-
GC.  Ibrutinib has shown as single agent preferential activity in non-GC DLBCL (Wilson, 2015). 
On the other hand, Venetoclax monotherapy demonstrated activity across the board in R/R 
follicular and DLBCL regardless of the subtype. In addition, in combination with Rituximab, 
Ibrutinib showed also significantly improved activity compared with single agent in R/R follicular 
lymphoma.  
 
1.5.1 
Rationale for Dose 
The rationale for the current dose and schedule of each agent is based not only upon the approved 
dose (ibrutinib and rituximab)for these treatments, but also based upon the safety data known 
regarding the use of these therapies for the treatment of NHL in the relapsed and refractory setting.  
 
Rituximab alone or in combination is approved at a dose of 375 mg/m2 IV on Day 1 of each cycle 
for up to 8 doses in patients with DLBCL.  
 
Since ibrutinib has been studied at the 560 mg dose in several types of NHL on a continuous daily 
dosing schedule and is well tolerated, it will be administered daily until disease progression or 
unacceptable toxicity.  
 
Combination studies with venetoclax have demonstrated a tolerable safety profile of venetoclax. 
We decided to proceed with the approved doses of ibrutinib and rituximab to maximize safety and 
we will escalate venetoclax across 2 dose cohorts. We will attempt to enroll 3 patients every 2 
months, based on the DLT period of 28 days (1 cycle of therapy followed by laboratory evaluation 
for toxicity on Cycle 2 Day 1, Study Day 29). We will attempt to complete no earlier than 4 months.  
 
1.5.2 
Hypothesis  
Our hypothesis is that the combination therapy of BTK Inhibitor Ibrutinib (PCI-32765) plus 
venetoclax and rituximab in relapsed or refractory DLBCL will have an increased activity with 
acceptable toxicity. Furthermore, this new novel therapeutic combination will be safe and well 
tolerated among this patient population. This hypothesis is based on prior clinical trial data detailed 
above. Our hypothesis will be tested in a 3 + 3 dose escalation model of venetoclax (ABT-199) 
plus Ibrutinib (PCI-32765) and rituximab. 
 
 
2. 
OBJECTIVES 
A dose-escalation will first determine the MTD and/or RP2D for combinations of ibrutinib (PCI-
32765) plus venetoclax (ABT-199) and rituximab in patients with relapsed/refractory diffuse 
large b-cell lymphoma. 


 
 
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2.1 
PRIMARY 
 
Define maximum tolerated dose (MTD) and /or recommended phase II dose for the 
combinations of venetoclax (ABT-199, GDC-0199) plus Ibrutinib (PCI-32765) and 
rituximab in Relapsed or Refractory DLBCL by assessing the incidence of dose limiting 
toxicities (DLTs) in first 29 days. 
2.2 
SECONDARY 
 
Assess safety and tolerability of the combinations  
 
Assess preliminary anti-tumor activity of the combinations by radiological progression-
free survival and radiological response rate  
3. 
OVERALL STUDY DESIGN 
This is a Phase 1b, single-arm, open-label, single-center study of venetoclax (ABT-199) in 
combination with ibrutinib and rituximab in Subjects with Relapsed/Refractory DLBCL. The trial 
consists of a dose-escalation of venetoclax in combination with standard doses of ibrutinib and 
rituximab. For the dose escalation part of the study, a standard 3+3 design will be utilized.  Once 
the MTD has been established, the dose escalation part will be followed by a dose expansion part 
in a cohort with a maximum of 24 subjects with DLBCL. The purpose of the dose expansion part 
is to investigate the efficacy of the combination. Between the dose-escalation and dose-expansion, 
the maximum number of subjects will be 30. 
 
Cycle length will be 28 days. Venetoclax will be administered orally QD, continuously for 24 
cycles (from C1D2). Ibrutinib will be administered orally QD, continuously for 24 cycles (from 
C1D2).  Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once 
on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from 
C1D1), Commercially available rituximab IV will be used. 
 
Dose escalation schema as follows: 
Dose Level 
Ibrutinib  
(PCI-32765) mg/d 
venetoclax 
mg/day 
Rituximab 
mg/m2 (starting C1D8) 
-1 
560* 
200 
375 
1 
560 
400 
375 
2 
560 
800 
375 
 
 


 
 
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4. 
STUDY POPULATION 
4.1 
INCLUSION CRITERIA 
Patients must meet the following criteria for study entry: 
1. Eastern Cooperative Oncology Group Performance Status </= 2. 
2. Histologically or cytologically confirmed diagnosis of advanced DLBCL. 
3. Ability and willingness to comply with the requirements of the study protocol 
4. Prior therapy: relapsed or refractory patients who have received one prior therapy are eligible. 
If treated with small molecule, washout therapy with a period of greater than 5x the half-life 
of the molecule. Patients who have previously received high-dose chemotherapy with 
peripheral stem cell support are eligible. Washout period of 21 days.  
5. Presence of at least one lymph node evaluable or mass measurable for response. 
6. Age greater than or equal to 18 years. 
7. Recovery from any previous treatment therapy. 
8. Laboratory parameters: 
– 
Absolute neutrophil count (ANC)  1000/mm3 independent of growth factor support 
(unless the treating physician deems the neutropenia is related to bone marrow 
involvement, then an ANC of > 750/mm3 is allowed) 
– 
Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of 
transfusion support in either situation 
– 
Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-
hepatic origin 
– 
AST (SGOT) and ALT (SGPT) ≤ 3 x upper limit of normal (ULN) 
– 
Creatinine: CrCl 50 ml/min (calculated using Cockcroft-Gault Formula-Appendix 2) 
Prothrombin time (PT)or international normalized ratio and partial thromboplastin time 
(PTT) not to exceed 1.2 times the institution’s normal range 
9. Women of childbearing potential and men who are sexually active must be practicing a 
highly effective method of birth control during and after the study consistent with local 
regulations regarding the use of birth control methods for subjects participating in clinical 
trials. Men must agree to not donate sperm during and after the study. For females, these 
restrictions apply for 3 months after Venetoclax and 12 months after Rituximab For males, 
these restrictions apply for 3 months after the last dose of study drug. 
10. Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or 
breastfeeding are ineligible for this study. 
11. Sign (or their legally-acceptable representatives must sign) an informed consent document 
indicating that they understand the purpose of and procedures required for the study, 
including biomarkers, and are willing to participate in the study 
 


 
 
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4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Known central nervous system lymphoma.  
2. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
3. Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon). 
4. Received the following agents within 7 days prior to the first dose of venetoclax or requires 
chronic treatment with strong CYP3A inhibitors (e.g., ketoconazole, ritonavir, 
clarithromycin, itraconazole, voriconazole), moderate CYP3A inhibitors (e.g., erythromycin, 
ciprofloxacin, diltiazem, fluconazole, verapamil), strong CYP3A inducers (e.g., 
carbamazepine, phenytoin, rifampin, St. John's wort) or moderate CYP3Ainducers (e.g., 
bosentan, efavirenz, etavirine). (See Appendix 4)  
5. Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, 
or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York 
Heart Association Functional Classification. 
6. Vaccinated with live, attenuated vaccines within 4 weeks of enrollment. 
7. Use of any other standard chemotherapy, radiation therapy, or experimental drug therapy for 
the treatment of DLBCL within 21 days of starting treatment 
8. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active 
Hepatitis B Virus infection or any uncontrolled active systemic infection or human T-cell 
leukemia virus 1 (HTLV-1) seropositive status or a Child – Pugh Class of B or C. 
9. Any life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or 
metabolism of ibrutinib capsules, venetoclax or rituximab or put the study outcomes at undue 
risk. 
10. History of uncontrolled or symptomatic angina 
11. Ejection fraction below the institutional normal limit 
12. History of other malignancy that could affect compliance with the protocol or interpretation 
of results 
– 
Patients with a history of curatively treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix are generally eligible.  Patients with a 
malignancy that has been treated, but not with curative intent, will also be excluded, 
unless the malignancy has been in remission without treatment for   2 years prior to 
enrollment. 
13. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, 
uncontrolled systemic infection (viral, bacterial, or fungal) 
14. Major surgery (within 4 weeks prior to the start of the first dose of study treatment), other 
than for diagnosis 


 
 
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15. Women who are pregnant or lactating 
16. Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must 
practice at least one of the following methods of birth control throughout the duration of 
study participation and for at least 12 months after study treatment: 
– 
Total abstinence from sexual intercourse 
– 
A vasectomized partner 
– 
Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at 
least 3 months prior to study drug administration 
– 
Double-barrier method (condom  diaphragm or cervical cup with spermicidal 
contraceptive sponge, jellies, or cream) 
17. Non-vasectomized male patients must comply with at least one of the following methods of 
birth control throughout the duration of study participation and for at least 12 months after 
study treatment: 
– 
A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is 
taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at 
least 3 months prior to study drug administration 
– 
Total abstinence from sexual intercourse 
– 
Double-barrier method (condom  diaphragm or cervical cup with spermicidal, 
contraceptive sponge, jellies, or cream) 
18. Malabsorption syndrome or other condition that precludes enteral route of administration 
19. Known allergy to both xanthine oxidase inhibitors and rasburicase 
 
4.2.1 
Justification for inclusion and exclusion criteria 
 
The criteria are set to minimize the risk to the volunteers, to ensure a subject population that will 
enable the investigation of the set objectives, to provide equal opportunity for inclusion and not to 
exclude subjects that may benefit directly from the trial.  
 
4.2.2 
Criteria for discontinuation 
 
Subjects may be discontinued from study treatment and assessments at any time, at the discretion 
of the investigator.  Specific reasons for discontinuing a subject from the study are: 
 
1. Withdrawal of informed consent. 
2. Development of exclusion criteria or other safety reasons during the study. 
3. Protocol non-compliance. 
4. Incorrect enrollment of the subject 
5. Disease progression 
6. Stem cell transplant 
 
 


 
 
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5. 
TREATMENT 
The investigator will instruct the patient to take the study drugs as per protocol. All dosages 
prescribed and dispensed to the patient and any dose change or interruption must be recorded in the 
dosage administration record CRF, as appropriately. 
This is an open-label dose escalation study using a 3+3design. Before applying the dose escalation 
rules, 3 subjects in any given cohort must have completed the DLT observation period which is 
defined as 28 days (1 cycle) of therapy followed by evaluation for toxicity on Cycle 2 Day 1 (Study 
Day 29 +/- 3 days).  The dose level in which 2 patients experience unacceptable toxicity is usually 
considered the maximum administered dose (MAD). We will define the MTD as the next lower 
dose level in which no more than 1/6 patients experience unacceptable toxicity. Dose escalation 
will cease if 2 or more patients develop DLT. There will be no intrapatient dose escalation. 
 
Enrollment in a cohort will proceed as follows: 
 
If no dose limiting toxicity (DLT) is observed during the DLT observation period in the initial 
3 subjects of a cohort, dose escalation to the next higher dose level cohort will occur. 
 
If 1 DLT is observed, 3 additional subjects will be enrolled at the same dose level for a total of 
at least 6 subjects. If no further DLT(s) are observed, escalation to the next higher dose level 
cohort will occur. 
 
Dose escalation will occur at the planned dose levels until the MTD is determined or until the 
highest dose level is tested. The MTD is defined as the highest dose at which <33% of the 
subjects enrolled in a cohort experience a DLT. At least 6 subjects will be treated at the MTD or 
highest tested dose. 
 
5.1 
DEFINITIONS OF DOSE-LIMITING TOXICITIES 
 
Incidence of Dose Limiting Toxicities (DLT). Time frame: 28 days (1 cycle of therapy followed 
by laboratory evaluation for toxicity on Cycle 2 Day 1, Study Day 29) Toxicity will be assessed 
using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events 
(CTCAE), version 4.03  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm unless otherwise 
specified. A DLT is defined as an adverse event or abnormal laboratory value assessed as at least 
possibly related to the study medication, that occurs ≤ 29  days or prior to the Cycle 2, Day 1 visit 
(whichever is longer) following the first dose, and meets any of the protocol-specified DLT 
criteria. 
 
Dose-limiting toxicity: The dose-limiting toxicity described in this section refers to toxicity 
derived from any or all of the agents used in the combination regimen.  
 
Hematologic: 
 
Grade 3 neutropenia (ANC <1,000/mm3) that does not resolve to < Grade 2 within 3 
weeks with the use of growth factor 


 
 
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 
Grade 4 neutropenia (ANC <500/mm3) 
 
Febrile neutropenia (ANC <1,000/mm3 with a fever ≥38.3ºC) 
 
Grade 4 thrombocytopenia (<25,000/ mm3) that persists for ≥7 days, despite holding 
treatment 
 
Grade 3 thrombocytopenia associated with Grade ≥2 bleeding or requiring RBC or 
platelet Transfusions 
 
Non-Hematologic: 
 
Any Grade 3 or higher non-hematologic adverse event where relationship to study 
drug(s) cannot be ruled out (Note: excludes rituximab infusion reactions) 
 
Grade ≥3 nausea, vomiting, or diarrhea uncontrolled by maximal supportive care and 
persisting greater than 7 days 
 
Grade 3 fatigue persisting for greater than 7 days 
 
Treatment delay of any drug greater than 7 days for toxicity 
 
5.2 
STUDY DRUG ADMINISTRATION 
All eligible subjects will be treated with ibrutinib and venetoclax and rituximab.  Each cycle is 
28-days in length. 
 
Venetoclax: Dose escalation administered daily orally for up to a total of 24 cycles. Each cohort 
will get assigned daily dose (from C1D2). 
Ibrutinib: 560 mg (4 capsules) orally administered daily for up to a total of 24 cycles (from C1D2). 
Rituximab: 375 mg/m2 IV per package insert. Rituximab will be administered IV per institutional 
standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until 
Cycle 24 (total 18 doses of Rituxan from C1D1). Commercially available rituximab IV will be 
used. 
 
6. 
TREATMENT PLAN 
Study Type: 
Interventional 
Study Design: Endpoint Classification: Safety/Efficacy Study 
 
 
Intervention Model: Single Group Assignment, non-randomized design 
 
 
Masking: Open Label 
Population:  
The patient population consists of adult subjects >18 years old with r/r DLBCL.  
The investigator or designee will complete a subject-screening log to document 
subjects considered for enrollment. 
 
Description: 
Phase Ib, open-label single group dose finding study of ibrutinib, venetoclax and 
rituximab in relapsed or refractory DLBCL 


 
 
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Study Design  
Description: 
A dose-escalation will first determine the MTD and/or RPII of Bruton’s Tyrosine 
Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765) plus venetoclax and rituximab in 
relapsed or refractory DLBCL / Dose level and escalation described below 
 
 
No of Pts 
Dose Level 
Ibrutinib a 
mg PO daily 
Venetoclaxb 
mg PO daily 
Rituximab c 
mg/m2 IV Day 1  
 
-1 
560 
200 
375 
3 
1 
560 
400 
375 
3 
2 
560 
800 
375 
 
a. Ibrutinib will be administered orally daily beginning Cycle 1 Day 2 for 24 cycles 
b. Venetoclax is being administered orally daily, continuously beginning Cycle 1 Day 2 for 24 
cycles 
c. Rituximab will be administered IV per institutional standards; weekly X 4 (Cycle 1); once on Day 
    1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1) 
 
Total number of patients: 
30 
Total Number of Centers: 
One center 
 
Sample Size 
Justification: 
The MTD will be determined in a standard fashion using 3–6 patients per dose 
level. No more than 2 dose levels will be used in order to find the MTD. As such, 
for the phase I escalation portion of the study, no more than 12 patients will be 
required. Also we plan an expansion cohort at the MTD to examine the efficacy 
of the combination. We plan an expansion cohort with a maximum of 24 patients. 
Between the dose-escalation and dose-expansion, the maximum number of 
subjects will be 30. 
 
Subjects with relapsed / refractory DLBCL that decide to participate on this study 
will sign consent and enter a screening period of 28 days.  Patients that fulfill and 
maintain eligibility criteria will start cycle 1 day 1 treatment by receiving 
Rituximab. Ibrutinib and venetoclax will be administered daily starting on cycle 1 
day 2. Follow up will be weekly during Cycle 1, on days 1 and 15 of cycles 2 and 
3, then follow up monthly until disease progression, unacceptable toxicity or 
withdraw of consent.   
 
Restaging/ Length 
Of Therapy: 
 
 
Repeat cycles every 28 days for a total of 6 cycles. Patient may need to be 
evaluated in the office more frequently if needed at physician discretion  
 
Patient will be restaged after every 2 cycles of therapy. Patients, who are in at 
least stable disease with minimal drug toxicity after 2 cycles, will receive 


 
 
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subsequent treatment. Patients who have progression of the disease will be 
taken off study and complete post treatment follow up as described above 
 
Patients will receive 6 cycles then continue with venetoclax (daily) and 
ibrutinib (daily) with rituximab every other cycle until POD or toxicity or 
decision of stem cell transplantation if applicable (24 cycles max of treatment) 
 
Restaging will be every 2 cycles for the 1st 6 cycles and then every 3 cycles 
during treatment and disease follow up.  
 
 
Post Treatment 
 
Follow Up: The post-treatment follow-up phase will begin once a subject 
discontinues ibrutinib, venetoclax and rituximab treatment and will continue a 
total of 36 months (from enrollment) has been reached or until death, lost to 
follow up, consent withdrawal, or study end, whichever occurs first. Subjects 
who discontinue for reasons other than disease progression (ie, for adverse 
event or Investigator decision), will complete an End-of-Treatment Visit (30 
± 3 days from the last dose of ibrutinib, venetoclax or rituximab, whichever is 
later), and must continue to have disease evaluations Q 3 months until disease 
progression, subject withdrawal, study is terminated or 36 months from 
enrollment has been reached.(12 weeks ±7 days). 
 
Subjects who discontinue due to disease progression will complete an End-of-
Treatment Visit and be followed for survival and subsequent anti-cancer 
therapy via phone call (12 weeks ±7 days) until death or subject withdrawal or 
study is terminated. 
 
 
 
7. 
STUDY MEDICATION 
 
7.1 
VENETOCLAX 
 
7.1.1 
Administration 
The first dose of venetoclax will be administered orally on Cycle 1 Day 2, of the Treatment Phase, 
after which venetoclax will be self-administered daily by the subjects on an outpatient basis. 
Venentoclax dosing will continue for up to a total of 24 cycles. 
 
Patients will self-administer venetoclax tablets by mouth QD.  Each dose of venetoclax will be 
taken with approximately 240 mL of water within 30 minutes after the completion of a low-fat 
breakfast.  Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of low-
fat margarine and 1 tablespoon of jam and 8 ounces/240 mL of skim milk (319 calories and 8.2 g 
fat) or 1 cup/30 g of cereal, 8 ounces/240 mL of skim milk, 1 slice of toast with jam, 1 cup/240 mL 
of apple juice, and 1 cup/240 mL of coffee or tea (520 calories and 2 g fat).  If vomiting occurs 
within 15 minutes after taking venetoclax and all expelled tablets are still intact, another dose may 


 
 
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be provided.  Otherwise, no replacement dose is to be given.  In cases where a dose of venetoclax 
is missed or forgotten, the patient should take the dose as soon as possible, ensuring that the dose 
is taken with food within 8 hours after the missed dose.  Otherwise, the dose should not be taken. 
Patient compliance in taking the assigned daily dose of venetoclax will be assessed by standard pill 
counts.  Bottles containing venetoclax tablets will be given to patients at regular scheduled visits.  
Previously distributed bottles will be returned to the clinic and tablets counted.  Any discrepancy 
will be resolved with the patient at each clinic visit and documented in the patient record. 
Guidelines for venetoclax dosage modification and treatment interruption or discontinuation are 
provided in Section 7.1.4. 
7.1.2 
Concomitant Therapies 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a patient between the 14 days preceding the study entry evaluation and the early study treatment 
termination visit/study treatment completion visit.  
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance therapy 
should continue their use for the duration of the study for at least 3 months after the last dose of 
venetoclax and 12 months after the last dose of Rituximab. 
Necessary supportive measures for optimal medical care will be given throughout the study 
according to institutional standards, including the use of growth factors (e.g., erythropoietin) if 
clinically indicated.  Granulocyte colony-stimulating factor (G-CSF) may be administered as 
primary prophylaxis in each cycle of therapy, per the American Society of Clinical Oncology 
guidelines (Smith et al. 2006) or each site’s institutional standards. 
7.1.3 
Prophylaxis and Management of Tumor Lysis Syndrome 
 TLS is a risk for patients with NHL who are treated with high cell-killing agents, including 
venetoclax.  Changes in blood chemistries consistent with TLS that require prompt management 
can occur as early as 6 to 8 hours following the first dose of venetoclax.  The risk of TLS is a 
continuum based on multiple factors, including tumor burden and comorbidities.  Risk is highest 
for those with bulky disease, elevated leukocyte count, elevated pretreatment LDH levels, 
compromised renal function, and dehydration.  Perform tumor burden assessment with CT scan 
and CBC with WBC differential, assess blood chemistry (potassium, uric acid, phosphorus, 
calcium, and creatinine) in all patients and correct pre-existing chemistry abnormalities prior to 
initiation of treatment with venetoclax.   
All patients must receive prophylaxis for TLS before the initiation of the first dose of venetoclax. 
Prophylaxis will include the following:  
 
Appropriate hydration, consisting of a fluid intake of approximately 2−3 L/day starting 
  24−48 hours before the start of treatment    


 
 
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 
Administration of an agent to reduce uric acid (such as allopurinol 300 mg/day orally 
beginning 72 hours before dose and continuing for 3−7 days afterwards)  or rasburicase 
IV (for those high risk patients with elevated uric acid levels before treatment, or when 
otherwise judged to be appropriate by the investigator) 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 before the first dose of venetoclax, or the patient 
should receive additional prophylactic treatment and hydration before the initiation of 
dosing.    
On the day of the initial visit with administration of venetoclax (Cycle 1 Day 2), serial vital signs, 
serum chemistry, and hematology samples will be drawn before the dose  of venetoclax and at 8 
and 24 hours following the dose (see Appendix 1). These samples are to be sent STAT to the 
laboratory and the investigator or designee must review the results promptly. Laboratory values 
obtained before the dose of venetoclax are to be used to determine whether a patient developed a 
change related to TLS. Laboratory results of the 24-hour postdose must be reviewed before 
receiving the dose of venetoclax for that day. Patients who develop electrolyte changes suggestive 
of TLS should undergo aggressive management and further monitoring per Appendix 5, 
Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor 
Lysis Syndrome.    
 
Guidelines for hospitalization due to TLS risk 
Patients exhibiting specific characteristics at screening or initiation of venetoclax treatment are 
considered to be at high risk of developing TLS and must be hospitalized for more intensive 
prophylaxis and monitoring for the initial dose of venetoclax.  These patients are identified by the 
presence of any of the following: 
• 
any lymph mass ≥10 cm on the screening CT scan 
• 
circulating lymphoma cells, defined by out of range (high) Absolute Lymphocyte Count 
(ALC) or the presence of abnormal cells in the peripheral blood differential signifying 
circulating lymphoma cells 
In addition to characteristics requiring mandatory hospitalization, other patient characteristics 
may suggest an increased risk of TLS. These include, but are not limited to, the following: 
• 
overall disease burden (e.g. several enlarged lymph nodes, even if none reaching 10 cm) 
• 
elevated LDH levels 
• 
compromised renal function, as evidenced by low creatinine clearance 


 
 
Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
44 
• 
extensive bone marrow involvement 
• 
Dehydration 
Hospitalization is not mandatory for patients exhibiting these characteristics, but these and any 
other factors considered relevant to TLS should be considered in an overall assessment of the 
patient’s state and their risk of TLS. Investigators should use their judgment in assessing TLS risk 
for their patients and may optionally hospitalize any patient they consider to be at risk for TLS for 
the first dose of venetoclax, with approval of the medical monitor.  
Hospitalization Procedures 
For pts requiring hospitalization, hospitalization will begin the evening before the first dose of 
venetoclax 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 before the first dose of venetoclax; 
otherwise, the patient should receive additional prophylactic treatment and hydration before the 
initiation of dosing. A nephrology (or acute dialysis) service must be consulted/contacted 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 signs and TLS laboratory samples will be drawn before the first dose of venetoclax 
and at 8-, 12-, and 24-hour postdose; additionally, hematology samples will be drawn at 8- and 
24-hour postdose  (see Appendix 1). These samples are to be sent STAT to the laboratory and the 
investigator or designee must review the results promptly. Laboratory values obtained before the 
dose of venetoclax are to be used to determine whether a patient developed a change related to 
TLS. Laboratory results of the 24-hour postdose must be reviewed before receiving the dose of 
venetoclax for that day. Patients who develop electrolyte changes suggestive of TLS should 
undergo aggressive management and further monitoring per Appendix 5, Recommendations for 
Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome. 
Patients felt by the investigator to have particularly high risk of TLS may, in addition to 
hospitalization, start at a lower dose of venetoclax at the investigator’s discretion, following 
discussion with the medical monitor. 
 
 
 
7.1.4 
Guidelines for Dosage Modification and Treatment Interruption or 
Discontinuation 
AE Attribution to study drugs will be assessed based on IB known data; for those not reported in 
the IB, relationship assessment will be at PI discretion to analyze. 


 
 
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Table 1 
Dose Modifications for Hematologic Toxicity Venetoclax Monotherapy 
Hematologic Toxicity 
Event(s) 
Dose Delay or Modification 
Grade 3 or 4 neutropenia, without 
infection or fever, and/or Grade 3 or 
4 thrombocytopenia, first episode 
 Hold venetoclax.   
 When counts recover to  Grade 2, resume previous doses of 
venetoclax.  
 Administer G-CSF or growth factors for neutropenia as indicated.  
 If the patient was not previously receiving prophylactic G-CSF, 
initiate prophylactic G-CSF for neutropenia as indicated.  
Grade 3 or 4 neutropenia with 
infection and/or fever, first episode 
 Begin anti-viral medication and hold venetoclax until fever and/or 
infection resolves. 
 Administer G-CSF or growth factors for neutropenia as indicated.  
 When counts recover to  Grade 2 and infection has been fully 
treated, resume previous doses of venetoclax.  
 If the patient was not previously receiving prophylactic G-CSF, 
initiate prophylactic G-CSF for neutropenia as indicated.  
Recurrent Grade 3 or 4 neutropenia 
with/without fever and infection 
despite G-CSF  
 Hold venetoclax for at least 7 days. 
 Administer G-CSF or growth factors for neutropenia as indicated.  
 When counts recover to  Grade 2 and/or platelets are 
 75  109/L, resume venetoclax at one dose level reduction (see 
Table 3). 
Grade 4 thrombocytopenia and/or 
symptomatic bleeding 
 Hold venetoclax for Grade 4 thrombocytopenia (platelets 
 25,000/L) or presence of symptomatic bleeding until resolution 
of bleeding. 
 Platelets may be transfused at the discretion of the investigator. 
 When platelet level rises to  Grade 2 without transfusional 
support for 5 consecutive days, restart venetoclax. 
 For a second episode of severe thrombocytopenia and/or 
symptomatic bleeding, hold venetoclax.  When platelet level rises 
to  Grade 2 without transfusional support for 5 consecutive days, 
restart venetoclax at one dose level reduction (see Table 3).  
 For subsequent episodes of severe thrombocytopenia, hold 
venetoclax. When platelet level rises to  Grade 2 without 
transfusional support for 5 consecutive days, restart venetoclax at 
one dose level reduction.   
G-CSF  granulocyte colony-stimulating factor. 
 


 
 
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Table 2 
Venetoclax Dose Modifications for Non-Hematologic Toxicity 
Non-hematologic Toxicity 
Event(s) 
Dose Delay or Modification 
Grade 3 or 4 TLS (first episode and 
subsequent episodes) 
 Hold all study treatments (venetoclax) until TLS resolves.  The 
patient’s next dose may be delayed for up to 28 days.  
 Following complete resolution of TLS, if venetoclax was held for 
14 days or less, venetoclax may be restarted at the same dose or at 
one lower dose level as determined by the investigator based on a 
risk assessment (including tumor burden status) in conjunction 
with prophylactic hydration and uricosuric agent; hospitalization 
for restarting the venetoclax dose may be considered at the 
discretion of the investigator.  Dose must be resumed at one lower 
dose level if interruption lasted more than 14 days. 
Grade 3 or 4 non-hematologic 
toxicity not specifically 
described above 
 Delay venetoclax for a maximum of 28 days. 
 First episode:  If improvement to Grade  1 or baseline, resume 
previous doses of venetoclax. 
 For subsequent episodes:  If improvement to Grade  1 or 
baseline, restart venetoclax at one dose level reduction (see 
Table 3). 
Grade 2 non-hematologic toxicity 
Delay treatment with venetoclax until resolution to Grade  1 (or 
baseline status) for a maximum of 28 days.  After resolution, resume 
the full dose of venetoclax. 
Grade 1 non-hematologic toxicity 
No dose reduction or delay 
TLS  tumor lysis syndrome. 
   
Table 3 
Venetoclax Dose Reduction 
Venetoclax Current Dose Level 
Venetoclax Dose Reduction 
800 mg 
400 mg 
400 mg 
200 mg 
200 mg 
 100 mg 
 100 mg 
Discontinue venetoclax 
  
Gradual dose increase following resolution of toxicity leading to a dose reduction may be 
considered if the patient is stable for 2 weeks on the lower dose; however, if the toxicity recurs, 
the patient may continue treatment on the lower dose. 
7.1.5 
Infections Prophylaxis 
All patients will be monitored closely for infection and treated aggressively according to 
institutional guidelines. If clearly indicated, anti-infective prophylaxis should be implemented at 
the investigator’s discretion, including appropriate prophylaxis for viral, fungal, bacterial, or 
pneumocystis infections. 


 
 
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Although there is a potential for drug-drug interactions, there is likely to be limited potential clinical 
effects. There will be careful monitoring by the PI in such cases.  
7.1.6 
Excluded Therapy 
 
Receipt of live viral vaccines 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 
 
Use of the following concomitant medications is prohibited from 7 days prior to initiation of 
drug treatment or during the study: 
– 
Strong CYP3A4 inhibitors such as fluconazole, ketoconazole, and clarithromycin 
– 
Strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and St. John’s 
wort 
– 
Warfarin 
As discussed in Section 8.1.2.1 detailing the use of CYP3A inhibitors and inducers with 
ibrutinib, for strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 
days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, 
telithromycin) consider interrupting venetoclax therapy during the duration of the use the 
inhibitor.  
 
 
7.2 
IBRUTINIB 
 
All subjects in this study will receive commercial ibrutinib (Ibrutinib capsules will be from 
commercial supply but will be provided by Janssen Scientific Affairs, LLC) and will follow 
guidelines for ibrutinib dosing and toxicity management. 
 
7.2.1 
Formulation, Packaging, and Storage of Ibrutinib 
 
Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It is a white to off-white solid with the 
empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in 
dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for 
ibrutinib 
is 
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[ 
3,4-d]pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one.  
 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. Ibrutinib 
PO hard gelatin capsule is an oral formulation containing micronized ibrutinib and the following 
compendial excipients: microcrystalline cellulose (National Formulary [NF]); croscarmellose 
sodium (NF); sodium lauryl sulfate (NF); may contain magnesium stearate (NF). 
 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. All study 
drug will be dispensed in child-resistant packaging. Refer to the USPI and IB for additional 
guidance on study drug storage, preparation and handling. Commercially available Ibrutinib will 
be used in this study.    


 
 
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7.2.2 
Dose and Administration of Ibrutinib 
 
The first dose of ibrutinib will be administered orally on Cycle 1 Day 2, of the Treatment Phase, 
after which ibrutinib will be self-administered daily by the subjects on an outpatient basis. Ibrutinib 
dosing will continue for up to a total of 24 cycles.  
 
Ibrutinib will be dosed 0−30 minutes before the rituximab infusion and at the same time as 
venetoclax on days where ibrutinib, rituximab and venetoclax are administered.   
 
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily with 8 ounces 
(approximately 240 mL) of water at approximately the same time each day. The capsules should 
be swallowed intact and patients should not attempt to open, break or chew capsules or dissolve 
them in water. The use of strong CYP3A4/5 inhibitors/inducers, and grapefruit and Seville oranges 
should be avoided for the duration of the study (CYP3A4/5 list, Appendix 4).  If a dose is missed, 
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. 
 
Ibrutinib dosing is continuous (without interruption) throughout the Treatment Phase. If Day 1 
venetoclax or rituximab dosing is delayed for toxicity that does not require ibrutinib to be held for 
toxicity, dosing of ibrutinib should continue. If a Day 1 (of any Cycle- starting cycle 2) rituximab 
infusion is delayed due to scheduling delays, ibrutinib dosing should continue. Treatment will 
continue until disease progression or other reason for treatment discontinuation or until 24 cycles 
or end of study (3 years after patient enrolled). 
 
7.2.3 
Dose Hold, Reduction or Discontinuation of Ibrutinib 
 
In order to continue ibrutinib at the start of a new cycle, the subject must not meet any of the criteria 
for ibrutinib dose modification. Treatment with ibrutinib should be withheld for any unmanageable, 
potentially study drug related non-hematological toxicity that is Grade 3 or higher in severity and 
any hematologic toxicity meeting criteria for dose hold. Subjects who require full-dose of 
anticoagulant treatment (eg, heparin) should have ibrutinib held until stable on anticoagulant 
therapy.  For subjects that require an invasive procedure or surgery, PI will consider the benefit-
risk of withholding ibrutinib for at least 3 to 7 days pre and post surgery depending upon the type 
of surgery and the risk of bleeding.     Ibrutinib may be withheld for a maximum of 28 consecutive 
days for toxicity. Ibrutinib should be discontinued in the event of an ibrutinib toxicity lasting more 
than 28 days. The decision to allow patients to continue in the event of an ibrutinib toxicity lasting 
more than 28 days will be at PI discretion  
 
7.2.4 
Dose Modification of Ibrutinib 
 
7.2.4.1 
Dose modifications for adverse events: 
 


 
 
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Interrupt ibrutinib therapy for any Grade 3 or greater non-hematological, Grade 3 or greater 
neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the 
toxicity have resolved to Grade 1 or baseline (recovery), ibrutinib therapy may be reinitiated at the 
starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second 
reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur 
following two dose reductions, discontinue ibrutinib (refer to Table 3 below). 
 
 
 
Table 3: Ibrutinib Dose Modifications 
 
Adverse Events  
Occurrence 
Action to be Taken 
First  
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 
original dose level  
Second  
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 
1 dose level lower (ie,420 mg/day) 
Third  
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 
1 dose level lower (ie,280 mg/day) 
Fourth  
Discontinue ibrutinib  
*if Ibrutinib is discontinued for toxicity, subject will end the Treatment Phase of the study.  
*Ibrutinib dosing at 420 mg could be administered on an individual patient basis as per Investigator 
discretion dose modifications are required.  Dose changes must be recorded in the Dose 
Administration eCRF.  
 
7.2.4.2 
Dose modifications for use with CYP3A inhibitors 
 
Table 4: Recommended Ibrutinib Dose Modifications for use with CYP3A Inhibitors 
 
Patient 
Population 
Coadministered Drug 
Recommended Ibrutinib Dose 
B-Cell 
Malignancies 
 
Moderate CYP3A inhibitor 
280 mg once daily 
Modify dose as 
recommended. 
 
Voriconazole 200 mg twice daily 
 
Posaconazole suspension 100 mg 
once daily, 100 mg twice daily, or 
200 mg twice daily 
140 mg once daily 
Modify dose as 
recommended. 


 
 
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 
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 
70 mg once daily 
Interrupt dose as 
recommended. 
 
Other strong CYP3A inhibitors 
Avoid concomitant use. 
If these inhibitors will be used 
short-term (such as anti-infectives 
for seven days or less), interrupt 
ibrutinib. 
 
Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents 
with less CYP3A inhibition. 
 
Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, 
indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For 
short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and 
antibiotics) consider interrupting ibrutinib therapy until the CYP3A inhibitor is no longer needed. 
 
Reduce ibrutinib dose to 280 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, 
darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, 
imatinib, verapamil, and ciprofloxacin). 
 
Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more 
closely for signs of ibrutinib toxicity. 
 
7.2.4.3 
Dose modifications for use in hepatic impairment  
 
For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg 
daily (one capsule). Avoid the use of ibrutinib in patients with moderate or severe hepatic 
impairment (Child-Pugh classes B and C). 
 
 
7.2.5 
Prohibitions and Restrictions  
The following guidance should be applied during the perioperative period for subjects who require 
surgical intervention or an invasive procedure while receiving ibrutinib: 
 
For any planned surgery or invasive procedure requiring sutures or staples for closure, 
ibrutinib should be held at least 7 days prior to the intervention 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.   


 
 
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 
For planned minor procedures (such as a central line placement, needle biopsy, 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. 
 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site 
is reasonably healed, for at least 7 days after the urgent surgical procedure, or at the discretion 
of the investigator. 
7.2.6 
Tumor Lysis Syndrome 
  
Tumor lysis syndrome has been reported with ibrutinib therapy. Monitor patients closely and take 
appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor 
burden).Additional information regarding TLS prophylaxis and management can be found in 
section 7.1.3  
 
7.3 
POTENTIAL FOR DRUG-DRUG INTERACTIONS 
 
Based on preliminary data from the combination studies of ibrutinib and venetoclax, venetoclax 
exposure (area under the concentration-time curve [AUC]) at 400 mg QD appears to be 
approximately 1.6-fold higher with 420 mg ibrutinib (chronic lymphocytic leukemia [CLL], 
N=32) and approximately 2-fold higher with 560 mg ibrutinib (mantle cell lymphoma [MCL], 
N=6) compared with venetoclax single agent exposure. 
 
Within the same dataset, ibrutinib exposures when dosed in combination with venetoclax were 
comparable to those observed at the respective therapeutic dose levels of ibrutinib single agent. 
 
To date, no new safety signals have been identified in the ongoing combination studies.  
 
Patients will be closely monitored for signs of toxicity. 
 
7.4 
RITUXIMAB  
 
7.4.1 
Rituximab Administration  
 
Investigators should refer to the package inserts for the storage and handling, and detailed 
instructions on the administration of rituximab. (MabThera (rituximab); Rituxan [prescribing 
information) It is strongly recommended that premedication guidelines are also followed per 
rituximab package insert. Rituximab is administered IV, per institutional standards, weekly X 4 
(Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses 
of Rituxan from C1D1) Commercially available rituximab IV will be used. 
 
7.5 
DRUG COMPLIANCE  
 


 
 
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Drug compliance will be monitored by recording dose administration by subjects in a diary.  The 
diary will be handed out with each new cycle and must be returned at the end of each cycle with 
the bottles of ibrutinib and venetoclax.   
 
7.6 
DISPOSAL, DESTRUCTION, AND ACCOUNTABILITY  
 
Drug destruction and accountability will be maintained by pharmacy.  Bottles of ibrutinib and 
venentoclax will be returned to pharmacy and accounted for and destroyed as per institutional 
policy. 
 
8. 
CONCOMITANT MEDICATIONS/PROCEDURES 
8.1 
CONCOMITANT MEDICATIONS  
 
 
8.1.1 
Permitted Concomitant Medications 
 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) are 
permitted. Erythropoietic growth factors (eg, erythropoietin) and hematopoietic growth factors are 
allowed per institutional policy and in accordance with the ASCO guidelines (Smith 2006). 
 
Transfusional support (packed red blood cells and platelets) may be given in accordance with 
institutional policyIf platelet transfusion is required during the DLT period, this will meet criteria 
of a DLT.  
 
Short courses (≤14 days) of steroid treatment for non-cancer-related medical reasons (eg, 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. 
 
Prophylaxis for hepatitis is permitted as per local guidelines provided no contraindicated antiviral 
medications are used. 
 
8.1.2 
Medications to be used with Caution 
 
8.1.2.1 
CYP3A4/5 Inhibiting/Inducing Drugs 
 
In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased 
Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated 
in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose 
AUC values of 1445 ± 869 ng ⋅ hr/mL which is approximately 50% greater than steady state 
exposures seen at the highest indicated dose (560 mg). 
 
Avoid concomitant administration of ibrutinib with strong or moderate inhibitors of CYP3A. For 
strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., 


 
 
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ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider 
interrupting ibrutinib therapy during the duration of inhibitor use. 
 
Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must 
be used, reduce the ibrutinib dose. Patients taking concomitant strong or moderate CYP3A4 
inhibitors should be monitored more closely for signs of ibrutinib toxicity. Avoid grapefruit and 
Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of CYP3A.  
 
Administration of ibrutinib with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and 
AUC by approximately 13- and 10-fold, respectively. 
 
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and 
St. John’s Wort). Consider alternative agents with less CYP3A induction.  
 
Please refer to USPI and IB for more information. 
 
 
8.1.2.2 
Drugs that may Have Their Plasma Concentrations Altered by 
Ibrutinib 
 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), 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. Currently, no clinical data is available; therefore, 
coadministration of narrow therapeutic index P-gp substrates (eg, digoxin) with ibrutinib may 
increase the substrate’s blood concentration and should be used with caution and subjects should 
be monitored closely for toxicity. 
 
8.1.2.3 
Concomitant Use of QT Prolonging Agents 
 
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with electrocardiograms and electrolytes should be considered. 
 
8.1.2.4 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied. 
Fatal bleeding events have occurred in patients treated with ibrutinib. Grade 3 or higher bleeding 
events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) 
have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and 
petechiae, occurred in approximately half of patients treated with ibrutinib. 


 
 
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The mechanism for the bleeding events is not well understood. 
 
Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant 
therapies. 
 
Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and postsurgery 
depending upon the type of surgery and the risk of bleeding 
 
 
8.1.3 
Prohibited Concomitant Medications 
 
Any chemotherapy, anticancer immunotherapy (besides rituximab), experimental therapy (besides 
venetoclax) or radiotherapy is prohibited while the subject is receiving study treatment. 
 
Corticosteroids for the treatment of the underlying disease is 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. See Section 8.1.2 for permitted uses. 
 
Erythropoietic and hematopoietic growth factors are also prohibited during the Phase 1b DLT 
assessment period. See Section 8.1.2 for permitted use. 
 
 
9. 
CRITERIA FOR PATIENT DISCONTINUATION 
Patients who meet the following criteria should be discontinued from the study: 
 
Disease progression, including disease transformation,  
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
Incorrect enrollment of subject 
 
Stem-cell transplant 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
o Treatment-emergent ALT or AST  3  ULN in combination with clinical 
jaundice  
 


 
 
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9.1 
GENERAL CRITERIA FOR DISCONTINUATION 
 
Inability of patient to comply with study requirements 
 
Determination by the investigator that it is no longer safe for the patient to continue 
therapy 
 
If there is evidence of a lack of efficacy associated with the experimental therapy or if 
there is sufficient evidence of efficacy to warrant phase II testing 
 
Medication may show serious adverse effects and trial may be stopped for unacceptable 
safety.  
 
Persistent abnormal laboratory results related to the trial medications.  
 
Rapid deterioration of patients secondary to primary neoplasia that would preclude the 
continuation of the systemic therapy. 
 
Patient preference to discontinue experimental treatment as well as poor compliance with 
protocol. 
 
10. 
CLINICAL AND LABORATORY EVALUATIONS 
10.1 
PRETREATMENT EVALUATIONS 
 
Pregnancy test (serum or urine) for women of childbearing potential. 
 
Medical history and documentation of the rationale for treatment of the patient's disease 
with Venetoclax, ibrutinib and rituximab.  
 
Physical examination, including vital signs, blood pressure, performance status and tumor 
assessment. 
Baseline laboratory evaluations such as : 
 
Hematology (within 2 weeks of treatment): complete blood count (CBC) with differential 
and platelet count. 
 
Serum Chemistries: glucose, BUN, creatinine, uric acid, total bilirubin, alkaline 
phosphatase, LDH, total protein, albumin, SGOT(AST), SGPT (ALT), and calcium. 
 
Baseline CT/PET, bone marrow evaluation 
 
10.2 
EVALUATIONS DURING TREATMENT 
Please refer to Study Flowchart, Appendix 1. 
 
10.3 
POST-TREATMENT EVALUATIONS 
Please refer to Study Flowchart, Appendix 1. 
 


 
 
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11. 
EVALUATION OF RESPONSE 
Preliminary efficacy of the combination of Ibrutinib, Venetoclax and Rituximab, objective tumor 
response rate (ORR) will be evaluated after 2, 4 and 6 cycles of 28 days after initiation of treatment 
and later every 3 cycles until disease progression, patient taken off study or study ends. 
 
Radiological tumor assessments (+/- 14 days): 
o Chest CT/MRI  
o Abdomen and pelvis CT/MRI scan  
o PET Scan evaluations Q2 cycles- based on investigator’s criteria. If positive at baseline, 
will be repeated to confirm CR 
o Response Evaluation using Cheson Criteria 2014 
 
The outcomes will be correlated with progression-free survival and overall survival. 
12. 
STATISTICAL CONSIDERATIONS 
The main aim of this Phase I study is determining maximum tolerated dose (MTD) among 2 doses 
of venetoclax once daily in combination with Ibrutinib/Rituximab.  The secondary aim of the study 
is to evaluate efficacy, progression-free survival and overall survival of patients in the expansion 
cohort at the determined MTD.  
 
Dose escalation part: 
 
Study Endpoints 
       
The primary endpoints for this Phase I study are to determine the MTD, safety, and toxicity of the 
combination of venetoclax in combination with ibrutinib/rituximab. For this study, cohorts of 3-6 
patients are used for each dose level.  The dose level in which 2 patients experience unacceptable 
toxicity is usually considered the MAD. We will define the MTD as the next lower dose level in 
which no more than 1/6 patients experience unacceptable toxicity. Counts (percentages) of toxicity 
events will be reported. 
 
 
Sample Size/Accrual Rate 
      
The MTD will be determined in a standard fashion using 3–6 patients per dose level. No more than 
2 dose levels will be used in order to find the MTD. As such, for the phase I escalation portion of 
the study, no more than 12 patients will be required. The Expansion cohort will be a maximum of 
24 patients. Between the dose-escalation and dose-expansion, the maximum number of subjects 
will be 30. 
 
MTD and Expansion Cohort Analysis 
 
The efficacy endpoint is progression-free survival (PFS) and overall survival (OS) of the patients 
enrolled in the expansion cohort and those treated at the MTD dose.  


 
 
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The duration of PFS is defined as the time from the beginning of the first cycle of treatment to the 
date of progressive disease or death from any cause whichever occurs first. 
The duration of OS is defined as the time from the beginning of the first cycle of treatment to the 
date of death from any cause. 
Both time-to-event variables, PFS and OS, will be estimated by the Kaplan-Meier method, 
estimates of survival in reported at 6, 12, 18, 24, 30 and 36 months and the corresponding 95% 
confidence intervals will be reported. 
Toxicity rate in the expansion cohort will be evaluated and summarized using frequency and a 
corresponding exact binomial 95% confidence interval. 
 
All subjects treated with an investigational product will be included in the analysis. 
 
DLT Definitions: 
The assessment of DLT will follow the guidelines provided in the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. A DLT is defined as: 
 
Hematologic: 
 
Grade 3 neutropenia (ANC <1,000/mm3) that does not resolve to < Grade 2 within 3 
weeks with the use of growth factor 
 
Grade 4 neutropenia (ANC <500/mm3) 
 
Febrile neutropenia (ANC <1,000/mm3 with a fever ≥38.3ºC) 
 
Grade 4 thrombocytopenia (<25,000/ mm3) that persists for ≥7 days, despite holding 
treatment 
 
Grade 3 thrombocytopenia associated with Grade ≥2 bleeding or requiring RBC or 
platelet Transfusions 
 
Non-Hematologic: 
 
Any Grade 3 or higher non-hematologic adverse event where relationship to study 
drug(s) cannot be ruled out (Note: excludes rituximab infusion reactions) 
 
Grade ≥3 nausea, vomiting, or diarrhea uncontrolled by maximal supportive care and 
persisting greater than 7 days 
 
Grade 3 fatigue persisting for greater than 7 days 
 
Treatment delay of any drug greater than 7 days for toxicity 
 
In the Dose Escalation Phase, if a subject is non-compliant with the prescribed therapy or ends 
treatment within the first cycle for reasons other than study drug(s) related toxicity, ie, withdraws 
consent, they will be replaced. Any subject that misses >4 doses of ibrutinib or venetoclax for 
reasons other than toxicity or subject that requires rituximab discontinuation during the first cycle 
will be replaced.  Replaced subjects will be included in the ITT analysis. 
 
There will be no intrapatient dose escalation. 
 
Stopping Guidelines   
 


 
 
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Based on prior studies such as the Ibrutinib–rituximab combination study by Wang et al (2016), an 
estimated rate of toxicity around 10-12% would be considered acceptable in lymphoma patients. 
Because it is a new combination adding venetoclax to ibrutinib +rituximab, there is a built-in dose 
escalation in the phase I part of the study. Regarding the expansion phase there is not yet clear data 
available to predict the toxicity profile over time. The addition of venetoclax to ibrutinib has been 
tested in mantle cell lymphoma in a rather small series with impressive activity (different 
lymphoma subtype though) with 17/24 pts experiencing grade 3 or more AE, mostly GI (diarrhea) 
and increased myelotoxicity (neutropenia but no increased infection / thrombocytopenia) 2 AFIB 
and 2 tumor lysis syndrome. All were managed with supportive care and again this was in a 
different disease setting.  
 
Given the lack of prior reference we believe that a 10% toxicity would be expected and that a 30% 
rate of cumulative related toxicity would be considered unacceptable in this population. The DSMC 
will also be monitoring the trial to review potential toxicities as per standard procedure.   
 Employing monitoring based on repeated significance testing and using O’Brien-Fleming 
boundary type boundary, for a maximum of 24 patients in the expansion cohort, 10.0% as lower 
proportion and 10% alpha level, , i.e. probability of crossing the boundary under assuming 
acceptable toxicity is 10.0%, an 80% power for the detection of crossing the boundary of high 
toxicity by at least 30%, a shape parameter, delta=0.1, the following stopping guidelines were 
computed using the Clinfun package version 1.0.15(2018) in R software(R  Foundation for 
Statistical Computing, Vienna, Austria).  
 
Table 1.  
Stopping Boundaries for Venetoclax +(Ibrutinib/Rituximab) Toxicity 
Monitoring Look 
Number 
of 
Patients 
at 
Monitoring Look 
Stop if Number of Toxicities 
is at least 
1 
5 
3 
2 
11 
4 
3 
17 
5 
4 
24 
6 
 
Table 1 shows boundary is for the experimental drug combination, Venetoclax 
+ibrutinib/rituximab), to monitor patients who experience high toxicity.  If out of the first 5 patients, 
3 or more experience high toxicity then the trial will be stopped. If at least 4 out of the first 11 
patients experience high toxicity, then the trial will be terminated. If at least 5 out of the first 17 
patients have high toxicity due to Venetoclax + (ibrutinib/rituximab), then the trial will be stopped. 
If at least 6 out of the 24 patients report high toxicity due to venetoclax + (ibrutinib/rituximab), 
then the combination will be deemed too toxic for patients with relapsed/refractory diffuse large B-
cell non-Hodgkin’s lymphoma. 
 
Table 2. Operating Characteristics of the Stopping Rule for Safety (n=24) 


 
 
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Toxicity 
Rate 
Probability of 
crossing low 
boundary 
Probability of 
stopping low 
boundary 
Expected 
sample 
size 
low 
boundary 
Probability 
of crossing 
high 
boundary 
Probability 
of stopping 
high 
boundary 
Expected 
sample 
size high 
boundary 
1 
0.100 
0.053 
0.049 
23.4 
0.047 
0.043 
23.5 
2 
0.118 
0.092 
0.086 
23.0 
0.084 
0.077 
23.2 
3 
0.136 
0.146 
0.135 
22.5 
0.135 
0.123 
22.7 
4 
0.155 
0.211 
0.196 
21.8 
0.198 
0.182 
22.1 
5 
0.173 
0.286 
0.267 
21.0 
0.272 
0.250 
21.4 
6 
0.191 
0.368 
0.344 
20.2 
0.353 
0.327 
20.5 
7 
0.209 
0.453 
0.425 
19.2 
0.438 
0.407 
19.6 
8 
0.227 
0.536 
0.506 
18.2 
0.522 
0.489 
18.6 
9 
0.245 
0.615 
0.584 
17.2 
0.602 
0.568 
17.6 
10 
0.264 
0.688 
0.657 
16.1 
0.677 
0.643 
16.6 
11 
0.282 
0.752 
0.723 
15.1 
0.743 
0.710 
15.6 
12 
0.300 
0.808 
0.781 
14.1 
0.800 
0.770 
14.6 
 
From the last the last row of the operating characteristics of the stopping rule, it is seen that when 
the probability of toxicity >0.30, the trial will be halted with power of 0.81 based on the low 
boundary with expected sample size at the termination of 14.1 patients. Based on the high 
boundary, the trial in the expansion cohort will be terminated when the probability of toxicity more 
than 0.30 with a power of 0.77 at expected sample size of 14.6. If the trial toxicity is at least 0.30, 
the probability that the trial will cross the boundaries is at least 80%. These operating characteristics 
seem reasonable to stop the trial early for safety for a moderate sample of 24 patients. 
 
 
13. 
REPORTING OF ADVERSE EVENTS 
13.1 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and reporting AEs and SAEs, including all events of 
death, pregnancy, and any study-specific issue of concern using Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 
 
All data will be collected in a timely manner and reviewed by the principal investigator and/or 
protocol chairperson every 2 weeks. In addition, there will be weekly meetings with the 
investigators, research nurse, protocol chairperson, and principal investigator to discuss patient 
issues, as well as important adverse events and trends in the data.  
 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the monitoring of hematology, blood chemistry, ECG and the regular monitoring 
of vital signs, and physical condition.  
 


 
 
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AEs, as reported throughout the course of the trial will be listed individually, per treatment group. 
Pre-, study and post-study findings of physical examination, vital sign variables, laboratory 
variables (hematology, clinical chemistry and urinalysis), and 12-lead ECG will be listed 
individually and summarized; values outside the normal range will be listed. 
13.1.1 
Adverse Events 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non- investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]) 
 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
This includes the following: 
 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with DLBCL that were not present 
prior to the AE reporting period 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
 
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 
 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 


 
 
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 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 
1.1.1. Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization 
that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the study 
must be reported as a serious adverse event, except hospitalizations for the following: 
 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons 
such as pending placement in long-term care facility) 
 
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were 
planned before the start of data collection and where the underlying condition for which the 
hospitalization was planned has not worsened will not be considered serious adverse events. Any 
adverse event that results in a prolongation of the originally planned hospitalization is to be reported 
as a new serious adverse event. 
 
1.1.2. Life-Threatening Conditions 
 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of efficacy 
will be reported if they fulfill the serious adverse event definition. 
  
13.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES  
The investigator is responsible for ensuring that all AEs and SAEs, that are observed or reported 
during the study, are collected and reported to the U.S. Food and Drug Administration (FDA), 
appropriate IRB(s), and Genentech and Janssen Scientific Affairs, LLC in accordance with Code 
of Federal Regulations (CFR) § 312.32 (IND Safety Reports).  
13.2.1 
Adverse Event Reporting Period 
Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events regardless 
of causality and special situations excluding those from subjects not exposed to a Janssen Medicinal 


 
 
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Product and product quality complaints with or without an adverse event as described in this section 
will be reported from the time a subject has signed and dated an Informed Consent Form (ICF) 
until completion of the subject’s last study-related procedure (which may include contact for 
follow-up safety).  Serious adverse events will be reported for 30 days after the last dose of study 
drug. 
 
For the purposes of this study, the Janssen medicinal product is: Ibrutinib (Imbruvica) 
 
13.2.2 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the venetoclax, 
ibrutinib and rituximab (see following guidance), and actions taken. AE Attribution to study drugs 
will be assessed based on IB known data; for those not reported in the IB, relationship assessment 
will be at PI discretion to analyze. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
the venetoclax, ibrutinib and rituximab and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 
known pattern of response to the venetoclax, ibrutinib and rituximab; and/or the AE abates 
or resolves upon discontinuation of the venetoclax, ibrutinib and rituximab or dose reduction 
and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the venetoclax, ibrutinib and 
rituximab (e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to venetoclax 
and ibrutinib administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected AEs are those AEs that are listed or characterized in the Package Insert or current 
Investigator’s Brochure.  
Unexpected AEs are those not listed in the Package Insert or current Investigator’s Brochure or not 
identified.  This includes AEs for which the specificity or severity is not consistent with the 
description in the Package Insert or Investigator’s Brochure.  For example, under this definition, 
hepatic necrosis would be unexpected if the Package Insert or Investigator’s Brochure only referred 
to elevated hepatic enzymes or hepatitis. 


 
 
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13.3 
PROCEDURES FOR ELICITING, RECORDING, AND 
REPORTING ADVERSE EVENTS  
13.3.1 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all patient evaluation timepoints should be adopted.  
Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?”  
 
13.3.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
13.3.2.1 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available.  If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
13.3.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 13.2.1), 
regardless of attribution, will be reported to the appropriate parties.  When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death.” 
13.3.2.3 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such conditions 
should be reported as medical and surgical history.  A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study.  When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
13.3.2.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be reported 
as the SAE.  For example, if a patient is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE. 


 
 
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Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions; 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study; or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
 
13.3.2.5 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior study drug exposure.  If the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female patient who participated in the study, this should be reported as an SAE.  
13.4 
ADVERSE EVENTS OF SPECIAL INTEREST  
13.4.1 
 Venetoclax 
AEs of special interest (AESIs) are defined as a potential safety problem, identified as a result of 
safety monitoring of the product. 
The following AEs are considered of special interest and must be reported to the Genentech, 
Janssen Scientific Affairs, LLC, and Abbvie expeditiously irrespective of regulatory seriousness 
criteria:  
For rituximab and venetoclax combination therapy, the AESIs are as follows: 
 
Grade  3 TLS 
 
Grade  3 infection 
 
Grade  3 elevations in AST, ALT, or serum bilirubin, OR cases of elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice 
 
Suspected transmission of an infectious agent by the study drug, as defined below:  
– 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when contamination of the study drug is suspected. 
 
13.4.2 
Ibrutinib 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC. Is actively 
monitoring as a result of a previously identified signal (even if non-serious). These adverse events 
are: 
 
Major Hemorrhage 
o Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater 
in severity or that results in 1 of the following: intraocular bleeding causing loss of 


 
 
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vision, the need for a transfusion of 2 or more units of red cells or an equivalent 
amount of whole blood, hospitalization, or prolongation of hospitalization. 
 
Intracranial Hemorrhage 
o Any 
intracranial 
hemorrhage 
adverse 
event, 
including 
subdural 
hematoma/hemorrhage, 
epidural 
hematoma/hemorrhage 
and 
intracerebral 
hemorrhage, of any grade severity, will be captured as an event of special interest. 
 
Other Malignancies  
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival. 
 
Any adverse event of special interest should be recorded on a Serious Adverse Event 
Report Form and be reported to the COMPANY within 24 hours of becoming aware of 
the event. 
 
13.4.3 
Adverse Drug Reaction (ADR) 
A noxious and unintended response to any dose of the drug (or biological) product for which there 
is a reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ means 
there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
13.4.4 
Pregnancy  
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, 
LLC/Genentech/AbbVie by the PRINCIPAL INVESTIGATOR within 24 hours of their 
knowledge of the event using the Serious Adverse Event Form. Abnormal pregnancy outcomes 
(e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study 
and discontinue further study treatment. 
 
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in partners 
of male subjects exposed to a Janssen medicinal product will be reported by the PRINCIPAL 
INVESTIGATOR within 24 hours of their knowledge of the event using the Serious Adverse 
Event Form.  Depending on local legislation this may require prior consent of the partner. 
 


 
 
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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
13.4.5 
Product Quality Complaint (PQC) 
Any discrete concern that questions the identity, quality, durability, reliability, safety, efficacy or 
intended performance of a drug product. 
 
A complaint may allege an injury or malfunction associated with the use of the drug product. It 
may also involve the design, literature, packaging, advertising, availability, physical appearance or 
promotion of the drug product. 
 
A product quality compliant is related to a potential quality issue during manufacturing, packaging, 
release testing, stability monitoring, dose preparation, storage or distribution of the product, or 
delivery system.  Not all PQCs involve a subject.  Lot and batch numbers are of high significance 
and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
 
Functional Problem: e.g., altered delivery rate in a controlled release product 
 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
 
Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, needle detaching 
from syringe 
 
Suspected Contamination 
Suspected Counterfeit. 
 
13.5 
RECORDING OF ADVERSE EVENTS 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events should 
be recorded immediately in the source document, and also in the appropriate adverse event module 
of the case report form (CRF).  Recording should be done in a concise manner using standard, 
acceptable medical terms. 
All clearly related signs, symptoms, and abnormal diagnostic procedures results should be recorded 
in the source document, though should be grouped under one diagnosis. 
 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a laboratory 
value or vital sign) but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study should also be 
recorded (a preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the procedure 
or surgery is considered an adverse event. Any event requiring in-patient hospitalization that occurs 


 
 
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during the course of a subject’s participation in a trial must be reported as an SAE. Hospitalizations 
that do not meet the criteria for SAE reporting are: 
A: 
Reasons described in the Protocol, e.g. drug administration, Protocol-required testing 
B. 
Surgery or procedure planned prior to entry into the Study. 
 
If, in the Principal Investigator’s judgment, a clinical significant worsening from baseline is 
observed in any laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), 
physical exam finding, or vital sign, a corresponding clinical adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as 
the adverse event, whenever possible.  However, a complete description of the signs, symptoms 
and investigations which led to the diagnosis should be provided. For example, if clinically 
significant elevations of liver function tests are known to be secondary to hepatitis, “hepatitis” and 
not “elevated liver function tests” should be recorded. If the cause is not known, the abnormal test 
or finding should be recorded as an adverse event, using appropriate medical terminology (e/g/ 
thrombocytopenia, peripheral edema, QT prolongation). 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.  Serious adverse events that are still ongoing at the 
end of the study period must be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately. 
 
13.6 
MAINTENANCE OF SAFETY INFORMATION 
Safety information will be maintained in a clinical database/repository in a retrievable 
format. At a minimum, at the end of the treatment phase (=”last patient off treatment”) as 
well as the end of the follow-up phase (=”last patient out”) of the Study, the 
Institution/Principal Investigator shall provide all adverse events, both serious and non-
serious, in report format. However, in certain circumstances more frequent review of the 
safety data may be necessary, e/g/ to fulfill a regulatory request, and as such the data shall 
be made available within a reasonable timeframe at Janssen Scientific Affairs’ request. 
 
13.7 
MONITORING 
Monitoring will be performed by internal methods. Ongoing monitoring of data will be 
conducted by the study team, and the protocol will be subject to auditing by the Corporate 
Compliance Office. 
 
13.8 
JTCC AT HACKENSACKUMC REPORTING: NOTIFYING THE 
FDA 
The study sponsor is required to report certain study events in an expedited fashion to the 
FDA [40].  These written notifications of adverse events are referred to as IND safety reports. The 


 
 
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following describes the safety reporting requirements by timeline for reporting and associated type 
of event: 
 
 Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug (ibrutinib, venetoclax, rituximab) 
– unexpected,  
– fatal or life-threatening,  
 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug (ibrutinib, venetoclax, rituximab) 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
13.8.1 
Additional reporting requirements 
Hackensack UMC is also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the previous 
reports 
 
J&J Medicinal Product 
. 
 
When a report contains a J&J product, an identifiable patient, and identifiable reporter, the 
following events represent Special Reporting Situations: 
 
Overdose of a Janssen medicinal product  
 
Pregnancy exposure (maternal and paternal) 
 
Exposure to a medicinal product from breastfeeding  
 
Suspected abuse/misuse of a medicinal Janssen product 
 
Inadvertent or accidental exposure to a Janssen medicinal product  
 
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen medicinal 
product 
 
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
Medication error involving a Janssen medicinal product (with or without patient exposure to 
the medicinal Johnson & Johnson product, e.g., name confusion) 
 
Suspected transmission of any infectious agent via a medicinal product. 


 
 
Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
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Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
 
an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address) 
 
an identifiable reporter (investigational site) 
 
a Janssen medicinal product 
 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
 
suspected Janssen medicinal product (doses, indication) 
 
date of therapy (start and end date, if available) 
 
batch or lot number, if available 
 
subject details (subject ID and country) 
 
gender 
 
age at AE onset 
 
reporter ID 
 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
 
Janssen protocol ID 
 
 
 
13.8.2 
Transmission Methods: 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Non-
Janssen Medicinal Products  
 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the 
appropriate regulatory/competent authority or the manufacturer of that medicinal product (in 
the absence of appropriate local legislation) as soon as possible. 
 
Transmission Methods 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
 
Electronically via Janssen SECURE Email service (preferred) IIS-BIO-VIRO-
GCO@its.jnj.com 
 
For business continuity purposes, if SECURE Email is non-functional: to 1-866-451-0371 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific 
Affairs, LLC 
 


 
 
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13.9 
MANAGEMENT OF ADVERSE EVENTS, SERIOUS ADVERSE 
EVENTS AND SPECIAL REPORTING SITUATIONS 
In general, the Institution/Principal Investigator must immediately report to Janssen Scientific 
Affairs any serious adverse event and Special Reporting Situations, whether or not considered drug 
related. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g., death as a result of anaphylactic reaction or fatal hepatic necrosis). In 
that case, the investigator must immediately report the event to Janssen Scientific Affairs. The 
Institution/Principal Investigator must record non-serious adverse events and report them to 
Janssen Scientific Affairs according to the timetable for reporting as specified either in the protocol 
or to fulfill regulatory reporting requirements. 
 
For each subject, AEs SAEs, and Special Reporting Situations should be recorded after informed 
consent is obtained until the subject has completed participation in the study as follows: 
 
A Serious Adverse event or Special Reporting Situations must be reported if it occurs during a 
subject’s participation in the Study (whether receiving Study Product or not) and within 30 days of 
receiving the last dose of Study Product. 
 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject completes 
his/her participation in the Study must be followed until any of the following occurs: 
 
The event resolves or stabilizes; 
 
The event returns to baseline condition or value (if a baseline value is available); 
 
The event can be attributed to agents(s) other than the Study Product, or to factors unrelated 
to Study conduct. 
 
13.9.1 
Procedures for Reporting Adverse Events (AE), Serious Adverse 
Events (SAE), Pregnancies, Special Reporting Situation, and Product 
Quality Complaints (PQCs) to Janssen Scientific Affairs 
All adverse events and special situations, whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to a Janssen medicinal product.  
 
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed-up in accordance with clinical practice. 
 
A: 
Serious Adverse Events (SAE), Adverse Events of Special Interest, Pregnancies, and 
Special Reporting Situations 
 


 
 
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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: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
The PRINCIPAL INVESTIGATOR will transmit all SAEs, Adverse Events of Special Interest and 
special situations following exposure to a Janssen product under study in a form provided by 
Janssen Scientific Affairs, LLC in accordance with defined Transmission Methods, in English 
within 24-hours of becoming aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an unblinded SAE 
or pregnancy exposure report to Janssen Scientific Affairs, LLC. 
 
All follow-up information for serious adverse events that are not resolved at the end of the study or 
by the time of patient withdrawal must be reported directly by the PRINCIPAL INVESTIGATOR, 
within 24 hours becoming aware, to Janssen Scientific Affairs, LLC using the Janssen Scientific 
Affairs, LLC Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE, Adverse Events of 
Special Interest, serious ADR or special situation is required. 
 
 
The PRINCIPAL INVESTIGATOR is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not considered 
complete until all clinical details needed to interpret the case are received. Reporting 
of follow-up information should follow the same timeline as initial reports. 
 
 
Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association 
with the Janssen Product under study, are to be provided to Janssen Scientific Affairs, 
LLC within 24 hours of such report or correspondence being sent to applicable 
health authorities. 
 
Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according to 
the timeframe outlined in the Research Funding Agreement section entitled Reporting of Data. 
 


 
 
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B. 
Product Quality Complaints 
 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
patients, investigators, and Janssen Scientific Affairs, LLC, and are mandated by regulatory 
agencies worldwide. Janssen Scientific Affairs, LLC has established procedures in conformity with 
regulatory requirements worldwide to ensure appropriate reporting of PQC information. Lot and/or 
Batch #s shall be collected or any reports failure of expected pharmacological action (i.e., lack of 
effect). The product should be quarantined immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen 
Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR within 24 hours after being made 
aware of the event. The Janssen contact will provide additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a serious adverse 
event or non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the PQC to 
Janssen Scientific Affairs, LLC according to the serious adverse event reporting timelines.  A 
sample of the suspected product should be maintained for further investigation if requested by 
Janssen Scientific Affairs, LLC. 
 
13.9.2 
 Procedures for Reporting Adverse Events (AE), Serious Adverse Events 
(SAE), Pregnancies, Special Reporting Situation, and Product Quality 
Complaints (PQCs) to Genentech 
SAFETY REPORTING OF ADVERSE EVENTS 
ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol.  This includes all events of death, and any study specific 
issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
This includes the following: 
 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with DLBCL that were not 
present prior to the AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 


 
 
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 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period.  
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
 
It requires or prolongs inpatient hospitalization. 
 
It 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). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. 
in accordance with CFR 312.32 (IND Safety Reports).  
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only 
report SAEs that are attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the {study drug} 
(see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of the 
{study drug}, and the AE cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to the {study 


 
 
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drug}; and/or the AE abates or resolves upon discontinuation of the {study drug} or dose 
reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to {study drug} administration (e.g., cancer diagnosed 2 days 
after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B).  
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section I), regardless 
of attribution, will be reported to the appropriate parties. When recording a death, the event or 
condition that caused or contributed to the fatal outcome should be reported as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
report “Unexplained Death”. 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 


 
 
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to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass surgery, 
record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
e. Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 12 months after the 
last dose of study drug (or if the female partner of a male study subject becomes pregnant while 
the study subject is receiving the study drug or within 12 months after the last dose of study 
drug), a report should be completed and expeditiously submitted to Genentech, Inc. Follow-up to 
obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, therapeutic, 
or spontaneous, should always be classified as serious, and expeditiously reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to the 
{study drug} should be reported as an SAE. 
 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior {study drug} exposure. If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this should be reported as 
an SAE.  
 
g.   Case Transmission Verification of Single Case Reports 
 
The Sponsor agrees to conduct  the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech  via the Sponsor  emailing Genentech a 
Quarterly line-listing documenting single case reports sent by the Sponsor to Genentech in the 
preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period mutually 
agreed upon. 
                    
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
 


 
 
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Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by the Sponsor to Genentech within five (5) calendar days from 
request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report 
will be sent to Genentech 
 
 
h.   AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product  
 
The following AEs are considered of special interest and must be reported to the Genentech Drug 
Safety expeditiously, irrespective of regulatory seriousness criteria: 
The Venetoclax Events of Special Interest are: 
            Tumor Lysis Syndrome (any grade) 
No Adverse Events of Special Interest specific only to Rituximab 
Adverse Events of Special Interest common to Venetoclax and Rituximab (non-drug specific) 
          Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
o 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice  
            Suspected transmission of an infectious agent by the study drug, as defined below: 
–           Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  A 
transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  This term applies 
only when contamination of the study drug is suspected. 
I.  Adverse Event Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. The 
completed MedWatch/case report should be faxed immediately upon completion to Genentech 
Drug Safety at: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available and/or upon request 


 
 
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Serious adverse events (SAEs), pregnancy reports (including pregnancy occurring in the partner 
of a male study subject) and AEs of special interest (AESIs), where the patient has been exposed 
to the Product, will be sent on a MedWatch or CIOMS I form to the Genentech Drug Safety. 
Transmission of these reports (initial and follow-up) will be either electronically or by fax and 
within the timelines specified below:] 
 
SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech within 
fifteen (15) calendar days of the awareness date. 
 
 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. 
 
 
Pregnancy reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports of 
pregnancy, where the fetus may have been exposed to the Product, shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be 
followed up until the outcome of the pregnancy is known, whenever possible, based upon 
due diligence taken to obtain the follow-up information. 
 
 
AESIs  
 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the 
awareness date 
 
 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech even in the absence of an Adverse Event within 
thirty (30) calendar days: 
 
 
Data related to the Product usage during pregnancy or breastfeeding 
 
Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous administration, 
medication error or occupational exposure, with or without association with an AE/SAE 
unless otherwise specified in the protocol 
 
Lack of therapeutic efficacy 
 
Drug interaction 
 
Use of a Medicinal Product in a Pediatric and Elderly population (in addition, reasonable 
attempts should be made to obtain and submit the age or age group of the patient, in order to 
be able to identify potential safety signals specific to a particular population) 
 
In addition, reasonable attempts should made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population 
 
j.   Aggregate Reports 
 
Dr. Andre Goy, Sponsor-Investigator, at the John Theurer Cancer Center at Hackensack 
University Medical Center will forward a copy of the Final Study Report to Genentech upon 
completion of the Study; will forward periodically listings of non-serious AEs originating from 


 
 
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the Study to Genentech; and will forward a copy of the Publication to Genentech upon 
completion of the Study.  
 
Note: Investigators should also report events to their IRB as required. 
 
Additional Reporting Requirements for IND Holders (if applicable): For Investigator-Initiated 
IND Studies, some additional reporting requirements for the FDA apply in accordance with the 
guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
 7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of Venetoclax and/or 
Rituximab. An unexpected adverse event is one that is not already described in the Venetoclax 
and/or Rituximab Investigator Brochure. Such reports are to be telephoned or faxed to the FDA 
and Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of Venetoclax and/or Rituimab. An unexpected adverse event is one that is not 
already described in the Venetoclax and/or Rituximab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter) 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed 
to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630  
And to the Site IRB: 
HackesackUMC IRB 
Hackensack University Medical Center 
40 Prospect Avenue, Suite #224 
Hackensack, NJ 07601 
 


 
 
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For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-4630 and emailed to Genentech Drug Safety 
CTV mail box: ctvist_drugsafety@gene.com 
 
 
13.10 
MEDWATCH 3500A REPORTING GUIDELINES 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
13.10.1.1 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or 
follow-up information is being submitted (The patient identifiers are important so 
that the new information is added to the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
13.11 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech and Janssen Scientific Affairs, LLC.  This includes all IND annual reports and the 
Clinical Study Report (final study report).  Additionally, any literature articles that are a result of 


 
 
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the study should be sent to Genentech.  Copies of such reports should be mailed to the assigned 
Clinical Operations contact for the study: 
Venetoclax Protocols 
Genentech Clinical Operations 
Email:  ga101-gsur@gene.com 
Fax:  (866) 706-3927 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
QUERIES 
 
Queries related to the Study will be answered by the Sponsor. However,  responses  
to  all  safety  queries  from  regulatory  authorities  or  for publications will be 
discussed and coordinated between the Parties. The Parties agree that 
Genentech/Roche shall have the final say and control over safety queries relating to 
the Product. The Sponsor agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Product independently but 
shall redirect such queries to Genentech/Roche. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The Parties will clearly indicate on the request the reason 
for urgency and the date by which a response is required. 
 
SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or 
regulatory actions that limit or restrict the way in which the Product is used, or 
where there is media involvement, the Party where the crisis originates will contact 
the other Party as soon as possible. 
 
The Parties agree that Genentech/Roche shall have the final say and control over 
safety crisis management issues relating to the Product. The Sponsor agrees that it 
shall not answer such queries from media and other sources relating to the Product 
but shall redirect such queries to Genentech/Roche. 
 
 
 
Janssen Scientific Affairs: 
Lauren Ey at ley@its.jnj.com and Patricia Corbin at IIS-BIO-VIRO-GCO@its.jnj.com.   


 
 
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14. 
STUDY ADMINISTRATION AND INVESTIGATOR 
RESPONSIBILITIES 
14.1 
ETHICS AND GOOD CLINICAL PRACTICE 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
 
14.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by Hackensack Institutional Review Board (IRB). A 
signed and dated statement that the protocol and informed consent have been approved by the IRB 
must be given to Genentech, Abbvie and to Janssen Scientific Affairs, LLC before study initiation. 
The name and occupation of the chairman and the members of the IRB/IEC/REB must be supplied 
to Genentech, Abbvie and Janssen. Any amendments to the protocol, other than administrative 
ones, must be approved by this committee. 
 
14.3 
INFORMED CONSENT 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that participation 
in the study is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical treatment or relationship with the 
treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient could 


 
 
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not read or sign the documents. No patient can enter the study before his/her informed consent has 
been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval.  
Fertile men and women of child bearing potential should be informed that taking the study 
medication may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the contraception 
requirement for the duration of the study. There also might be the risk of decreased 
spermatogenesis.  If there is any question that the patient will not reliably comply, they should not 
be entered in the study. 
14.4 
AMENDMENTS TO THE PROTOCOL 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Genentech, Abbvie and Janssen Scientific Affairs, LLC and the investigator before 
implementation. Amendments significantly affecting the safety of subjects, the scope of the 
investigation or the scientific quality of the study, require additional approval by the IRB. A copy 
of the written approval of the IRB, must be sent to Genentech, Abbvie and Janssen Scientific 
Affairs, LLC. 
 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB of each center must be kept informed of such 
administrative changes.  
 
14.5 
PUBLICATION OF RESULTS 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Genentech, Abbvie and Janssen Scientific Affairs, LLC and prior to any outside 
submission.  Genentech, AbbVie and Janssen Scientific Affairs, LLC must receive copies of any 
intended communication in advance of publication (at least sixty working days). Principal 
Investigator/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the interests of 
Genentech, Abbvie and Janssen Scientific Affairs, LLC and, in accord with the trial contract and 
shall not permit disclosure of Genentech, Abbvie and Janssen Scientific Affairs, LLC confidential 
or proprietary information. 


 
 
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14.6 
DATA HANDLING AND RECORD KEEPING 
14.6.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
 
14.6.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
14.6.3 
Case Report Forms 
The study case report form (CRF) on Velos is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”. Velos eResearch will be 
the eCRF system to capture the data for this study. 
 
14.6.4 
Retention of Records 
U.S. FDA regulations (21 CFR § 312.62[c]) and the International Conference on Harmonisation 
(ICH) Guideline for Good Clinical Practice (GCP; see Section 4.9 of the guideline) require that 
records and documents pertaining to the conduct of clinical trials and the distribution of 
investigational drug, patient records, consent forms, laboratory test results, and medication 


 
 
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inventory records, must be retained for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational product.  All state and local laws for retention of records also 
apply.  
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must comply 
with the record retention requirements set forth in the FDA IND regulations and the relevant 
national and local health authorities, whichever is longer. 
14.6.5 
Data 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 Phase I or 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 reviewed 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 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 


 
 
Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
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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.   
 
15. 
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Ivanova A, Qaqish BF and Schell MJ. (2005). Continuous Toxicity Monitoring in Phase II Trials 
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Jennison C and Turnbull BW. (2000). Group Sequential Methods with Applications to Clinical 
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Matutes E, Polliack A. Morphological and immunophenotypic features of chronic lymphocytic 
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Oldereid NB, Angelis PD, Wiger R, et al. Expression of Bcl-2 proteins and spontaneous apoptosis 
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Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like 
chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with 
good-prognosis diffuse large-B-cell lymphoma: a randomized controlled trial by the MabThera 
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Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary 
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Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 
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Sugiyama N, Obinata M, Matsui Y. Bcl-2 inhibits apoptosis of spermatogonia and growth of 
spermatogonial stem cell in a cell-intrinsic manner. Mol Reprod Dev 2001;58:308. 
Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly 
diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008;49:4956. 
Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in combination with chop 
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Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-
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Wang ML, Lee H, Chuang H, Wagner-Bartak N, Hagemeister F, Westin J, Fayad L, Samaniego 
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Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-
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Yancik R. Cancer burden in the aged: an epidemiologic and demographic overview. Cancer 
1997;80(7):127383.


 
 
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Appendix 1  
Study Flowchart 
 
Screening 
Treatment Period  
Study 
Completion/Early 
Term Visit 
 
Follow-Up (36 mos after 
enrollment)  
 
Cycle 1 
Cycles  2 and 3 
Cycles 4 -
24 
 
Disease 
Follow up 
Survival 
Follow up  
Day * 
-28 to -1 
1 
2 
3 
8 
15 
22 
1 
15 
1 
30 days post last 
dose 
Q3 months 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria review a 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
General med history & baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs b 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Weight & height c 
x 
x 
x 
 
 
 
 
x 
 
x 
x 
x 
 
Physical examination 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG Performance Status 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
Laboratory tests  
Hematology d, m 
x 
xm 
xm 
xm 
x 
x 
x 
x 
x 
x 
x 
x 
 
Chemistry e, m 
x 
xm 
xm 
xm 
x 
x 
x 
x 
x 
x 
x 
x 
 
12- Lead ECG 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
Hepatitis Serologies f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Radiology h, j, k 
       x h, j, k 
 
 
 
 
 
 
x h, j, k 
 
x h, j, k 
x h, j, k 
 
 
Bone Marrow Aspiration/Biopsy i 
x 
To confirm CR for patients with baseline bone marrow involvement 
 
 
Drug administration 
 
Dispense Ibrutinib 
 
Dispense on Cycle 1 Day 2 then day 1 of each subsequent cycle; continuous daily dosing 
until disease progression or toxicity or decision of stem cell transplantation if applicable 
(with 24 cycles max of treatment) 
 
 


 
 
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Screening 
Treatment Period  
Study 
Completion/Early 
Term Visit 
 
Follow-Up (36 mos after 
enrollment)  
 
Cycle 1 
Cycles  2 and 3 
Cycles 4 -
24 
 
Disease 
Follow up 
Survival 
Follow up  
Day * 
-28 to -1 
1 
2 
3 
8 
15 
22 
1 
15 
1 
30 days post last 
dose 
Q3 months 
Dispense venetoclax 
 
Dispense on Cycle 1 Day 2 then day 1 of each subsequent cycle; continuous daily dosing 
until disease progression or toxicity or decision of stem cell transplantation if applicable 
(with 24 cycles max of treatment) 
 
 
Administer Rituximab 
 
Administer weekly x 4 (cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle 
until C24 (total 18 doses). 
 
 
Response assessment j 
 
Post Cycle 2, 4 and 6  (+/- 14 days); Q3 cycles until disease progression and at study 
completion. 
 
 
Concomitant medications 
Continuous Monitoring  
 
 
Adverse events 
Continuous Monitoring  
 
 
Survival visit or phone call 
 
x 


 
 
Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
91 
 
Screening 
Treatment Period  
Study 
Completion/Early 
Term Visit 
 
Follow-Up (36 mos after 
enrollment)  
 
Cycle 1 
Cycles  2 and 3 
Cycles 4 -
24 
 
Disease 
Follow up 
Survival 
Follow up  
Day * 
-28 to -1 
1 
2 
3 
8 
15 
22 
1 
15 
1 
30 days post last 
dose 
Q3 months 
 
*      All visits +/- 3 days (except for survival follow –up) 
a Confirm eligibility criteria; complete eligibility worksheet with PI/Sub I signature 
b   Heart rate, systolic and diastolic blood pressure and temperature. 
c Weight at Cycle 1 Day 1 should be used for dose calculations for all cycles, unless there is a > 10% change. If a weight change >10 % occurs, recalculate BSA. 
Weight should be done every cycle D1. 
d   Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count (neutrophils, bands, eosinophils, lymphocytes, 
monocytes, basophils, other cells). 
e Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, ALT, 
AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid. During treatment phase, perform mini chem or as clinically indicated. 
f   All patients must be screened for hepatitis B infection before starting treatment. Carriers of Hep B with active HBV infection should be recommended 
prophylaxis to prevent reactivation and monitored accordingly for several months after rituximab treatment and should be managed as indicated.  
g   Only for women of child-bearing potential; Please note that female patients of reproductive potential who are not surgically sterile must practice adequate birth      
control for a minimum of twelve months post-treatment; male patients who are not surgically sterile must practice adequate birth control for 3 months after 
venetoclax and 12 months after Rituxan. 
h    Radiology includes: CT Chest/Abdomen/Pelvis for staging of disease and PET scan; Neck CT to be followed if clinically indicated. 
i    Perform baseline bone marrow analysis less than or equal to 42 days before first dose of study drug. BM evaluation should also be performed during the study for 
confirmation of CR within 6 weeks of initial documentation of CR by other assessments for patients with a positive screening bone marrow. 
j    Physician will access disease status post cycle 2, 4, and 6 and then every 3 cycles (+/- 14 days ) until PD, subject withdrawal, death, study is terminated, or until 
2 years after the last patient has been enrolled.  
k    PET and CT (CT neck if clinically indicated at screening) during screening (at baseline) Q2 cycles during treatment (post cycle 2, 4 and 6) – CT and PET to be 
done separately ; if PET/CT done during screening (at baseline) repeat CT only. PET repeated at time points at investigator’s discretion. PET can be repeated to 
confirm CR if baseline PET was positive.  
l  - Follow up: During disease follow up, patients will be seen by MD and disease evaluations will be done until PD, subject withdrawal, death, study is terminated 
or 36 months after enrollment is reached. Survival follow up (after PD), patients will be followed for survival until death or subject withdrawal or study is 
terminated 
m- hematology and complete chemistry as listed in e at 8 hrs (+/- 30 min) and 24 hrs (+/- 2 hrs) post-1st dose of venetoclax.  


 
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Appendix 2  
Calculation of Creatinine Clearance Using the Cockcroft-Gault 
Formula 
 
Creatinine Clearance (men)  (140-Age)   Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
 
Creatinine Clearance (women)  0.85  (140-Age)   Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
 
 
Reference: Cockcroft DW, Gault HM. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976; 16:31-41


 
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Appendix 3  
Safety Reporting Fax Cover Sheet 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No:  
 
Alternate Fax No:  (650) 238-6067 
 
 
Genentech Study Number 
ML30063 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
Version 2 Effective 14-Jan-2016 


 
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Appendix 4  
Inhibitors and Inducers of CYP3A 
 
Examples of inhibitors and inducers of CYP3A can be found at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/  and 
http://www.pharmacologyweekly.com/content/pages/online-drug-therapy-tables. 
 
The list below reflects information obtained from the Indiana University, Division of Clinical 
Pharmacology, Indianapolis, IN website on July 2013. 
 
 
 
 
Inhibitors of CYP3A 
 
Strong inhibitors: 
All other inhibitors: 
INDINAVIR  
amiodarone 
NELFINAVIR  
NOT azithromycina 
RITONAVIR  
chloramphenicol 
CLARITHROMYCIN  
boceprevir 
ITRACONAZOLE  
ciprofloxacin 
KETOCONAZOLE  
delaviridine 
NEFAZODONE  
diethyl-dithiocarbamate 
SAQUINAVIR  
fluoxetine-metabolite norfluoxetine 
TELITHROMYCIN  
fluvoxamine 
 
gestodene 
Moderate inhibitors:  
imatinib 
Aprepitant 
mibefradil 
erythromycin  
mifepristone 
diltiazem  
norfloxacin 
fluconazole 
norfluoxetine 
grapefruit juice  
star fruit 
Seville orange juice  
telaprevir 
verapamil  
troleandomycin 
 
voriconazole 
Weak inhibitors:  
 
cimetidine 
 
 
 
 


 
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Appendix 5  
RECOMMENDATIONS FOR INITIAL MANAGEMENT OF ELECTROLYTE 
IMBALANCES AND PREVENTION OF TUMOR LYSIS SYNDROME IN THE 
SETTING OF TREATMENT WITH VENETOCLAX 
FIRST DOSE OF VENETOCLAX OR DOSE INCREASE 
 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 GDC-0199 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 1/2 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, phosphorus, 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 
responsesrequired. If a diagnosis of TLS is established, ongoing intensive monitoring 
and multi-disciplinary management will be as per institutional protocols. 
 


 
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Protocol 54179060LYM1004/ML30063 Version 03 dated 12 October 2018 
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ONGOING DOSING OF VENETOCLAX 
Management of electrolyte changes from last value at intervals > 24 hours after 
eitherthe first dose or dose increase (e.g., 48 or 72 hours) are as stated below. 
Note: If thepatient is hospitalized, no additional GDC-0199 doses should be 
administered until resolution. 
 For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level 
> upper limit of normal. 
 Refer to the management guidelines for electrolyte changes observed within 
 the first 24 hours after either the first dose or dose increase (table above). 
 If a smaller potassium increase is observed that does not meet the criteria for 
 admission above, recheck potassium, phosphorus, uric acid, calcium, and creatinine 
 in 24 hours and confirm no evidence of tumor lysis prior to further GDC-0199 dosing. 
 For uric acid, calcium, phosphorus, and creatinine, refer to the management 
 guidelines for electrolyte changes observed within the first 24 hours after either the 
first dose or dose increase (table above) 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 6 
The Lugano Classification for Response Assessment of Non-Hodgkin 
Lymphoma 
 
 
 
 
 
 
 
 


 
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As published by Cheson et al, JCO August 11, 2014