Clinical trial NCT03583424
Conditions: Hematopoietic Cell Transplantation Recipient Recurrent Diffuse Large B-Cell Lymphoma Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Non-Hodgkin Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Follicular Lymphoma Refractory Marginal Zone Lymphoma Refractory Non-Hodgkin Lymphoma Refractory Transformed Indolent Non-Hodgkin Lymphoma
Sponsor: Ohio State University Comprehensive Cancer Center
Start date: 2018-09-10; Completion date: 2021-09-30
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of venetoclax when given together with carmustine, etoposide, cytarabine, and melphalan before stem cell transplant in treating participants with non-Hodgkin lymphoma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as venetoclax, carmustine, etoposide, cytarabine, and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of venetoclax that can be safely combined with carmustine, etoposide, cytarabine, and melphalan (BEAM) prior to autologous stem cell transplant which will the recommended phase II dose (RP2D).

II. Determine the safety and efficacy of venetoclax as measured by overall response rate (ORR) at day 100, 12-month survival and freedom from relapse (FFR-12).

SECONDARY OBJECTIVES:

I. Long term effects (progression-free survival \[PFS\] and overall survival \[OS\]) of addition of venetoclax to BEAM.

II. Correlation of response and survival with expression of BCL-2, BCL-XL, and MCL-1 as measured by immunohistochemistry (IHC).

OUTLINE: This is a dose-escalation study of venetoclax.

Participants receive venetoclax orally (PO) once daily (QD) on days -10 to -1, carmustine intravenously (IV) on day -6, etoposide IV twice daily (BID) on days -5 to -2, cytarabine IV BID on days -5 to -2, and melphalan IV on day -1. Participants then undergo hematopoietic stem cell transplantation on day 0.

After completion of study treatment, participants are followed up for 2 years.

Arms: arm 1: Participants receive venetoclax PO QD on days -10 to -1, carmustine IV on day -6, etoposide IV BID on days -5 to -2, cytarabine IV BID on days -5 to -2, and melphalan IV on day -1. Participants then undergo hematopoietic cell transplantation on day 0.
Interventions: intervention 1: Carmustine intervention 2: Cytarabine intervention 3: Etoposide intervention 4: Hematopoietic Cell Transplantation intervention 5: Melphalan intervention 6: Venetoclax
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo hematopoietic cell transplantation intervention 5: Given IV intervention 6: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
  
 
IRB Approval Date: 12/09/2020 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Study Title: A phase I, open-label, dose-escalation study of Venetoclax and BEAM 
conditioning followed by autologous stem cell transplantation for patients with relapsed, 
refractory, or high-risk non-Hodgkin lymphoma 
 
IRB Protocol Number:  
2018C0087 
 
Protocol Version: 
Version 5.0 
Protocol Date: 
December 2, 2020 
 
Study Phase: 
Phase I 
 
Agents: 
Venetoclax Supplier: Commercial 
Carmustine  Supplier: Commercial 
Etoposide  
Supplier: Commercial 
Cytarabine  Supplier: Commercial 
Melphalan  Supplier:     Commercial 
 
ClinicalTrials.gov 
Identifier: 
NCT03583424 
 
Corresponding 
Organization: 
The Ohio State University 
 
Coordinating Center: 
The Ohio State University 


  
 
IRB Approval Date: 12/09/2020 
 
STUDY PERSONNEL 
PRINCIPAL INVESTIGATOR: 
Kami Maddocks, MD 
The Ohio State Wexner Medical Center 
The James Cancer Center and Solove Research Institute 
460 W 10th Ave 
Columbus, OH 43210 
Phone: (614) 293 - 3196 
  Kami.Maddocks@osumc.edu 
SPONSOR: 
OSU-CCC The James Cancer Center and Solove Research Institute 
 
 
TEST PRODUCTS: 
Venetoclax (ABT-199, GDC-0199, RO5537382) 


  
 
IRB Approval Date: 12/09/2020 
 
Contents 
CLINICAL STUDY PROTOCOL ....................................................................................... 1 
IRB Protocol Number:   2018C0087 .............................................................................. 1 
ClinicalTrials.gov.............................................................................................................. 1 
STUDY PERSONNEL ......................................................................................................... 2 
PRINCIPAL INVESTIGATOR: ...................................................................................... 2 
SPONSOR: ....................................................................................................................... 2 
TEST PRODUCTS: .......................................................................................................... 2 
LIST OF ABBREVIATIONS ............................................................................................... 7 
1 
PROTOCOL SYNOPSIS: ............................................................................................ 8 
1.1 
Summary ................................................................................................................ 8 
1.2 
Hypotheses: ............................................................................................................ 8 
1.3 
Objectives: .............................................................................................................. 8 
1.3.1  Primary Objectives: ................................................................................................ 8 
1.3.2  Secondary Objectives: ............................................................................................ 8 
1.3.3  Optional Exploratory objectives ............................................................................. 8 
1.4 
Trial Design ............................................................................................................ 8 
2 
INTRODUCTION ...................................................................................................... 11 
2.1 
High-dose chemotherapy and ASCT for relapsed/refractory NHL ...................... 11 
2.2 
Venetoclax (ABT-199, GDC-0199) ..................................................................... 11 
2.2.1  Pharmacology ....................................................................................................... 11 
2.2.2  Pharmacokinetics and pre-clinical toxicology ..................................................... 12 
2.2.3  Clinical Safety and Pharmacology ....................................................................... 14 
2.2.4  Clinical Experience with Venetoclax ................................................................... 15 
2.2.5  Clinical Experience with Venetoclax in Lymphomas .......................................... 15 
2.3 
Rationale ............................................................................................................... 17 
2.4 
Background and rationale of secondary and exploratory objectives .................... 18 
3 
OBJECTIVES ............................................................................................................. 18 
3.1 
Primary Objectives: .............................................................................................. 18 
3.2 
Secondary Objectives: .......................................................................................... 18 
3.3 
Optional Exploratory objectives ........................................................................... 18 
4 
INCLUSION AND EXCLUSION CRITERIA .......................................................... 19 
4.1 
Inclusion Criteria .................................................................................................. 19 


  
 
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4.2 
Exclusion Criteria ................................................................................................. 19 
5 
STUDY DESIGN ........................................................................................................ 20 
5.1 
Summary .............................................................................................................. 20 
5.2 
Treatment Regimen Overview ............................................................................. 20 
5.2.1  Screening Evaluation ............................................................................................ 20 
5.2.2  Before starting venetoclax and BEAM ................................................................ 21 
5.2.3  During transplant (T-6 through hospital discharge) ............................................. 21 
5.2.4  Day +30, +60, and +100 visit (+/- 7 days) ........................................................... 21 
5.2.5  Follow-up during first year post-ASCT (q3 months +/- 7 days) .......................... 21 
5.2.6  First Annual visit post-ASCT (+/- 7 days) ........................................................... 21 
5.2.7  Study Schema / Calendar ..................................................................................... 22 
5.2.8  Drug administration and schedule ........................................................................ 24 
5.2.9  Dosing cohorts ...................................................................................................... 25 
5.2.10 Phase I Dose Escalation ....................................................................................... 25 
5.3 
Definition of Dose-Limiting Toxicity (DLTs) ..................................................... 25 
5.4 
Hematopoietic Stem Cell Collection .................................................................... 26 
5.5 
Venetoclax Administration .................................................................................. 26 
5.6 
Body surface area calculation............................................................................... 27 
5.7 
Administration of BEAM high-dose regimen ...................................................... 27 
5.8 
Hematopoietic Stem Cell Infusion ....................................................................... 27 
5.9 
Concomitant Medications and Supportive Care Guidelines ................................ 27 
5.10  Criteria for Removal from Study ......................................................................... 28 
5.11  Duration of Follow Up ......................................................................................... 28 
5.12  Dose Delays/Dose Modifications ......................................................................... 28 
5.13  Dose Adjustments for Changes in BSA ............................................................... 28 
5.14  Missed or Vomited Doses .................................................................................... 28 
5.15  Number of Subjects .............................................................................................. 28 
5.16  Expected Duration of Treatment and Subject Participation ................................. 28 
5.17  Subject Selection .................................................................................................. 29 
5.18  Inclusion of Women and Minorities ..................................................................... 29 
6 
STATISTICAL ANALYSIS ...................................................................................... 29 
6.1 
Primary End Points ............................................................................................... 29 
6.2 
Secondary End Points ........................................................................................... 29 
6.3 
Sample Size .......................................................................................................... 29 


  
 
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6.4 
Stopping Rules ..................................................................................................... 30 
6.5 
Evaluable Patients ................................................................................................ 30 
6.6 
Analysis of Primary Endpoint .............................................................................. 30 
6.7 
Analysis of Secondary Endpoints ........................................................................ 30 
6.8 
Optional Correlative Outcomes ............................................................................ 31 
6.9 
Expected Accrual ................................................................................................. 31 
7 
POTENTIAL RISKS .................................................................................................. 31 
7.1 
Potential Risks of venetoclax ............................................................................... 31 
7.2 
Potential Risks of stem cell mobilization with filgrastim .................................... 33 
7.3 
Potential Risks of stem cell collection ................................................................. 33 
7.4 
Potential Risks of autologous stem cell transplantation (ASCT) ......................... 34 
7.5 
Potential Risks of Carmustine (BCNU) ............................................................... 34 
7.6 
Potential Risks of Etoposide (VP-16) .................................................................. 34 
7.7 
Potential Risks of Cytarabine (Ara-C) ................................................................. 34 
7.8 
Potential Risks of Melphalan ............................................................................... 34 
8 
SAFETY AND REPORTING REQUIREMENTS .................................................... 35 
8.1 
Assessment of safety ............................................................................................ 35 
8.2 
Definitions ............................................................................................................ 35 
8.2.1  Adverse event ....................................................................................................... 35 
8.2.2  Serious Adverse Events ........................................................................................ 35 
8.2.3  Suspected Adverse Reaction ................................................................................ 36 
8.2.4  Unexpected ........................................................................................................... 36 
8.3 
Adverse Event Evaluation .................................................................................... 36 
8.4 
SAE Report Form ................................................................................................. 37 
8.5 
Reporting Procedures for Serious Adverse Events .............................................. 37 
8.6 
SAE Reporting Requirements .............................................................................. 37 
8.7 
SAE of Special Interest ........................................................................................ 38 
8.8 
Data Safety and Toxicity Committee ................................................................... 38 
8.9 
Data and Safety Monitoring Plan (DSMP) .......................................................... 38 
8.10 
Ethical Considerations .......................................................................................... 38 
8.11 
Retention of records ............................................................................................. 38 
8.12 
PHARMACEUTICAL INFORMATION ............................................................ 39 
9 
INVESTIGATIONAL AGENTS ................................................................................ 39 
9.1 
Venetoclax ............................................................................................................ 39 


  
 
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9.1.1  Nomenclature ....................................................................................................... 39 
9.1.2  Structural formula ................................................................................................ 39 
9.1.3  Molecular Formula and Molecular Weight .......................................................... 39 
9.1.4  Physical and Chemical Properties of the Drug Substance ................................... 39 
9.1.5  Pharmaceutical properties (Formulation) ............................................................. 40 
9.1.6  Storage and Handling ........................................................................................... 40 
9.2 
Commercial Agents .............................................................................................. 40 
9.2.1  Filgrastim ............................................................................................................. 40 
9.2.2  BCNU (bis-chloronitrosourea or carmustine) Other Names: Carmustine ............ 41 
9.2.3  Etoposide .............................................................................................................. 41 
9.2.4  Cytarabine ............................................................................................................ 42 
9.2.5  Melphalan ............................................................................................................. 42 
10  DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF STUDY 
RECORDS .................................................................................................................. 43 
10.1 
Written Informed consent ..................................................................................... 43 
10.2 
Subject Data Protection ........................................................................................ 43 
10.3 
Retention of records ............................................................................................. 43 
10.4 
Audits and inspections ......................................................................................... 43 
10.5 
Adverse Events ..................................................................................................... 43 
10.6 
Data Reporting ..................................................................................................... 43 
10.7 
Regulatory Considerations ................................................................................... 43 
REFERENCES ................................................................................................................... 44 
APPENDIX I ...................................................................................................................... 46 
APPENDIX II - BEARMAN SCALE ................................................................................ 47 
APPENDIX III – LUGANO RESPONSE CRITERIA [20] ............................................... 48 
 


  
 
IRB Approval Date: 12/09/2020 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALL 
Acute lymphoblastic leukemia 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem cell transplant 
Bcl-2 
B-cell lymphoma 2 
BEAM 
BCNU, Etoposide, Cytarabine, Melphalan 
BMP 
Basic metabolic profile 
CBC 
Complete blood count 
CLL 
Chronic lymphocytic leukemia 
CMP 
Complete metabolic profile 
CT 
Computed tomography 
DDI 
Drug-drug interactions 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DLT 
Dose-limiting toxicity 
EFS 
Event-free survival 
FL 
Follicular lymphoma 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage 
colony- 
stimulating factor 
HDC 
High-dose chemotherapy 
LMW 
Low molecular weight 
MCL 
Mantle cell lymphoma 
MM 
Multiple myeloma 
NHL 
Non-Hodgkin’s lymphoma 
OS 
Overall Survival 
PET 
Positron emission tomography 
PFS 
Progression Free Survival 
R/R 
Relapsed or refractory 
TLS 
Tumor lysis syndrome 
T-PLL 
T-cell Prolymphocytic Leukemia 


  
 
IRB Approval Date: 12/09/2020 
 
1 PROTOCOL SYNOPSIS: 
1.1 
Summary 
This is a single-center, open-label, phase I study of escalating doses of venetoclax (in 3 
dosing cohorts) followed by high dose chemotherapy with BEAM (carmustine, etoposide, 
cytarabine, melphalan) and autologous stem cell transplantation (ASCT) in patients with 
relapsed/refractory non-Hodgkin lymphoma (NHL) or high-risk NHL in first complete 
remission. The primary objective of this study will be to determine the maximal dose of 
venetoclax that can be safely combined with BEAM and ASCT. The secondary objective 
will be to determine the efficacy of this regimen as measured by ORR at day 100, in 
addition to progression free survival and overall survival at one year. Traditional 3+3 
design will be used to find the maximum tolerated dose (MTD). After the MTD is 
established, 10 more patients will be accrued to that dose level as an expansion cohort to 
obtain a preliminary estimate of overall response rate (ORR). The maximum number of 
patients enrolled will be 28 patients. 
 
1.2 
Hypotheses: 
Venetoclax is safe in combination with BEAM in patients with relapsed or refractory non- 
Hodgkin lymphoma (NHL) 
 
1.3 
Objectives: 
1.3.1 Primary Objectives: 
1. Determine the maximum tolerated dose (MTD) of venetoclax that can be 
safely combined with BEAM prior to autologous stem cell transplant 
 
1.3.2 Secondary Objectives: 
1. To evaluate the safety and tolerability of venetoclax combined with BEAM 
prior to autologous stem cell transplant 
2. To obtain a preliminary estimate of the efficacy of venetoclax in 
combination with BEAM as measured by overall response rate (ORR) at 
day 100 
3. To estimate the progression free survival (PFS) and overall survival (OS) 
of venetoclax and BEAM followed by ASCT 
 
1.3.3 Optional Exploratory objectives 
1. Determine any correlation of response and survival endpoints with the 
expression of BCL-2, BCL-XL, and MCL-1 as measured by 
immunohistochemistry (IHC) 
 
1.4 
Trial Design 
Phase IB, open-label, dose-escalation using 3+3 design with an expansion cohort 


  
 
IRB Approval Date: 12/09/2020 
 
2 INTRODUCTION 
2.1 
High-dose chemotherapy and ASCT for relapsed/refractory NHL 
High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT), using 
regimens such as carmustine, etoposide, cytarabine, and melphalan (BEAM) is standard 
treatment of patients with chemosensitive relapsed diffuse large B-cell lymphoma 
(DLBCL); the most common type of NHL. However, relapse post-HDC/ASCT remains a 
major problem, particularly in patients who received transplant for primary refractory 
disease or had high-risk features at relapse. Patients relapsing within one year of initial 
therapy, patients without chemosensitive disease, or patients not in complete remission at 
time of HDC have a 2-year event-free survival (EFS) of less than 30% and are in clear need 
for more active therapies [1, 2]. 
 
The CORAL trial demonstrated that, in the post-rituximab era, patients with DLBCL who 
relapse in the first year after treatment, or sustain only partial response to induction therapy 
have a poor prognosis. For those patients, salvage chemotherapy followed by ASCT results 
in a dismal 20% PFS at 3 years. This clearly highlights the need for better therapies for 
these patients [3]. 
 
In follicular lymphoma, ASCT is indicated at first relapse in the absence of a suitable donor 
for allogeneic transplantation. However, ASCT is non-curative and most patients progress 
afterwards [4]. 
 
Indeed, ASCT does improve long term survival in many patients with relapsed or high-risk 
NHL. Patients with NHL relapsing after ASCT have poor outcomes [1, 5]. and prior 
interventions aimed at augmenting the HDC regimen to improve chemosensitivity or 
maintenance strategies post ASCT have not been successful. Prevention of relapse after 
ASCT for NHL represents an unmet medical need. 
 
BEAM has gained popularity as the HDC regimen of choice for ASCT for patients with 
lymphoma. Although there has been no prospective trials, large retrospective trials have 
shown superior outcomes compared to older regimens like cyclophosphamide, BCNU, and 
etoposide (CBV) or busulfan and cyclophosphamide [6]. Prior attempts to add novel drugs 
to the BEAM backbone has not revealed any extra toxicity beyond what to be expected of 
BEAM regimen itself. Agents that has been safely combined with BEAM before included 
rituximab [7], bortezomib [8], bendamustine to substitute BCNU [9], yttrium-90, 
ibritumomab tiuxetan [10], and iodine-131 tositumomab [11]. None of such novel regimens 
have proven superior to standard BEAM either in a direct prospective comparison or as 
compared to historic controls. No attempt to directly target bcl family of proteins, or other 
targets within mitochondria/apoptosis pathways, has been attempted to date. 
 
2.2 
Venetoclax (ABT-199, GDC-0199) 
2.2.1 Pharmacology 
Venetoclax (also referred to as ABT-199 and GDC-0199) is a novel, orally bioavailable, 
small-molecule, B-cell lymphoma-2 (Bcl-2) family inhibitor in the biarylacylsulfonamide 


  
 
IRB Approval Date: 12/09/2020 
 
chemical class. Venetoclax binds with high affinity (inhibition constant [Ki] < 0.010 nM) 
to the antiapoptotic protein Bcl-2 and with lower affinity to other antiapoptotic Bcl-2 
family proteins, like Bcl-xl and BCL-w (> 4,000-fold and > 2,000- to > 20,000-fold lower 
affinity than to Bcl-2, respectively). 
Antiapoptotic Bcl-2 family members are associated with tumor initiation, disease 
progression, and chemotherapy resistance, as well as autoimmunity. Overexpression of 
Bcl-2 is a major contributor to the pathogenesis of some lymphoid malignancies; 
antagonism of the action of these proteins may enhance response to therapy and overcome 
resistance, and thus, these proteins are compelling targets for anti-tumor therapy. 
 
In vitro, venetoclax demonstrated cell killing activity against patient-derived chronic 
lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) cells and a variety of 
lymphoma and leukemia cell lines, including B-cell follicular lymphomas (FLs), mantle 
cell lymphomas (MCLs), DLBCLs, AMLs, and multiple myeloma (MM) cell lines. 
Venetoclax was especially potent against NHL cell lines expressing high levels of Bcl-2. 
Venetoclax inhibits subcutaneous xenograft growth of human tumor cell lines derived from 
acute lymphoblastic leukemia (ALL), NHL, and AML, and is highly efficacious using 
various doses and combined with other regimens. The drug is also active in a model of 
disseminated ALL and AML. Venetoclax enhanced the activity of a broad variety of 
chemotherapeutic agents in other human hematological models. 
 
Multiple pre-clinical observation supports the hypothesis that combination of ABT-199 
with cytotoxic chemotherapeutic agents potentiates their cytotoxicity. The combination of 
chemotherapy with ABT-199 and doxorubicin or cytarabine synergistic cell kill against 
double-hit lymphoma (DHL) cell lines; DHL is an aggressive subtype of DLBCL usually 
characterized by refractoriness to cytotoxic chemotherapy [12]. The combination of ABT- 
199 with doxorubicin or etoposide led to a significant decrease in cell viability at 48 hours 
compared to each single agent alone in 4 different DLBCL cell lines [13]. ABT-199 was 
also shown to restore sensitivity to cyclophosphamide in murine xenograft models for 
neuroblastoma [14]. ABT-199 synergizes with etoposide in cytochrome C release and 
induction of apoptosis in leukemia cell lines [15]. 
 
Bcl-2 is also expressed in T-cell lymphomas and correlates with apoptotic rate and 
proliferation index [16]. Boidol et al. reported on venetoclax activity in single-cell 
suspension of T-cell prolymphocytic leukemia (T-PLL) [17]. Most of peripheral blood 
malignant T-cells isolated from 25 patients with cutaneous T-cell lymphomas (CTCL) were 
also shown to be sensitive to venetoclax; with mean IC50 as low as 79 nM [18]. 
 
2.2.2 Pharmacokinetics and pre-clinical toxicology 
Venetoclax exhibited moderate permeability in the Caco-2 assay. 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, bone, and pigmented tissues. In rat, 
14.3% of the dose was recovered as parent drug after 48 hours post dose, while 76.9% of 
the dose was excreted as metabolites in bile. Profiles in bile indicated that metabolism was 
the major clearance mechanism, while biliary excretion of parent drug played a secondary 
role in drug elimination. Biotransformation of [3H]venetoclax proceeded via a combination 
of oxidation and conjugation. 


  
 
IRB Approval Date: 12/09/2020 
 
 
Venetoclax and its major human metabolite, M27, are predominately metabolized by 
CYP3A4 in vitro, thus CYP3A4 inhibitors or inducers are expected to cause changes in 
venetoclax and M27 exposures. Clinical studies have supported the in vitro observations 
for venetoclax as a sensitive substrate of CYP3A4: > 5-fold increase in AUC when co- 
dosed with ketoconazole (Study M13-364), and > 50% decrease in AUC when co-dosed 
with rifampin (Study M14-497). At the 400 mg QD dose venetoclax and M27 are not 
predicted to be perpetrators of the major CYP enzymes, but venetoclax may weakly inhibit 
UGT1A1. Both venetoclax and M27 are substrates for the efflux transporters P-gp and 
BCRP, and inhibitors or inducers of these transporters are expected to cause change in the 
exposure of venetoclax and M27. Venetoclax and M27 are P-gp and BCRP inhibitors and 
may interact with substrates for these transporters. Venetoclax may inhibit OATP1B1 and 
cause weak interaction with drugs that are substrates of this transporter. 
 
Venetoclax was tested in a battery of safety pharmacology assays and produced no effects 
in central nervous system (CNS)/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 µg/mL; concentrations greater than the 
concentration of venetoclax in humans (average maximum observed plasma concentration 
[Cmax] = 6.09 µg/mL at 1200 mg dose). However, no effects on blood pressure, heart rate, 
or electrocardiogram (ECG) parameters were observed in dogs at a maximum drug 
concentration of 46 µg/mL. 
 
The primary toxicities associated with repeat-dose administration of venetoclax were 
effects on the hematologic system (decreased lymphocytes and red blood cell [RBC] mass) 
in mice, rats and dogs, the male reproductive system (testicular germ cell depletion in dogs) 
and embryo fetal toxicity in mice. Other noteworthy findings were epithelial single cell 
necrosis in multiple tissues and hair coat color change, both in dogs. 
 
In mice, rats, and dogs, venetoclax produced robust decreases in lymphocytes in the 
peripheral blood (up to 75% in mice, 64% in rats, and 81% in dogs) and in lymphoid tissues. 
These findings are consistent with the expected pharmacologic effects of venetoclax (a 
selective Bcl-2 inhibitor). In mice, total lymphocyte counts at 600 mg/kg/day after 4 weeks 
of dosing were minimally decreased 21% to 6% relative to concurrent controls at the end 
of the 4-week recovery period. In dogs, the recovery of peripheral blood decreases in total 
lymphocytes and lymphocyte subsets (CD4+ T-cells and CD8+ T-cells and [CD21+] 
mature B cells) was prolonged, requiring up to 18 weeks after a single dose or after 
completion of 2 weeks of dosing. B-cells were the most sensitive lymphocyte subtype 
based on the magnitude of decrease (> 90%) and/or the length of time required for recovery. 
Lymphocyte decreases in lymphoid tissues were reversible in mice and dogs. Venetoclax 
produced dose-related decreases in RBC mass due to decreased cellular hemoglobin in 
mice and dogs; these effects were adverse at the highest dosages in the 4- week mouse and 
dog studies and were reversible. In studies to select carcinogenicity dose levels, RBC mass 
decreases were also observed in rats and were generally more severe than in mice or dogs. 
Venetoclax produced adverse, non-dose related microscopic findings of testicular germ cell 
depletion in dogs at all doses tested; reversibility was not observed following a 4-week 
recovery period. There were no testicular effects in mice. Venetoclax resulted in increased 


  
 
IRB Approval Date: 12/09/2020 
 
post-implantation loss and decreased fetal body weights in the mouse embryo fetal 
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. In mice and 
rabbits, venetoclax was not teratogenic, and there were no other effects on development or 
fertility. 
 
Additional noteworthy effects of venetoclax included white hair coat discoloration in dogs 
(occurring after approximately three months of dosing in the 9-month study) and minimal 
to mild single cell necrosis in multiple epithelial tissues (e.g., gallbladder and exocrine 
pancreas) in dogs. None of these effects were considered to be adverse. 
 
M27 is a major human metabolite of venetoclax. Although observed in mice and dogs, 
M27 is present at much lower levels (0.05- to 0.09-fold), as compared with steady-state 
levels in humans, and therefore is a disproportionate metabolite. By in silico analysis, M27 
does not generate new alerts for mutagenicity, as compared with the venetoclax parent 
compound. Additionally, M27 shows low in vitro potency (at least 58-fold less than parent) 
and produced no evidence of in vitro genotoxicity in Ames and chromosome aberration 
assays. In a secondary pharmacology receptor panel screening study, M27 produced 
significant displacement of control-specific binding at the delta-opioid receptor (DOP Ki 
= 0.65 µM); however, when evaluated in a functional assay, agonist or antagonist activity 
was not observed at the DOP receptor up to a maximum concentration of 10 µM. No CNS 
or respiratory adverse events that could be attributed to off-target receptor-mediated 
pharmacologic effects of M27 have been observed in clinical trial subjects. 
 
2.2.3 Clinical Safety and Pharmacology 
As of 28 November 2016, based on data available in the AbbVie and Genentech/Roche 
clinical databases, a total of 2759 subjects have been exposed to at least 1 dose of 
venetoclax in the oncology and immunology development programs. A total of 2534 
oncology subjects had data available in AbbVie and Genentech/Roche studies as of 28 
November 2016. Of these 2534, 1435 subjects had CLL/small lymphocytic leukemia 
(SLL), 626 subjects had NHL, 178 subjects had MM, and 295 had AML. An additional 
127 subjects were healthy volunteers. A total of 663 oncology subjects received the drug 
as monotherapy and 1871 received the drug in combination with other therapies. 
Additionally, 98 subjects were exposed to at least 1 dose of venetoclax in the AbbVie 
immunology study, Study M13-093, as of 28 November 2016. 
 
Pharmacokinetic data for venetoclax are available from studies in subjects with cancer 
(CLL/SLL, AML, NHL, and MM), healthy subjects, and a single study in subjects with 
SLE. Following multiple-dose administration, the maximum plasma concentration of 
venetoclax was attained 5 to 8 hours after dosing. The harmonic mean terminal half-life 
(t1/2) ranged from 17 to 41 hours following a single oral dose of venetoclax. In subjects 
with CLL, venetoclax showed minimal accumulation, and steady-state AUC increased 
proportionally over the dose range of 150 to 800 mg. Venetoclax has been administered 
with food in all clinical studies, as food increased the bioavailability of venetoclax by 
approximately 3- to 5-fold. Venetoclax is highly bound to plasma proteins with unbound 
fraction (fu) < 0.01, and it is primarily eliminated as metabolites in feces with negligible 
renal elimination (< 0.1%). 


  
 
IRB Approval Date: 12/09/2020 
 
 
Drug-drug interaction studies of venetoclax with ketoconazole, rifampin, warfarin, 
ritonavir, and digoxin were conducted to provide dosing recommendations for patients 
concomitantly taking CYP3A and/or P-gp inhibitors, inducers, and/or warfarin. 
Pharmacokinetic studies were conducted in healthy Chinese subjects and in Japanese 
subjects to provide dosing recommendations for those specific populations. Additionally, 
a dedicated study to evaluate the pharmacokinetics of venetoclax in subjects with hepatic 
impairment is ongoing. Based on the population pharmacokinetic analysis, age, sex, race, 
weight, mild and moderate renal or hepatic impairment do not have an effect on venetoclax 
clearance. 
 
2.2.4 Clinical Experience with Venetoclax 
Multiple ongoing Phase 1/2 AbbVie and Phase 1/2/3 Genentech/Roche clinical studies are 
evaluating safety, tolerability, pharmacokinetics, and efficacy of venetoclax as 
monotherapy or in combination with other therapies (rituximab [R], obinutuzumab 
(GA101) [G], rituximab or obinutuzumab plus CHOP [cyclophosphamide, doxorubicin, 
vincristine, and prednisone; R-CHOP or G-CHOP, respectively], BR, bendamustine plus 
obinutuzumab [BG], bortezomib plus dexamethasone, azacitidine or decitabine, and 
cytarabine) in subjects with hematologic malignancies. Data are available from drug-drug 
interaction (DDI) studies of venetoclax interaction with ketoconazole, rifampin, warfarin, 
digoxin, and ritonavir. Additionally, two Phase 3 studies are ongoing: one study in 
relapsed/refractory (R/R) CLL exploring the combination of venetoclax and rituximab 
against BR and one Phase 3 study in first-line CLL exploring the combination of venetoclax 
and obinutuzumab against obinutuzumab plus chlorambucil. All oncology clinical studies 
which enrolled subjects as of 28 November 2016 are summarized in Table 7 in the 
investigator brochure submitted with this protocol. 
 
Based on nonclinical and clinical data available with venetoclax administration, important 
identified risks are tumor lysis syndrome (TLS) and neutropenia. The risk of TLS is highest 
in CLL and MCL. Infection is a potential risk. Other adverse events commonly observed 
with venetoclax include nausea, diarrhea, and other hematological effects (including 
anemia, thrombocytopenia, and lymphopenia). Decreased spermatogenesis has been 
observed in nonclinical studies with dogs and could present a risk to male infertility. In 
addition, 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. 
 
Preliminary efficacy results are available for subjects with CLL/SLL, NHL, MM, and AML 
as listed below. Preliminary data indicate that venetoclax continues to show promising 
efficacy in various hematological malignancies. 
 
2.2.5 Clinical Experience with Venetoclax in Lymphomas 
Arm B of M12-175 was a phase I first-in-human study of venetoclax in patients with R/R 
NHL that included 106 patients. They received venetoclax once daily until progressive 
disease or unacceptable toxicity at target doses from 200 to 1200 mg in dose-escalation and 
safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for 
most patients in dose-escalation cohorts and for all patients in safety expansion. It included 


  
 
IRB Approval Date: 12/09/2020 
 
patients with lymphoproliferative disorders excluding Burkitt or Burkitt-like lymphomas, 
lymphoblastic lymphoma/leukemia and post-transplant lymphoproliferative diseases. 
Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed. 
Three patients had evidence of laboratory TLS. Treatment emergent adverse events were 
reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 
to 4 events were reported in 59 patients (56%), and the most common were hematologic, 
including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response 
rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free 
survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month) [16]. 
 
Venetoclax was also studied in combination with other chemotherapies. In the ongoing 
study M12-630 (NCT01594229), venetoclax was given for short courses of 3, 7, or 28 days 
in 28-day cycles in combination with Rituximab and Bendamustine. The ORR as of 
10/20/2016 was 65.0%. Most common grade 3/4 AEs (≥10%) during combination therapy 
were neutropenia (32%), lymphocyte count decrease (26%), thrombocytopenia (21%), 
anemia (15%), and leukopenia (13%). The most frequent serious AE was febrile 
neutropenia (9%). Three deaths occurred; none were drug-related AEs [17]. 
 
Venetoclax is also being studied in the front-line setting and minimally-treated patients (≤ 
1 line of therapy) in a phase IB, dose-escalation manner in combination with either R- 
CHOP or G-CHOP. As of 6/10/2016, 56 patients were enrolled. The most common DLTs 
were hematologic including cytopenias and gastrointestinal toxicities. They are 
summarized in Table 1. The most common Grade 3/4 AEs were neutropenia (46%), febrile 
neutropenia (29%), and thrombocytopenia (21%). Three pts had laboratory TLS after the 
first venetoclax dose without any clinical sequelae, which resolved by no intervention (1) 
or medical intervention including holding dose (2). No cases of clinical TLS were 
observed. Of the 42 pts in the intent-to-treat analysis that were evaluable for efficacy 
response (≥1 cycles with available end of treatment response assessment or discontinued 
prior to assessment), 18/21 (85.7%) in Arm A and 17/21 (81%) in Arm B had a response 
(Table 2) [21]. 


  
 
IRB Approval Date: 12/09/2020 
 
 
 
In T-cell malignancies, Bose and Konopleva treated two patients with relapsed/refractory 
T-PLL with venetoclax and both achieved a partial response for several months [22]. This 
was based on the preclinical data mentioned previously about the activity of venetoclax in 
single-cell suspensions of T-PLL [17]. There is an ongoing phase II trial of venetoclax in 
patients with relapsed or refractory T-cell lymphomas (NCT03534180) based on promising 
pre-clinical activity of venetoclax in T-cell malignancies.  
 
2.3 
Rationale 
Based on the above preclinical and clinical data, we believe that venetoclax is sufficiently 
active in NHL, both as monotherapy and in combination. Given that patients with primary 
refractory NHL have little treatment options, and that the available treatment options 
(HDC/ASCT) are not ideal, we postulate that adding venetoclax to the BEAM conditioning 
regimen prior to ASCT will be safe and will improve response rates. 
 
The toxicities observed with venetoclax in the above studies include grade 1-2 
gastrointestinal (GI) toxicities and grade 3-4 cytopenias. These toxicities overlap with 
those of the conditioning regimen. However, we expect the GI toxicities of the conditioning 
regimen to occur later throughout the treatment course, well after venetoclax would have 
been discontinued. Thus, they would not be additive because of temporal spacing. 
 
The purpose of the venetoclax lead-in is to down-regulate the anti-apoptotic pathways 
before BEAM administration. Having a lead-in will also allow for more accurate 
assessment of acute toxicities of venetoclax. The MTD of venetoclax in combination with 
BEAM is unknown, we propose a dose escalation in three dosing cohorts. After the MTD 
is determined in phase I of the study, we plan on enrolling 10 additional patients using the 
MTD as a dose expansion cohort. Although venetoclax has modest activity in DLBCL on 
its own, we postulate that combining it with BEAM HDC would augment cytotoxicity of 
HDC and that would translated into better patient outcomes. Although prior attempts of 
incorporating novel agents into the BEAM backbone has not been successful in improving 
outcomes; albeit proven safe, no prior attempts have been made to incorporate drugs that 
directly target bcl family of proteins, or other targets within mitochondria/apoptosis 
pathways. Another clinical trial that is currently open to accrual (NCT03064867) 
incorporates venetoclax with the standard regimen rituximab, ifosfamide, carboplatin, and 
etoposide (RICE) regimen in relapsed/refractory DLBCL building on the same hypothesis 


  
 
IRB Approval Date: 12/09/2020 
 
we are proposing; improving chemosensitivity to standard cytotoxic agents by directly 
inhibiting pathways involved in resistance to apoptosis. 
 
As detailed in section 2.2.5 above; total of 209 patients were reported from 3 separate trials 
in patients with non-Hodgkin lymphomas (NHL); 2 trials in relapsed/refractory patients 
(as a single agent and in combination with chemotherapy) and 1 trial upfront in 
combination with chemotherapy. In only one trial, laboratory evidence of TLS syndrome 
was seen in three patients with no evidence of clinical TLS observed. One of the two 
patients with T-PLL treated experienced evidence of TLS. Hence, we believe that the risk 
of clinically significant TLS is low to warrant exclusion of patients with high tumor burden 
or to warrant inpatient monitoring of such patients.  
 
We will also investigate markers of response and resistance. Venetoclax is more active in 
malignancies that overexpress Bcl-2. We will correlate response with levels of expression 
of Bcl-2 by IHC. 
 
2.4 
Background and rationale of secondary and exploratory objectives 
Venetoclax is a Bcl-2 inhibitor and is most active in malignancies that are known to 
overexpress that pathway. However, it maintains activity in malignancies that do not 
overexpress it. Furthermore, not all tumors with high Bcl-2 expression are sensitive to 
venetoclax. Given the targeted nature of the drug, mechanisms of action and resistance 
have been examined. A proposed mechanism of resistance is upregulation of other anti- 
apoptotic proteins, namely BCL-XL and MCL-1. Changes in the BH3 drug-binding domain 
have also been observed [19]. We will attempt to examine the levels of expression of these 
proteins by IHC on our clinical samples and correlate that to ORR and survival outcomes. 
 
3 OBJECTIVES 
3.1 
Primary Objectives: 
1. 
Determine the maximum tolerated dose (MTD) of venetoclax that can be 
safely combined with BEAM prior to autologous stem cell transplant 
 
3.2 
Secondary Objectives: 
1. To evaluate the safety and tolerability of venetoclax combined with BEAM 
prior to autologous stem cell transplant 
2. To obtain a preliminary estimate of the efficacy of venetoclax in combination 
with BEAM as measured by overall response rate (ORR) at day 100 
3. To estimate the progression free survival (PFS) and overall survival (OS) of 
Venetoclax and BEAM followed by ASCT 
 
3.3 
Optional Exploratory objectives 
1. Determine any correlation of response and survival endpoints with the 
expression of BCL-2, BCL-XL, and MCL-1 as measured by 
immunohistochemistry (IHC) 


  
 
IRB Approval Date: 12/09/2020 
 
4 INCLUSION AND EXCLUSION CRITERIA 
4.1 
Inclusion Criteria 
 
Subjects must have histologically confirmed diagnosis of non-Hodgkin’s 
lymphoma that is refractory after upfront induction therapy, in partial remission or 
worse after salvage, or relapsed. Refractory and partial remission are defined by the 
Lugano criteria listed in Appendix III [24]. Excluded histologies are post-
transplant lymphoproliferative disorder, and chronic lymphocytic leukemia/small 
lymphocytic lymphoma.  All other histologies are eligible. These include but are 
not limited to: diffuse-large B-cell lymphoma, mantle cell lymphoma, peripheral T-
cell lymphoma (PTCL), hairy cell leukemia (classic or variant), lymphoblastic 
lymphoma, prolymphocytic leukemia (T or B-cell), follicular lymphoma (grades I, II, 
and III), marginal zone lymphoma, transformed indolent lymphoma, grey zone 
lymphoma, and undifferentiated B-cell lymphoma. Patients with NHL who are at 
high risk of relapse can be regardless of response. 
o High risk is defined as 1) requiring 3 or more lines of therapy, 2) 
transformed lymphoma, 3) relapse within 12 months of D1 of last cycle 
of induction chemotherapy, 4) MCL or PTCL undergoing consolidation 
with ASCT in CR1/PR1 
 Expected survival of more than six months 
 Age >18 years 
 Karnofsky Performance status ≥ 80% (appendix-I) 
 Subjects must have normal organ and marrow function, within 1 week prior to 
initiation of treatment, as defined below: 
 AST/ALT < 3x upper limits of normal (ULN) unless due to disease 
 Total bilirubin <2x ULN unless due to disease 
 Calculated GFR of 30 ml/min or greater 
 ANC > 500 cells/mm3 
 Platelet Count > 50 mm3. 
 Left ventricular ejection fraction ≥ 40% (within 6 weeks of start of treatment) 
 Diffusion capacity of carbon monoxide (DLCO) ≥ 50% predicted (within 6 weeks 
of start of treatment) 
 Ability to collect 2 x 106/kg CD34+ cells for transplantation 
 Patient must be otherwise eligible for ASCT per local institutional guidelines 
 No serious disease, or condition, that, in the opinion of the investigator, would 
compromise the patient’s ability to participate in the study 
 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 
4.2 
Exclusion Criteria 
 
Subjects who sustained a complete metabolic response (CMR) by PET-CT (5- 
point scale of <  3) unless lymphoma relapsed within 12 months from the first day 
of last cycle of induction chemotherapy or patients have “high risk disease” as defined 
in section 4.1 above.  
 Subjects receiving any other investigational agents. 
 Patients with central nervous system (CNS) involved by lymphoma can be 


  
 
IRB Approval Date: 12/09/2020 
 
included if CNS disease is deemed controlled prior to enrollment as determined 
by the investigator. Patients with uncontrolled CNS disease will be excluded. 
 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to venetoclax or other agents used in this study. 
 Subjects with uncontrolled intercurrent illness including, but not limited to 
ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 Patients who are HIV positive and receiving combination antiretroviral therapy 
will be excluded; because of the potential for pharmacokinetic interactions with 
venetoclax. 
 Patients receiving strong inhibitors or inducers of CYP3A4 (see Appendix IV). 
All such medications would have to be discontinued for 72 hours prior to start of 
venetoclax.  
 Female patients who are pregnant or breast-feeding. Confirmation that the 
subject is not pregnant must be established by a negative serum -human 
chorionic gonadotropin (β-hCG) pregnancy test result obtained during 
screening. Pregnancy testing is not required for post-menopausal or surgically 
sterilized women. Male or female patients, who are sexually active and of the 
child bearing age, must be willing to practice accepted birth control measures 
 
5 STUDY DESIGN 
5.1 
Summary 
This is an open-label, single-center, phase I trial with a dose expansion cohort in which up 
to 28 patients with relapsed/refractory or high-risk NHL will receive venetoclax in 
combination with BEAM and autologous hematopoietic stem cell transplantation. In 
addition to the BEAM and ASCT, venetoclax will be administered in three doses, 400 mg, 
800 mg, and 1200 mg in a ramp-up schedule. Patients will be accrued in a 3+3 study design, 
described in the statistical analysis part below. These subjects will be evaluated for 
toxicities to establish the maximum tolerated dose (MTD) of venetoclax that can be 
tolerated in combination with BEAM/ASCT. Once established, the maximum tolerated 
dose will be utilized in treating an additional 10 subjects. Data collected will be utilized to 
obtain a preliminary estimate of the response rate, cumulative incidence of progression, 
PFS and OS using this regimen. 
 
5.2 
Treatment Regimen Overview 
5.2.1 Screening Evaluation 
Prior to initiating the process of mobilization and collection 
 History and physical examination 
 Disease status assessments with CT scans or PET scans (results within 6 
weeks of screening are acceptable). PET-CTs are preferred. 
 Bone marrow biopsy if clinically indicated (results within 6 weeks of 
screening are acceptable) 
 CBC/Differential and complete metabolic panel 


  
 
IRB Approval Date: 12/09/2020 
 
 MUGA or Echocardiogram 
 Pulmonary function testing including DLCO 
 Pregnancy test (serum beta-HCG) for females of childbearing age 
 HIV testing 
5.2.2 Before starting venetoclax and BEAM 
 History and physical examination 
 CBC/Differential and complete metabolic panel 
 Repeat pregnancy test (serum beta-HCG) for females of childbearing age if the 
prior test has been more than 14 days ago 
 Tumor lysis labs for baseline 
 Start on prophylactic allopurinol 
 
5.2.3 During transplant (T-6 through hospital discharge) 
 Standard of practice care with daily history and physical examinations, 
complete blood count and metabolic profile 
 Management of complications per standard of practice 
 
5.2.4 Day +30, +60, and +100 visit (+/- 7 days) 
 History and physical examination 
 CBC/Differential and complete metabolic panel 
 Disease assessment by PET or CT scans; PET-CT scan is preferred (to be 
done between days 91 and 100 post-ASCT) 
 
5.2.5 Follow-up during first year post-ASCT (q3 months +/- 7 days) 
 History and physical examination 
 CBC/Differential and complete metabolic panel 
 Disease assessment by imaging (ONLY if clinically indicated) 
 
5.2.6 First Annual visit post-ASCT (+/- 7 days) 
 History and physical examination 
 CBC/Differential and complete metabolic panel 
 Disease assessment by imaging (ONLY if clinically indicated) 
 Would be considered “study closure” visit 


  
 
IRB Approval Date: 12/09/2020 
 
5.2.7 Study Schema / Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*S = Screening visit. Can coincide with day -17. If less than 5 days apart from day -17, blood work and scans need not be repeated.  Evaluation includes pulmonary function testing 
with DLCO and bone marrow biopsy if clinically indicated (results within 6 weeks of screening are acceptable). 
1Study preferred to begin on a Monday so that stem cell infusion will occur on Thursday 
2Tumor lysis labs include (in addition to the metabolic profile), uric acid, phosphate, lactate dehydrogenase. Tumor lysis labs will occur 8 (+/-2) hours after every dose of venetoclax 
during the escalation phase with the venetoclax. If deemed stable, frequency can be decreased later 
3Allopurinol can be held when uric acid is less than 4 mg/dL 
4PET-CT will occur per clinical guidelines for documentation of disease and assessment. Screening CT or PET scan can be done up to 6 weeks prior to the screening visit. Re-staging 
PET-CT is typically performed at day +91-100 post-ASCT or sooner as clinically indicated (if there is high clinical suspicion for progression).  
5Venetoclax dosing will occur in a ramp-up fashion. All patients on all dosing cohorts will begin with 100 mg. If no toxicity or tumor lysis is observed, they will go on to receive 200 
mg the following day, then 400 mg. The dose the following day will depend on their dosing cohort (400, 800, or 800-1200). 
6Discharge is per the discretion of the treating physician but usually occurs around this range 
7Patients will not start venetoclax until peripheral blood stem collection is completed and confirmed to be adequate for ASCT.
Day1 
S* 
-17 
-16 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
+21 
+30 
+60 +100 
H and P 
X 
X  
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC-D 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
TLS Labs2 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
 
 
Allopurinol3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
 
 
 
HIV Test 
     X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA/ECHO 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-hCG 
     X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Collection 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Venetoclax5  
 
 
100 
200 
400 
X 
X 
X 
X 
X 
X 
X  
 
 
 
 
 
Admission 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
BEAM 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Transplant 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 


  
 
IRB Approval Date: 12/09/2020 
 
5.2.8 Drug administration and schedule 
- 
Patients will be started on allopurinol per institutional guidelines for tumor lysis prophylaxis 
preferably on the Monday preceding their mobilization and collection date. They will remain on 
allopurinol until they are no longer at risk for tumor lysis, which usually coincides with a consistent 
downtrending of their uric acid levels after administration of their treatment 
- 
They will undergo stem cell mobilization and apheresis for collection of CD34+ cells per standard 
institutional guidelines. They will be assigned an admission date that preferably falls on a Thursday 
(day -7). 
- 
They will start venetoclax four days prior to that, which would coincide with day -10. They will 
continue venetoclax per the assigned schedule till day -1. 
- 
They will start BEAM following their admission. They will receive standard doses of BEAM in 
parallel with venetoclax till day -1, followed by ASCT as per standard of care.  Dose adjustment for 
renal impairment is allowed per institutional guidelines. 
o BCNU is given on day -6 at 300 mg/m2 
o Etoposide is given at 100 mg/m2 IV bid days -5 through -2 
o Cytarabine is given at 100 mg/m2 IVbid days -5 through -2 
o Melphalan is given at 140 mg/m2 on day -1 
- 
Venetoclax is an oral medication and can be taken as an outpatient or inpatient. It is best bioavailable 
when given with food. Tumor lysis labs will be checked 8 hours after every dose of venetoclax during 
the escalation phase in all cohorts. A grade 3 or 4 adverse event will prompt holding the medication 
o Cohort 1 will receive 100 mg on day -10, 200 mg on day -9, then 400 mg on d-8 till d -1 if 
there are no grade 3/4, non-hematological, adverse effects related to venetoclax occur (please 
see DLT definition in section 5.3 below) 
o Cohort 2 will receive 100 mg on day -10, 200 on d -9, 400 on d-8, then 800 mg starting d-7 till 
d -1 if no grade 3/4, non-hematological, adverse effects related to venetoclax occur (please see 
DLT definition in section 5.3 below) 
o Cohort 3 will receive 100 mg on d-10, 200 on d-9, 400 on d-8, 800 on d-7, 1200 on d-6 till d- 
1 if no grade 3/4, non-hematological, adverse effects related to venetoclax occur (please see 
DLT definition in section 5.3 below) 
- 
Please see below table for a summary 
 Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
D -17 
D -16 
D -15 
D -14 
D -13 
D -12 
D -11 
Allopurinol 
Mobilization and collection 
D -10 
D -9 
D -8 
D -7 
D -6 
D -5 
D -4 
Venetoclax* 
Venetoclax 
Venetoclax 
Venetoclax+ 
Venetoclax 
Venetoclax 
Venetoclax 
100 mg PO 
200 mg PO 
400 mg PO 
per dosing cohort per dosing cohort Etoposide 
Etoposide 
 
 
 
Coh 1 = 400 
BCNU  
100 mg/m2 IV bid 
100 mg/m2 IV bid 
 
 
 
Coh 2 = 800 
300 mg/m2 
Cytarabine  
Cytarabine 
 
 
 
Coh 3 = 1200 
 
100 mg/m2 IV bid  
100 mg/m2 IV bid  
D -3 
D -2 
D -1 
D 0 
 
 
 
Venetoclax 
Venetoclax 
Venetoclax 
SC Infusion 
 
 
 
Etoposide 
Etoposide 
Melphalan 
 
100 mg/m2 
100 mg/m2 
140 mg/m2 
 
IV bid 
IV bid 
 
 
Cytarabine 
Cytarabine 
 
 
100 mg/m2 
100 mg/m2 
 
 
IV bid 
IV bid 
 
 


  
 
IRB Approval Date: 12/09/2020 
 
5.2.9 Dosing cohorts 
Venetoclax will be administered in three dose cohorts, 400 mg, 800 mg, and 1200 mg in a ramp-up scheduled 
detailed in the below table. Three patients will be accrued to dose level 1. BEAM will be given at the same 
standard dose for all cohorts. 
 
Cohort 
D -10 
D -9 
D -8 
D -7 
D -6 
D -5 till D -1 
1 
100 
200 
400 
400 
400 
400 
2 
100 
200 
400 
800 
800 
800 
3 
100 
200 
400 
800 
1200 
1200 
Venetoclax dosing 
 
5.2.10 Phase I Dose Escalation 
Dose escalation will proceed within each cohort using the 3+3 design according to the following scheme. DLT is 
defined in the following section. 
 
Number of Subjects with DLT at 
a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next dose level. 
1 out of 3 
Enter 3 more subjects at this dose level. 
 If 0 of these 3 subjects experience 
DLT, proceed to the next dose level. 
 If 1 or more of this group suffer DLT, 
then dose escalation is stopped, and 
this dose is declared the maximally 
administered 
dose. 
Three 
(3) 
additional subjects will be entered at 
the next lowest dose level if only 3 
subjects were treated previously at that 
dose. 
>2 
Dose escalation will be stopped. This dose level 
will be declared the maximally administered dose 
(highest dose administered). Three (3) additional 
subjects will be entered at the next lowest dose 
level if only 3 subjects were treated previously at 
that dose. If ≥2 DLTs are encountered in first 
cohort, the study will terminate. 
<1 out of 6 at highest dose level 
below 
the 
maximally 
administered dose 
This is generally the recommended maximally 
tolerated dose. At least 6 subjects should be 
entered. This will be the dose used for the 
expansion cohort. 
 
5.3 
Definition of Dose-Limiting Toxicity (DLTs) 
Transplant related toxicities will be followed for determination of DLTs. The CTCAE v4.03 which is available 
online (http://ctep.info.nih.gov) will be used to define DLTs from days -10 to -7. During this period, DLT is defined 
as any non-disease-related, non-hematological adverse event of CTCAE grade 3 or higher with the exceptions 
of alopecia, grade 3 or 4 electrolyte disturbances that resolve within 24 hours with electrolyte correction and not 


  
 
IRB Approval Date: 12/09/2020 
 
clinically significant, grade 3 nausea or vomiting that does not require hospitalization or support with total 
parenteral nutrition and resolves to < grade 2 within 72 hours, grade 3 or 4 infection/bleeding, and grade 3 or 4 
cytopenias. 
 
If the patient experiences a DLT between days -10 to -7 (prior to start of BEAM and defined above), and is 
deemed unsafe to continue on trial, patient may proceed to standard BEAM followed by ASCT or receive another 
therapy at the discretion of the treating physician. 
 
The Bearman scale [21] for Transplant-related toxicities (Appendix-II) will be used for defining DLTs from days 
-6 through hospital discharge after engraftment (usually occurs between day +14 to day +21 after ASCT). Per the 
Bearman scale, a DLT is defined as a grade 3 or higher toxicity. No dose modifications are planned as all patients 
will be receiving a single course of venetoclax. Each cohort will be reviewed after being fully accrued for time to 
neutrophil engraftment (defined as ANC ⩾0.5 × 109), time to platelet engraftment (defined as platelet levels of 
⩾20 × 109 unsupported by transfusions). In a recent study, reflecting contemporary practice, median time to 
neutrophil was 9 (range 8-11 days) and median time to platelet engraftment was 10.5 days (7-19 days) [22]. Each 
cohort will also be reviewed for average number of red blood cell (RBC) transfusions received. In a contemporary 
study, the average number of RBC transfusions received after ASCT was 4-6 units [23]. Time to neutrophil 
engraftment  21 days, time to platelet engraftment 30 days, or more than 10 RBC units transfused before 
discharge from the hospital will also constitute a DLT. 
 
The DLT observation period will end at the time of discharge from the hospital. Per institutional policy, patients 
are not discharged until engraftment has occurred and all acute toxicities have resolved. This usually falls around 
day +21 after transplant. Patients who experience early progression prior to start of BEAM regimen, die, or 
withdraw for other reasons prior to start BEAM will be considered unevaluable for dose-escalation decisions and 
will be replaced. After each dosing cohort has finished accrual, the PI will review all patients treated on such 
cohort for unusual infections or other toxicities. Each cohort needs to fully accrue and all patients treated on 
that cohort will be observed until hospital discharge before the subsequent cohort is opened for accrual; 
PI will review data on each cohort after all patients treated on that dose level has been discharged from the 
hospital before opening subsequent cohort to accrual. Deaths will be reviewed if they are related to 
venetoclax or not with stopping rules followed as detailed in section 6.4 below. 
 
5.4 
Hematopoietic Stem Cell Collection 
Peripheral blood stem cells will be mobilized and collected as per the discretion of the treating physician. Once 
an adequate number of CD34+ cells/kg have been collected (as per existing institutional guidelines) the patient 
will begin the preparative regimen for transplant. The minimum number of CD34+ cells required for enrollment 
is 2 x 106/kg. A clinical trial consent is not required prior to stem cell mobilization and collection being a standard 
of care procedure for ASCT. 
 
5.5 
Venetoclax Administration 
Venetoclax is currently FDA-approved for chronic lymphocytic leukemia (CLL) with 17p deletion after one line 
of therapy. The approved dose is 400 mg with a ramp up from 20 mg given the high incidence of TLS in the CLL 
population. In the NHL studies, there was no observed clinical TLS. We are planning on starting with 100 mg on 
day -10, 200 mg on day -9, 400 mg on day -8. For cohort 1, this will be the target dose. For cohort 2, the dose on 
day -7 will be 800 mg. Cohort 3 will receive 1200 mg on day -6. Tumor lysis labs will be checked 8 hours after 
each dose during the escalation phase. A TLS mitigation strategy will be implemented. 
 
In the pharmacokinetic studies, venetoclax was administered orally, in the morning, after a low-fat breakfast.  
Patients would need to avoid grapefruit or St John’s Wort, and Seville oranges as well as other strong CYP3A4 
inhibitors and inducers (outlined in Appendix IV). 


  
 
IRB Approval Date: 12/09/2020 
 
5.6 
Body surface area calculation 
Dosage calculations for all cycles of treatment will be based on the patient’s body surface area, as determined 
during the screening evaluations. Actual height and weight should be used in determining body surface area. 
However, ideal body weight or corrected ideal body weight can be used per local institutional practice. 
 
5.7 
Administration of BEAM high-dose regimen 
Administration of BEAM (BCNU, etoposide, cytarabine, and melphalan) is as per standard institutional practice 
and is as follows: 
 
Day –6: 
Carmustine 300 mg/m2 IV once 
Day –5 to Day –2: 
Etoposide 100 mg/m2 and cytarabine 100 mg/m2 IV twice daily 
Day –1: 
Melphalan 140 mg/m2 IV once 
 
Volumes of reconstitution of chemotherapeutic agents, duration of infusion, and premedications/supportive care 
is per standard institutional practice. 
 
5.8 
Hematopoietic Stem Cell Infusion 
On day 0 of treatment, the previously stored hematopoietic stem cells will be re-infused. The cells will be removed 
from the storage freezer, brought to the patient area, thawed in a water bath, and administered intravenously 
through a central catheter to the patient. Patients will then be cared for as standard transplant patients. Criteria for 
release of stem cells, parameters for infusion, and monitoring throughout infusion is per standard institutional 
practice. 
 
5.9 
Concomitant Medications and Supportive Care Guidelines 
The patients will be cared for as standard bone marrow transplant patients. All patients during the period of 
neutropenia will be cultured for temperatures >100.4 F and will receive appropriate other examinations, cultures 
and antibiotic therapy which will be adjusted clinically according to the patients’ status. Patients are monitored 
with physical examinations, CBC, liver and renal function routinely throughout the treatment. Transfusional 
support will occur per institution guidelines. Patients will be discharged from the hospital and followed on an 
outpatient basis as clinically indicated. 
 
The use of hematopoietic growth factors (G-CSF or GM-CSF) to stimulate blood cell production will be initiated 
post stem-cell transplant as per existing institutional policy on day +5. Antibiotics, medications to help with 
nausea, vomiting, diarrhea, and pain medication will be administered as required. Patients will be followed by a 
transplant dietician and will receive hyperalimentation through central venous access if oral intake is not adequate. 
 
Appropriate anti-coagulation is allowed during the study (i.e. LMW heparin, direct factor Xa inhibitors, etc.) for 
patients who have an indication for anticoagulation and have a sustained platelet count above 50,000. Warfarin is 
allowed during the study provided that patients are monitored for INR twice a week. In general, oral Factor Xa 
inhibitors are preferred. 
 
External beam radiation therapy will not be administered during the transplant course. External beam radiation 
may, however be given following the transplant as felt to be clinically indicated for areas of bulky tumor prior to 
transplant. Treatment with corticosteroids is permitted per standard of care as need for control or prevention of 
nausea or vomiting or for infusion reactions to medications or blood products including hematopoietic stem cells 
or any other indication at the discretion of treating physician.  Non-steroidal hormones administered for non-
lymphoma-related conditions, e.g., insulin for diabetes, are acceptable. 
 
No other cancer therapy or investigational agents will be permitted while patients are on this study. 


  
 
IRB Approval Date: 12/09/2020 
 
5.10 Criteria for Removal from Study 
- 
Withdrawal of consent 
- 
Unacceptable toxicity deemed to be related to venetoclax. For example, tumor lysis syndrome that 
cannot be controlled occurring prior to BEAM administration. 
- 
The investigator considers it, for safety reasons, to be in the best interest of the subject. 
- 
Pregnancy during the course of the study for a child-bearing participant 
- 
Death 
- 
Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. The date and 
reason for discontinuation must be documented. Every effort should be made to complete the 
appropriate assessments. 
 
5.11 Duration of Follow Up 
Patients will be followed for adverse events (AEs) starting at day -10 through day +100 after transplantation. 
Patients will be followed for one year after transplantation for PFS and OS. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-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 will be recorded and reported immediately. 
 
5.12 Dose Delays/Dose Modifications 
Should unanticipated circumstances arise that might require minor variances from the prescribed dosing and 
schedule of protocol therapy in order to ensure safety and allow patients to continue to receive treatment on study, 
the PI should be contacted in advance for discussion and approval. 
 
The dose of BEAM will remain constant for each subject throughout the study. The assigned dose of venetoclax 
will remain constant for each subject throughout the study. 
 
Venetoclax may be held or discontinued completely for uncontrolled grade 3 or 4 toxicities during the course of 
treatment that are not manageable with supportive care. This excludes hematological toxicities. 
 
5.13 Dose Adjustments for Changes in BSA 
No adjustments in doses for post-screening changes in body surface area will be made. 
 
5.14 Missed or Vomited Doses 
Missed doses maybe replaced within 2 hours. If a dose is vomited within one hour of ingestion, it will be 
considered a missed dose. The dose will not be repeated that same day but the patient will follow regular schedule 
starting the next study dosing day. If vomiting occurs more than 1 hour after dosing, it will still be considered a 
complete dose. 
 
5.15 Number of Subjects 
The number of patients accrued to this study is variable and will depend on the toxicities seen. The maximum 
number of patients accrued to phase I will be 18 with the maximum number of patients accrued to the entire study 
as 28. 
 
5.16 Expected Duration of Treatment and Subject Participation 
The duration of treatment will be 10 days. For standard BEAM, it is 6 days. Four days of lead-in venetoclax will 
be added. Venetoclax administration will continue with BEAM. Patients will be followed till day 100 after 
transplant. The long-term outcomes will also be recorded. 


  
 
IRB Approval Date: 12/09/2020 
 
5.17 Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be considered eligible for this 
study. Use the eligibility criteria to confirm a subject’s eligibility. 
 
5.18 Inclusion of Women and Minorities 
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
6 STATISTICAL ANALYSIS 
6.1 
Primary End Points 
1. To establish the maximum tolerated dose (MTD) of venetoclax that can be safely given with BEAM 
in patients with relapsed or refractory NHL. 
 
6.2 
Secondary End Points 
1. To evaluate the safety and tolerability of venetoclax combined with BEAM prior to autologous 
stem cell transplant 
2. To obtain a preliminary estimate of the efficacy of venetoclax in combination with BEAM as 
measured by overall response rate (ORR) at day 100 
3. To estimate the progression free survival (PFS) and overall survival (OS) of Venetoclax and 
BEAM followed by ASCT 
 
6.3 
Sample Size 
This is a dose-escalation, phase I study with an expansion cohort. The number of patients enrolled will vary 
depending on the dose escalation portion of the trial. We will use the 3+3 design for accruing patients. Please 
refer to study section 5.2.10 for details regarding the 3+3 design. A schematic is provided for reference below. 
Thus, the minimum number of patients will be 3 and the maximum number will be 28 (maximum number accrued 
to dose escalation portion is 18 in addition to 10 patients accrued to expansion cohort at MTD). Patients who 
experience early progression prior to start of BEAM regimen, die, or withdraw for other reasons prior to start 
BEAM will be considered unevaluable for dose-escalation decisions and will be replaced. The study is not 
powered for efficacy however if the ORR and OS compares favorably against the recently reported dismal 
outcomes in the SCHOLAR-1 analysis of 636 patients of with primary refractory DLBCL; ORR 26% (CR 7%) 
and median OS of 6.3 months [24], along with demonstrated safety, a well-powered phase II (or randomized 
phase II trial) may be entertained in the future. 


  
 
IRB Approval Date: 12/09/2020 
 
 
3+3 Design. [25] 
 
6.4 
Stopping Rules 
During the dose-escalation portion, the safety stopping rules are defined by the dose escalation plan. Analysis of 
day +100 treatment-related mortality (TRM) will be performed after each dosing cohort has accrued. If 1, or more, 
of the first 10 patients treated on trial experience TRM due to the addition of the venetoclax, the protocol will be 
suspended for further accrual until reviewed by DSMB. The study will not be terminated unless the TRM is 
deemed to be directly related to the addition of venetoclax and not due to the usual toxicities of ASCT (sepsis 
and/or multi-organ failure is the leading cause of mortality after ASCT). Examples of TRM related to venetoclax 
after start of BEAM conditioning would be massive tumor lysis or unexplained grade 3 toxicity on the Bearman 
scale (appendix II). If 2 or more out of 10 experience any TRM (90% confidence interval 5.5%-100%), the trial 
will be suspended for further accrual until reviewed by DSMB. given that the expected TRM of a standard BEAM 
and ASCT is expected to be 5%. 
 
6.5 
Evaluable Patients 
All patients who receive at least one dose of venetoclax will be included in the analysis for toxicity, efficacy and 
survival outcomes. 
 
6.6 
Analysis of Primary Endpoint 
The MTD will be determined by 3+3 design. The rate and severity of toxicities encountered will be reported. 
Toxicities will be tabulated by type and grade using NCI-CTCAE Version 4.03 and Bearman criteria, and 
displayed in summary form. 
 
6.7 
Analysis of Secondary Endpoints 
The overall response rate (ORR) will be estimated as the proportion of patients who achieve a CR or PR divided 
by the number of evaluable patients. 
Response to therapy will be classified as complete response (CR), partial response (PR), no response (NR), 
progressive disease (PD), early death, or not evaluable. Response to therapy will be determined at Day 100. The 
use of PET-CT imaging is preferred at day +100 for measurement of response (unless not indicated). These will 


  
 
IRB Approval Date: 12/09/2020 
 
be defined according to the Lugano criteria, referenced in Appendix III. Any patient who receives at least one 
dose of venetoclax and have day +100 assessment will be evaluable for the response. Patients who fail to have 
the response assessment due to early progression, death or toxicity will be considered evaluable for response and 
categorized as no-response. Patients who fail to have the response assessment for other reasons (withdraw 
consent, travel constraints) will be considered unevaluable and will not be included in the denominator when 
calculating response rate. The overall response rate will be reported with their associated 95% confidence interval. 
 
Progression-free survival will be defined from the first treatment date until the date of progression or death, 
whichever occurs first, and patients will be censored at the last date of clinical assessment if no progression. Any 
patient who begins a non-protocol therapy will be censored at the last assessment date prior to the subsequent 
therapy. Overall survival (OS) will be defined from the first treatment date until the date of death or date last 
known alive. PFS and OS will be summarized by the Kaplan-Meier method. The cumulative incidence of 
progression will be estimated from the cumulative incidence curves treating death without relapse as competing 
risk. 
 
6.8 
Optional Correlative Outcomes 
We will evaluate the association between response/survival endpoints and patient genetic characteristics such as 
the expression of BCL-2, BCL-XL, and MCL-1 as measured by immunohistochemistry (IHC), using various 
graphical displays to identify patterns and trends. Given the small numbers, this analysis is exploratory in nature 
however we will attempt quantitative analysis using univariable logistic regression model for response outcome, 
or Cox proportional hazard regression model for survival outcomes. The association between outcome and various 
subtypes of NHL will be analyzed using a similar approach. Based on prior investigations, BCL-2 expression of 
40% is considered “positive” [26]. Plan to analyze BCL-2 positivity as a binary variable (positive/negative) 
against ORR but also will analyze BCL-2 positivity as a continuous variable against ORR. As part of research, 
we plan to obtain slides and blocks from department of pathology and outside hospitals. Patients will sign a 
consent addendum to obtain slides from outside hospitals.  
 
6.9 
Expected Accrual 
We are expected to accrue 1 patient/month for this trial. Given the DLT observation period is approximately 38 
days, it will take about 4.5 months for a 3 patient cohort. The minimum of 9 months and maximum of 27 months 
will be needed for the MTD stage of the study. The maximum accrual will take about 37 months including 10 
patients for the expansion cohort. 
 
7 POTENTIAL RISKS 
7.1 
Potential Risks of venetoclax 
As of 11/28/2016, 7 phase I/II studies were ongoing with venetoclax in NHL. Preliminary safety data came from 
Arm B of M12-175. This was a phase I study of venetoclax monotherapy in patients with relapsed or refractory 
NHL. Most subjects (97.2%) experienced at least 1 treatment-emergent adverse event. An overview of adverse 
events, grade ≥ 3 adverse events, and serious adverse events reported are summarized below which is duplicated 
from the Investigator’s Brochure. 


  
 
IRB Approval Date: 12/09/2020 
 
 
 
The most common adverse events in these NHL subjects were nausea (48.1%), diarrhea (45.3%), fatigue (42.5%), 
and vomiting and decreased appetite (21.7% each). Adverse events grade 3 and above were reported for 55.7% 
subjects. 
The 
most 
common 
events   grade   3   or   above   were   anemia   (17.0%)   and   neutropenia   (11.3%).    Serious    adverse   events  
were  reported  in   34.9%   subjects.   The   most   common   serious   adverse   events   were   malignant neoplasm 
progression (9.4%), and influenza, lower respiratory tract infection, pneumonia, and hyponatremia (2.8% each). 
A total of 18 (17.0%) subjects experienced adverse events that led to discontinuation of venetoclax. The most 
common adverse events leading to discontinuation were malignant neoplasm progress (6 [5.7%] subjects), and 
thrombocytopenia and nausea (2 [1.9%] subjects each). All other events leading to discontinuation were reported 
in 1 subject each. A total of 10 (9.4%) subjects experienced adverse events that led to death, including 9 events of 
malignant neoplasm progression and 1 event each of disease progression and respiratory failure. All fatal events 
were considered to have no reasonable possibility of being related to venetoclax. 
 
Study M13-834, titled "Phase 1 Study Evaluating the Safety and pharmacokinetics of Venetoclax in Japanese 
Subjects with Hematological Malignancies," is an ongoing, open-label, dose-escalation study. The primary 
objectives of this study are to assess the safety profile and characterize the pharmacokinetics of venetoclax when 
administered in Japanese subjects with hematological malignancies. The secondary objectives are to evaluate 
preliminary efficacy data regarding the effect of venetoclax on overall response rate, time to tumor progression 
and duration of response. All (100%) subjects in Study M13-834 experienced at least 1 treatment-emergent 
adverse event. The most common adverse events were lymphopenia (73.1%), neutropenia (61.5%), nausea 
(46.2%), and leukopenia (38.5%). Of the 26 subjects, 20 (76.9%) experienced adverse events grade 3 or above, 
including events of lymphopenia and neutropenia (13 subjects each), and leukopenia (6 subjects). One subject 
experienced an adverse event of drug eruption that led to discontinuation of study drug. None of the adverse 
events resulted in death. 
 
Study M13-835, titled "An Extension Study of ABT-199 in Subjects with Advanced Non-Hodgkin Lymphoma," 
is an ongoing, open label, extension study of subjects with advanced NHL who completed a prior venetoclax 
study or were active and assigned to venetoclax when the study completed. The primary objective is to evaluate 
the safety of venetoclax monotherapy in adults with advanced NHL. As of 28 November 2016, 11 subjects have 
been rolled over from Study M13-364 (drug-drug interaction study of ketoconazole), and had safety data available 
in Study M13-835. An overview of adverse events, grade 3 adverse events, and serious adverse events reported 
in Study M13-835 is presented in the above table. Of the 11 subjects, 9 (81.8%) subjects experienced at least 1 


  
 
IRB Approval Date: 12/09/2020 
 
treatment adverse event; the most common events were diarrhea (4 subjects), thrombocytopenia, nausea, 
malignant neoplasm progression, and cough (3 subjects each). Seven subjects experienced events grade 3 or 
above, including serious malignant neoplasm progression in 3 subjects, serious syncope in 2 subjects, and 
thrombocytopenia in 2 subjects; other events occurred in 1 subject each. Three subjects experienced events that 
led to study drug discontinuation. Fatal events occurred in 3 subjects: malignant neoplasm progression in 2 
subjects and ischemic stroke in 1 subject. Below is a table duplicated from the Investigator’s Brochure 
summarizing adverse events that occurred at a rate of ≥ 10%. 
 
 
7.2 
Potential Risks of stem cell mobilization with filgrastim 
Filgrastim (G-CSF) is the agent most commonly used in stem cell mobilization. G-CSF stimulates the production, 
maturation and activation of neutrophils and activates neutrophils to increase their migration and cytotoxicity. 
Toxicities that are likely to occur include myalgias and medullary bone pain. The bone pain can be generally 
controlled with non-narcotic analgesia. Less likely side effects include fluid retention, pericardial effusion, local 
inflammation at the injection site and transient laboratory abnormalities including mild elevations in uric acid, 
lactic dehydrogenase (LDH), alkaline phosphatase, and leukocytosis. Rare but serious side effects include 
reported cases of spleen swelling resulting in splenic rupture, adult respiratory distress syndrome (ARDS) and 
allergic reactions. 
 
7.3 
Potential Risks of stem cell collection 
A central venous catheter is usually required for stem cell collection, but can also be done peripherally. Central 
catheter placement is associated with a small risk of infection, bleeding, or pneumothorax. The apheresis 


  
 
IRB Approval Date: 12/09/2020 
 
procedure, used to collect mobilized stem cells, is associated with a small risk of hypersensitivity reaction due to 
cytokine release and hypocalcemia. 
 
7.4 
Potential Risks of autologous stem cell transplantation (ASCT) 
ASCT recipients incur risks from high-dose conditioning and post-ASCT therapy, which must be weighed against 
the risk of the disease for which the ASCT is prescribed. Major risks following transplantation include: 1) 
Infection which can be bacterial, viral, parasitic, or fungal. Often, these infections are life-threatening, particularly 
when caused by viral or fungal agents, and are associated with high mortality in the transplant population; 2) 
Damage of all or any of the major organs may occur as a result of reactions to drugs (e.g., chemotherapy, 
antibiotics, anti-fungal medications), and as a result of destructive processes (e.g., infection), and may have a fatal 
outcome; brain damage can result in severe loss of cognitive or neurologic function; 3) Relapse or progression of 
lymphoma may occur, especially in patients with advanced disease status at time of treatment; 4) Unknown 
toxicities may occur in any individual patient due to multiple events and cumulative effects which may involve 
any and all organs, including the brain; and 5) Death (there is standard mortality risk with ASCT of about 5%). 
 
7.5 
Potential Risks of Carmustine (BCNU) 
Carmustine is an alkylating agent. Common side effects include myelosuppression, nausea, vomiting, headache, 
and jaw pain. Less common side effects include transient hypotension, dizziness, hyperpigmentation of the skin, 
hepatoxicity and a delayed inflammatory lung response (pneumonitis). 
 
7.6 
Potential Risks of Etoposide (VP-16) 
VP-16 is a semi-synthetic podophyllotoxin derivative. Side effects that are likely to occur include nausea, 
vomiting and diarrhea, myelosuppression, mucositis, alopecia, and fatigue. Less likely side effects include a skin 
rash, peripheral neuropathy, and hepatotoxicity. Hypotension may occur if the drug is infused quickly. A rare but 
serious side effect is a small risk of developing a second cancer. 
 
7.7 
Potential Risks of Cytarabine (Ara-C) 
Cytarabine, commonly known as Ara-C, is a synthetic nucleoside. Likely side effects include myelosuppression, 
nausea, vomiting and diarrhea, oral and anal inflammation or ulceration, hepatic dysfunction, fever, rash, and 
thrombophlebitis. Less likely side effects include conjunctivitis (when Ara-C is given at high doses, and 
preventable by the prophylactic use of corticosteroid eye drops), abdominal pain, alopecia, pruritis, headache, and 
the occurrence of a cytarabine syndrome characterized by fever, myalgias, arthralgias, chest pain, maculopapular 
rash, conjunctivitis and malaise - this syndrome occurs 6-12 hours following drug administration. Corticosteroids 
are beneficial in treating this syndrome. A rare but serious side effect is cerebral/cerebellar dysfunction (more 
common at very high doses and in older patients). 
 
7.8 
Potential Risks of Melphalan 
Melphalan, an alkylating agent, is a phenylalanine derivative of nitrogen mustard. At high doses, the likely 
toxicities include myelosuppression, gastrointestinal toxicity and alopecia. The duration of profound 
myelosuppression decreases with the use of stem cell transplantation and colony stimulating factors. 
Gastrointestinal toxicity, which includes potentially severe stomatitis, esophagitis and diarrhea, may require 
intravenous narcotics for mucositis related pain, intravenous hydration and alimentation, and antibiotics. Less 
likely is hepatotoxicity. Rare but serious toxicities reported include pulmonary fibrosis and interstitial 
pneumonitis, venoocclusive disease of the liver, skin hypersensitivity, vasculitis, hemolytic anemia, allergic 
reactions, and a small risk of developing second cancers. 


  
 
IRB Approval Date: 12/09/2020 
 
8 SAFETY AND REPORTING REQUIREMENTS 
8.1 
Assessment of safety 
Safety assessments will consist of monitoring and recording adverse events (and serious adverse events; 
measurements of protocol-specified hematology, clinical chemistry, and other laboratory variables; measurement 
of protocol-specified vital signs; and other protocol-specified tests that are deemed critical to the safety evaluation 
of the study drug(s) and should be consistent with institutional standards and Good Clinical Practice. 
 
8.2 
Definitions 
8.2.1 Adverse event 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, associated with a 
research study, which causes harm or injury to a research participant as a result of the participant’s involvement 
in a research study. The event can include abnormal laboratory findings, symptoms, or disease associated with 
the research study. The event does not necessarily have to have a causal relationship with the research, any risk 
associated with the research, the research intervention, or the research assessments. 
 
Adverse events may be the result of the interventions and interactions used in the research; the collection of 
identifiable private information in the research; an underlying disease, disorder, or condition of the subject; and/or 
other circumstances unrelated to the research or any underlying disease, disorder, or condition of the subject. 
 
8.2.2 Serious Adverse Events 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any of the following 
outcomes: 
 Results in death. 
 Is a life-threatening adverse experience. The term life-threatening in the definition of serious refers 
to an adverse event in which the subject was at risk of death at the time of the event. It does not refer 
to an adverse event which hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. Any adverse event 
leading to hospitalization or prolongation of hospitalization will be considered as Serious, UNLESS 
at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., planned admission to the hospital for BEAM and 
ASCT) OR 
o The admission is not associated with an adverse event (e.g., social hospitalization for 
purposes of respite care. 
However, it should be noted that invasive treatment during any hospitalization may fulfill the criteria of 
“medically important” and as such may be reportable as a serious adverse event dependent on clinical judgment. 
In addition, where local regulatory authorities specifically require a more stringent definition, the local regulation 
takes precedent. 
 Results in persistent or significant disability/incapacity. The definition of disability is a substantial 
disruption of a person’s ability to conduct normal life’s functions. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event. Important medical events that may not result death, be life- 
threatening, or require hospitalization may be considered a serious adverse experience when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood disease or disorders, or convulsions that do not result in inpatient hospitalization, or the 


  
 
IRB Approval Date: 12/09/2020 
 
development of drug dependency or drug abuse. The development of a new cancer is always 
considered an important medical event. 
 For the purpose of this study, a toxicity of grade 4 or greater on CTCAE version 4.03 during venetoclax 
treatment, or 3 or greater on the Bearman scale from days -10 through hospital discharge after 
transplant (usually occurs between day +14 to day +21 after ASCT), would constitute an SAE. 
Hematological toxicities and alopecia will be excluded from AE assessment. 
 
8.2.3 Suspected Adverse Reaction 
A Suspected Adverse Reaction is any adverse event for which there is a “reasonable possibility” that the drug 
caused the adverse event. “Reasonable Possibility”, for the purposes of safety reporting, means there is evidence 
to suggest a causal relationship between the drug and the adverse event. Examples of evidence that would suggest 
a causal relationship between the drug and the adverse event are: 
• A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., 
angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, anaphylaxis, and Stevens-Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g., include tendon rupture or heart valve lesions in young 
adults, or intussusception in healthy infants). If the event occurs in association with other factors strongly 
suggesting causation (e.g., strong temporal association, event recurs on rechallenge), a single case may be 
sufficiently persuasive; but often, more than one occurrence (from one or multiple studies) would be needed 
before the sponsor could make a determination of whether the drug caused the event. 
• An aggregate analysis of specific events that can be anticipated to occur in the study population independent of 
drug exposure. Such events include known consequences of the underlying disease or condition under 
investigation (e.g., symptoms or disease progression), or events unlikely to be related to the underlying disease 
or condition under investigation, but commonly occur in the study population independent of drug therapy (e.g., 
cardiovascular events in an elderly population). An aggregate analysis (across studies) will identify those events 
that occur more frequently in the drug treatment group than in a concurrent or historical control group. 
 
8.2.4 Unexpected 
An “unexpected” AE is an AE that is not listed in the Investigator Brochure or is not listed at the specificity or 
severity that has been observed. For example, hepatic necrosis would be “unexpected” (by virtue of greater 
severity) if the Investigator Brochure referred only to elevated hepatic enzymes or hepatitis. "Unexpected" also 
refers to AEs that are mentioned in the Investigator Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the study 
drug under investigation. 
 
8.3 
Adverse Event Evaluation 
The investigator or designee is responsible for ensuring that all adverse events (both serious and non-serious) 
observed by the clinical team or reported by the subject which occur after the subject has signed the informed 
consent are fully recorded in the subject’s medical records. Source documentation must be available to support 
all adverse events. 
 
A laboratory test abnormality considered clinically relevant should be reported as an adverse event. As all patients 
will be undergoing ASCT, hematological toxicities and alopecia will not be considered AEs. 
 
The investigator or sub-investigator (treating physician if applicable) will provide the following for all adverse 
events (both serious and non-serious): 
 Event term (as per CTCAE days -10 to -7, then utilizing the Bearman scale) 
 Description of the event 
 Date of onset and resolution 


  
 
IRB Approval Date: 12/09/2020 
 
 Expectedness of the toxicity 
 Grade of toxicity 
 Attribution of relatedness to the investigational agent- (this must be assigned by an investigator, sub- 
investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, dose interrupted, 
reduced, discontinued, etc. or action taken with regard to the event, i.e. no action, received concurrent 
medication or other intervention, etc. 
 Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 will be utilized for AE reporting. 
 
Attribution is the relationship between an adverse event or serious adverse event and the study drug. Attribution 
will be assigned as follows: 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
8.4 
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported as instructed. The 
electronic FDA SAE reporting forms should not be used. 
 
8.5 
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events will be reported that occur from days -10 through hospital 
discharge after transplant (usually occurs between day +14 to day +21 after ASCT). Adverse events, both serious 
and non-serious, and deaths that occur during this period will be recorded in the source documents. All SAEs 
should be monitored until they are resolved or are clearly determined to be due to a subject’s stable or chronic 
condition or intercurrent illness(es). Related AEs will be followed until resolution to baseline or grade 1 or 
stabilization. 
 
8.6 
SAE Reporting Requirements 
Participating investigators must report all serious adverse events to the Principal Investigator within 24 hours of 
discovery or notification of the event. The participating investigator must also provide follow-up information on 
the SAE until final resolution. 
 
Kami Maddocks 
Kami.Maddocks@osumc.edu 
Fax (614) 293-7526 
 
The Principal Investigator will review the SAE and report the event to the FDA, external collaborator(s), and IRB 
as applicable. It is the Investigator’s responsibility to ensure that ALL serious adverse events that occur on the 
study are reported to all participating sites. 
 
All SAEs (initial and follow-up information) will be reported on an Event Reporting form and submitted to the 
OSU IRB within 24 hours of the discovery of the event or information. All deaths should be reported with the 
primary cause of death as the AE term, as death is typically the outcome of the event, not the event itself. The 


  
 
IRB Approval Date: 12/09/2020 
 
primary cause of death on the autopsy report should be the term reported. If study drug is discontinued because 
of an SAE, this information must be included in the SAE report. 
 
8.7 
SAE of Special Interest 
Venetoclax events of special interest are 
- 
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 
 
8.8 
Data Safety and Toxicity Committee 
The PI will ensure that ALL SAEs occurring on this trial (internal or external) are reported to the FDA, appropriate 
IRBs, sponsoring company and other applicable parties. 
 
8.9 
Data and Safety Monitoring Plan (DSMP) 
The Phase 1 clinical trial proposed in this application will be conducted using a DSMP that is in compliance with 
the Institutional (OSU-CCC) DSMP guidelines approved by the NCI in 2008. The data and safety monitoring 
plan for this phase 1 trial will involve the continuous evaluation of safety, data quality and data timeliness. 
Investigators will conduct continuous review of data and patient safety at the program meetings (twice monthly) 
and at the Phase 1/2 weekly meeting which is led by Dr. Michael Grever. This review of the trials includes 
discussion of ‘milestone’ events such as dose escalation or encounters of DLT or SAEs. All discussions will be 
documented in the minutes. The PI of the trial will review toxicities and responses of the trial, where applicable, 
at these disease center meetings and determine if the risk/benefit ratio of the trial changes. Frequency and severity 
of adverse events will be reviewed by the PI and compared to what is known about the agent/device from other 
sources; including published literature, scientific meetings and discussions with the sponsors, to determine if the 
trial should be terminated before completion. Serious adverse events and responses will also be reviewed by the 
OSU-CCC Data and Safety Monitoring Committee (DSMC). 
 
8.10 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. 
Investigators and study staff will undergo training on Good Clinical Practice (GCP) through the Collaborative 
Institutional Training Initiative (CITI). GCP training sets the standard for the design, conduct, recording, and 
reporting of studies involving human subjects, ensuring that study subjects rights, safety, and well-being are 
protected. The IRB will review all appropriate study documentation in order to safeguard the rights, safety and 
wellbeing of the patients. The study will only be conducted at sites where IRB approval has been obtained. The 
protocol, Investigator’s Brochures, informed consent form, written information given to the patients (including 
pill diaries), safety updates, annual progress reports, and any revisions to these documents will be provided to the 
IRB by the investigator, as allowable by local regulations. The principal investigator will ensure that the study 
will be conducted according to the protocol and all applicable regulations. The protection of each subject’s rights 
and welfare will be maintained. 
 
8.11 Retention of records 
FDA regulations (21 CFR § 312.62[c]) and the ICH Guideline for 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 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 


  
 
IRB Approval Date: 12/09/2020 
 
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 United States 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. 
 
8.12 PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 9. 
 
9 INVESTIGATIONAL AGENTS 
9.1 
Venetoclax 
9.1.1 Nomenclature 
Associated Name(s): ABT-199, A-1195425.0, GDC-0199, RO5537382 
Generic Name: venetoclax 
INN (International Nonproprietary Name): venetoclax 
USAN 
(United 
States 
Adopted 
Name): 
venetoclax 
Chemical 
Abstracts 
Service 
(CAS) 
Registry Number 1257044-40-8 
Japanese Accepted Name (JAN): venetoclax 
9.1.2 Structural formula 
 
 
 
9.1.3 Molecular Formula and Molecular Weight 
Molecular Formula: C45H50ClN7O7S 
Molecular Weight: 868.44 
 
9.1.4 Physical and Chemical Properties of the Drug Substance 
Description: Light yellow to yellow to dark yellow powder. 
Solubility: The solubility of venetoclax in various media is detailed in the table below. 


  
 
IRB Approval Date: 12/09/2020 
 
Optical Isomerism: There are no optical isomers. 
 
 
9.1.5 Pharmaceutical properties (Formulation) 
Dosage form: Tablets 
Strength: 10, 50, 100 mg 
Excipients: Copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, calcium phosphate 
dibasic 10 mg and 100 mg: coating contains iron oxide yellow, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, and talc. 50 mg: coating contains iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, 
titanium dioxide, polyethylene glycol, and talc. 
 
9.1.6 Storage and Handling 
The clinical supply should be stored at 15 – 25 ℃ (59 – 77 ℉) 
 
9.2 
Commercial Agents 
9.2.1 Filgrastim 
Other Names: Neupogen, G-CSF 
Product description: Filgrastim is commercially available from Amgen, Inc. (Thousand Oaks, CA) in single- 
dose vials containing either 1 ml or 1.6 ml, in boxes of 10 vials each. Each vial of filgrastim contains 300 µg/ml. 
The product is formulated in a 10nM sodium acetate buffer at pH 4.0, containing sorbitol and 0.004% Tween 80. 
 
Solution preparation: N/A 
 
Storage requirements: Filgrastim should be stored at 2 C to 8 C (36 F to 46 F) and should not be frozen. 
 
Stability: Filgrastim vials and prefilled syringes are stable for 7 days at 9°C to 30°C (47°F to 86°F), however, 
the manufacturer recommends discarding after 24 hours because of microbiological concerns. The product is 
packaged without a preservative. 
Undiluted filgrastim is stable for 24 hours at 15°C to 30°C and for 2 weeks at 2°C to 8°C (36°F to 46°F) in 
tuberculin syringes. However, the manufacturer recommends using immediately because of concern for bacterial 
contamination. 
 
Route of administration: Filgrastim is administered subcutaneously in single per institutional standard of care 
practices. Filgrastim should not be administered earlier than 24-48 hours after chemotherapy, nor should it be 
administered in the 24-hour period prior to chemotherapy. 


  
 
IRB Approval Date: 12/09/2020 
 
Drug Procurement: From commercial supply 
 
9.2.2 BCNU (bis-chloronitrosourea or carmustine) 
Other Names: Carmustine 
Product description: BCNU is supplied as a lyophilized powder containing no preservatives. 
 
Solution preparation: Due to its water insolubility, it is to be reconstituted with the diluent provided (3 ml of 
absolute ethanol) and then with either 27 ml or 17 ml of sterile water for injection to provide a resulting 
concentration of 3.3 mg/ml or 5 mg/ml, respectively. 
 
Storage requirements: Unopened vials are stable under refrigeration for two years. BCNU has a low melting 
point requiring refrigeration at all times prior to reconstitution. Do not use if an oil film is present at the bottom 
of vial. 
 
Stability: Stability upon reconstitution (less than 8% potency lost) is eight hours at room temperature or 24 hours 
if refrigerated and protected from light. BCNU solution may be further diluted with 500 ml of 5% Dextrose OR 
sodium chloride injection, USP, and will be stable for 8 hours. Diluted solution should be protected from light. 
 
Route of administration: BCNU should be administered by IV drip over three hours. Absorption of BCNU to 
plastics has been documented. Thus, PVC free bags and polyethylene tubing should be used during the 
administration of BCNU. 
 
Drug Procurement: From commercial supply 
 
9.2.3 Etoposide 
Other Names: VP-16, Toposar® 
 
Product description: Etoposide Injection USP is available for intravenous use as 20 mg/mL solution in 100 mg 
(5 mL), 500 mg (25 mL), and 1 g (50 mL) sterile, multiple-dose vials. The pH of the clear, nearly colorless to 
yellow liquid is 3 to 4. Each mL contains 20 mg etoposide USP, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. 
 
Solution preparation: Etoposide Injection must be diluted prior to use with either 5% Dextrose Injection, or 
0.9% Sodium Chloride Injection, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at 
concentrations above 0.4 mg/mL, precipitation may occur. 
 
Storage requirements: Unopened vials of Etoposide Injection are stable for 24 months at room temperature 
(25°C). 
 
Stability: Vials diluted as recommended to a concentration of 0.2 or 0.4 mg/mL are stable for 96 and 24 hours, 
respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers. 
The use of non-PVC containers and tubing is recommended due to the potential for polysorbate 80 leaching of 
diethylhexyl phthalate (DEHP), from polyvinyl chloride (PVC) containers and tubing into etoposide IV solution. 
 
Route of administration: Etoposide should be given by intravenous infusion over 2 hours. 
 
Drug Procurement: From commercial supply 


  
 
IRB Approval Date: 12/09/2020 
 
9.2.4 Cytarabine 
Other Names: Ara-C, Cytosar® 
 
Product description: Cytarabine is provided as a sterile lyophilized material for reconstitution and intravenous, 
intrathecal or subcutaneous administration. It is available in multi-dose vials containing 100 mg, 500 mg, 1 g or 
2 g sterile cytarabine. 
 
Solution preparation: For IV use, reconstitute the 100-mg vial with 5 mL bacteriostatic water for injection to 
achieve a concentration of 20 mg/mL. Add 10 mL of bacteriostatic water to the 500-mg vial to achieve a final 
concentration of 50 mg/mL. Add 10 and 20 mL of bacteriostatic water to the 1 and 2 gm vials respectively to 
achieve a final concentration of 100 mg/mL. For subcutaneous use, reconstitute the powder with sterile water or 
saline to a concentration of 50-100 mg/mL. 
 
Storage requirements: The drug is stored unreconstituted at controlled room temperature, 15° to 30°C (59° to 
86°F). 
 
Stability: Solutions reconstituted with sterile water without preservative should be used immediately; solutions 
reconstituted with Bacteriostatic of Water are stable up to 48 hours at controlled room temperature (15o to 30oC). 
Solutions with a slight haze should be discarded. 
 
Route of administration: Cytarabine is administered by IV infusion over 1-2 hours. 
 
Drug Procurement: From commercial supply 
 
9.2.5 Melphalan 
Other Names: L-phenylalanine mustard, phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran® 
 
Product description: Melphalan is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single-use vial 
contains melphalan hydrochloride equivalent to 50 mg melphalan and povidone. ALKERAN for Injection is 
reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium citrate, propylene 
glycol, ethanol (96%), and water for injection to a total of 10 mL. 
 
Solution preparation: Melphalan must be reconstituted at room temperature by rapidly injecting 10 mL of the 
supplied diluent directly into the vial of lyophilised powder using a sterile needle (20-gauge or larger needle 
diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. Rapid addition of the 
diluent, as a single quantity, followed by immediate vigorous shaking is important for proper dissolution. 
Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection to a concentration not greater 
than 0.45 mg/mL. 
 
Storage requirements: Melphalan vials should be stored below 30°C and protected from light. 
 
Stability: Following reconstitution with sterile diluent, melphalan hydrochloride solution containing 5 mg/ml is 
stable for up to 90 minutes at room temperature; this reconstituted solution should not be refrigerated since a 
precipitate may form at 5oC. The reconstituted solution should be diluted further with 0.9% sodium chloride 
injection to provide a solution with a concentration not exceeding 0.45 mg/ml. This diluted solution is stable for 
60 minutes at room temperature. 
 
Route of administration: Melphalan should be administered as IV push or rapid infusion over 10 minutes. 


  
 
IRB Approval Date: 12/09/2020 
 
Drug Procurement: From commercial supply 
 
10 DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF STUDY 
RECORDS 
10.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. The Principal 
Investigator will ensure that the subject is given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of the study as well as the subject’s financial responsibility. Subjects must 
also be notified that they are free to discontinue from the study at any time. The subject should be given the 
opportunity to ask questions and be allowed time to consider the information provided. 
 
The original, signed written Informed Consent Form must be kept with the Research Chart in conformance with 
the institution’s standard operating procedures. A copy of the signed written Informed Consent Form must be 
given to the subject. Additionally, documentation of the consenting process should be located in the research 
chart. 
 
10.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject must sign an 
authorization to release medical information to the sponsor and/or allow the sponsor, a regulatory authority, or 
Institutional Review Board access to subject’s medical information that includes all hospital records relevant to 
the study, including subjects’ medical history. 
 
10.3 Retention of records 
The Principal Investigator of supervises the retention of all documentation of adverse events, records of study 
drug receipt and dispensation, and all IRB correspondence for as long as needed to comply with local, national 
and international regulations. No records will be destroyed until the Principal Investigator confirms destruction 
is permitted. 
 
10.4 Audits and inspections 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics Committee (IEC) or an 
Institutional Review Board (IRB) may visit the site to perform audits or inspections, including source data 
verification. The purpose of an audit or inspection is to systematically and independently examine all study- 
related activities and documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements. 
 
10.5 Adverse Events 
Adverse events will be reported as outlined in section 8. 
 
10.6 Data Reporting 
The Investigator will prepare and maintain adequate and accurate source documents. These documents are 
designed to record all observations and other pertinent data for each patient enrolled in this clinical trial. Source 
records must be adequate to reconstruct all data transcribed onto the Case Report Forms (CRFs). 
 
10.7 Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 21 CFR 
parts 56 & 50), state or local laws. 


  
 
IRB Approval Date: 12/09/2020 
 
REFERENCES 
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2. 
Gisselbrecht, C., et al., Rituximab maintenance therapy after autologous stem-cell transplantation in 
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3. 
Gisselbrecht, C., et al., Salvage regimens with autologous transplantation for relapsed large B-cell 
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Schouten, H.C., et al., High-dose therapy improves progression-free survival and survival in relapsed 
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Ayala, E., Hematopoietic cell transplantation for B-cell lymphoma: an update. Cancer Control, 2012. 
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Chen, Y.B., et al., Impact of conditioning regimen on outcomes for patients with lymphoma undergoing 
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Khouri, I.F., et al., Concurrent administration of high-dose rituximab before and after autologous stem- 
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William, B.M., et al., Phase I/II study of bortezomib-BEAM and autologous hematopoietic stem cell 
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Visani, G., et al., BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell 
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Shimoni, A., et al., A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high- 
dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell 
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Vose, J.M., et al., Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and 
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Johnson-Farley, N., et al., ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor 
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McConnell, I., E. Anderson, and V. Yazbeck, Abstract 2770: Bcl-2 overexpression is a predictive 
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Tanos, R., et al., Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma. 
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Grundy, M., et al., Predicting effective pro-apoptotic anti-leukaemic drug combinations using co- 
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Davids, M.S., et al., Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory 
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IRB Approval Date: 12/09/2020 
 
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Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma. Blood, 
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Zelenetz, A.D., et al., Results of a Phase Ib Study of Venetoclax Plus R- or G-CHOP in Patients with B- 
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Tahir, S.K., et al., Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC 
Cancer, 2017. 17(1): p. 399. 
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Cheson, B.D., et al., Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol, 2014. 32(27): p. 3059-68. 
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Bearman, S.I., et al., Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin 
Oncol, 1988. 6(10): p. 1562-8. 
22. 
Remenyi, P., et al., Peripheral blood stem cell mobilization and engraftment after autologous stem cell 
transplantation with biosimilar rhG-CSF. Adv Ther, 2014. 31(4): p. 451-60. 
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Tay, J., et al., Transfusion of Red Cells in Hematopoietic Stem Cell Transplantation (TRIST Study): A 
Randomized Controlled Trial Evaluating 2 Red Cell Transfusion Thresholds. Blood, 2016. 128(22): p. 
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Crump, M., et al., Outcomes in refractory diffuse large B-cell lymphoma: results from the international 
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CHOP or R-EPOCH. Blood, 2016. 128(22): p. 5396-5396. 


  
 
IRB Approval Date: 12/09/2020 
 
APPENDIX I 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able to 
carry on all pre-disease performance 
without restriction. 
 
100 
Normal, 
no 
complaints, 
no 
evidence of disease. 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities. Up and 
about more than 50% if waking hours. 
 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
 
50 
Requires considerable assistance 
and frequent medical care. 
 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
 
40 
Disabled, requires special care and 
assistance. 
 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
 
20 
Very 
sick, 
hospitalization 
indicated. Death not imminent. 
 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead 


  
 
IRB Approval Date: 12/09/2020 
 
APPENDIX II - BEARMAN SCALE 
Seattle criteria (Bearman) assess post-transplant regimen-related toxicity in eight organs: the heart, bladder, 
kidneys, lungs, liver, mucosa, central nervous system (CNS), and gut. As the criteria exclusively assess RRT, 
they exclude adverse events attributable to GVHD and infection. Similarly, renal failure is excluded when it 
coincides with the administration of known nephrotoxic agents. 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
 
 
 
Heart 
 
Mild 
electrocardiogram 
abnormality, not requiring 
medical intervention; or noted 
heart enlargement on CXR 
with no clinical symptoms 
Moderate 
electrocardiogram 
abnormalities 
requiring 
and 
responding 
to 
medical 
intervention; 
or 
requiring 
continuous monitoring without 
treatment; or congestive heart 
failure responsive to digitalis or 
diuretics 
Severe 
electrocardiogram 
abnormalities with no or only 
partial response to medical 
intervention; or heart failure 
with no or only minor 
response 
to 
medical 
intervention: or decrease in 
voltage by more than 50% 
 
 
Bladder 
Macroscopic hematuria after 2 
days from last chemotherapy 
dose 
with 
no 
subjective 
symptoms of cystitis and not 
caused by infection 
Macroscopic hematuria after 7 
days from last chemotherapy 
dose not caused by infection; or 
hematuria after 2 days with 
subjective symptoms of cystitis 
not caused by infection 
Hemorrhagic cystitis with 
frank blood, necessitating 
invasive local intervention 
with installation of sclerosing 
agents, nephrostomy or other 
surgical procedures 
 
Kidney 
Increase in creatinine up to 
twice the baseline value 
Increase in creatinine above 
twice baseline but not requiring 
dialysis 
 
Requirement of dialysis 
 
Dyspnea 
without 
CXR CXR with extensive localized 
 
 
changes 
not 
caused 
by infiltrate or moderate interstitial  
 
infection or congestive heart 
changes combined with dyspnea 
Interstitial changes requiring 
 
failure; or CXR showing and not caused by infection or 
mechanical 
ventilatory 
Lung 
isolated infiltrate or mild CHF; or decrease of PO2 (>10% 
support or >50% oxygen on 
 
interstitial changes without from baseline) but not requiring 
mask and not caused by 
 
symptoms not caused by mechanical ventilation or >50% 
infection or CHF 
 
infection or congestive heart 
O2 on mask and not caused by 
 
 
failure 
infection 
 
 
Mild hepatic dysfunction with Moderate hepatic dysfunction 
 
 
2.0 mg/dl 
<bilirubin with 
bilirubin 
>6 mg/dl  
 
<6.0 mg/dl or weight gain 
<20 mg/dl; 
or 
serum 
AST Severe hepatic dysfunction 
 
>2.5% 
and 
<5% 
from increase 
>five-fold 
from with bilirubin >20 mg/dl; or 
Liver 
baseline, of noncardiac origin; preconditioning; 
or 
clinical hepatic encephalopathy; or 
 
or serum AST increase more 
ascites or image-documented ascites 
compromising 
 
than two-fold but less than 
ascites >100 ml; or weight gain 
respiratory function 
 
five-fold 
from 
lowest >5% 
from 
baseline 
of  
 
preconditioning 
noncardiac origin 
 
 
 
CNS 
 
Somnolence but the patient is 
easily arousable and oriented 
after arousal 
Somnolence 
with 
confusion 
after arousal; or other new 
objective CNS symptoms with 
no loss of consciousness not 
more easily explained by other 
Seizures 
or 
coma 
not 
explained (documented) by 
other 
medication, 
CNS 
infection, or bleeding 


  
 
IRB Approval Date: 12/09/2020 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
 
 
medication, bleeding, or CNS 
infection 
 
 
 
Stomatitis 
 
Pain and/or ulceration not 
requiring a continuous i.v. 
narcotic drug 
 
Pain and/or ulceration requiring 
a continuous i.v. narcotic drug 
(morphine drip) 
Severe 
ulceration 
and/or 
mucositis 
requiring 
preventive 
intubation; 
or 
resulting 
in 
documented 
aspiration pneumonia with or 
without intubation 
 
 
GI 
toxicity 
 
 
Watery stools >500 ml but 
<2000 ml 
every 
day 
not 
related to infection 
Watery stools >2000 ml every 
day not related to infection; or 
macroscopic hemorrhagic stools 
with no effect on cardiovascular 
status not caused by infection; or 
subileus not related to infection 
Ileus requiring nasogastric 
suction and/or surgery and 
not related to infection; or 
hemorrhagic 
enterocolitis 
affecting 
cardiovascular 
status 
and 
requiring 
transfusion 
Grade IV regimen-related toxicity is defined as fatal toxicity. 
CXR=chest X ray; i.v.=intravenous; CNS=central nervous system; GI=gastrointestinal; CHF=congestive heart 
failure. 
 
 
APPENDIX III – LUGANO RESPONSE CRITERIA [20] 
 
 
Response and site PET/CT-based response 
CT-based response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the 
following) 
Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 3* with or without a residual mass 
on 5PS¶ 
 
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (eg, 
with 
chemotherapy 
or 
myeloid 
colony- 
stimulating factors), uptake may be greater than 
normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake. 
Target nodes/nodal masses must regress 
to ≤1.5 cm in LDi 
 
No extralymphatic sites of disease 
Nonmeasured 
lesions 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 


  
 
IRB Approval Date: 12/09/2020 
 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal 
by 
morphology; 
if 
indeterminate, IHC negative 
Partial 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic 
sites 
Score 4 or 5¶ with reduced uptake compared 
with baseline and residual mass(es) of any size 
≥50 percent decrease in SPD of up to six 
target measurable nodes and extranodal 
sites 
 
At interim, these findings suggest responding 
disease 
 
At end of treatment, these findings indicate 
residual disease 
 
When a lesion is too small to measure on 
CT, assign 5 mm x 5 mm as the default 
value 
 
 
When no longer visible, 0 x 0 mm 
 
 
For a node >5 mm x 5 mm, but smaller 
than normal, use actual measurement for 
calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, 
regressed, 
but 
no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by >50 
percent in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given to further evaluation with MRI 
or biopsy or an interval scan. 
Not applicable 
No response or 
stable disease 
No metabolic response 
Stable disease 
Target 
Score 4 or 5 with no significant change in FDG <50 percent decrease from baseline in 
nodes/nodal 
uptake from baseline at interim or end of 
SPD of up to six dominant, measurable 
masses, 
treatment 
nodes and extranodal sites; no criteria 
extranodal lesions  
for progressive disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression 
Organ 
enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease 
Progressive metabolic disease 
Progressive disease requires at least one 
of the following 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
PPD progression 
Extranodal 
lesions 
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment 
An individual node/lesion must be 
abnormal with: LDi >1.5 cm and 


  
 
IRB Approval Date: 12/09/2020 
 
 
 
Increase by ≥50 percent from PPD nadir 
and 
 
An increase in LDi or SDi from nadir 
 
0.5 cm for lesions ≤2 cm 
 
1.0 cm for lesions >2 cm 
 
In the setting of splenomegaly, the 
splenic length must increase by >50 
percent of the extent of its prior increase 
beyond baseline (eg, a 15 cm spleen 
must increase to >16 cm). If no prior 
splenomegaly, must increase by at least 
2 cm from baseline. 
 
New or recurrent splenomegaly 
Nonmeasured 
lesions 
None 
New or clear progression of preexisting 
nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any 
axis; if <1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
 
Assessable 
disease 
of 
any 
size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
5PS: 5-point scale; CT: computed tomography; FDG: fluorodeoxyglucose; IHC: immunohistochemistry; LDi: 
longest transverse diameter of a lesion; MRI: magnetic resonance imaging; PET: positron emission tomography; 
PPD: cross product of the LDi and perpendicular diameter; SDi: shortest axis perpendicular to the LDi; SPD: sum 
of         the         product         of         the         perpendicular         diameters         for         multiple         lesions. 
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow), 


  
 
IRB Approval Date: 12/09/2020 
 
FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher 
than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid 
growth 
factors). 
¶ PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 


  
 
IRB Approval Date: 12/09/2020 
 
Appendix IV – CYP3A4 INHIBITORS OR INDUCERS