Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Relapsed multiple myeloma Refractory multiple myeloma Multiple myeloma Relapsed/refractory multiple myeloma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 117
Healthy volunteers: no

Brief summary:
The Phase 1 primary objectives of this study were to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and recommended Phase 2 dose (RPTD) of ABT-199 (venetoclax) when administered in participants with relapsed or refractory multiple myeloma. This study also assessed the safety profile and PK of venetoclax in combination with dexamethasone in participants with t(11;14)-positive multiple myeloma.

The Phase 2 primary objective was to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in participants with t(11;14)-positive multiple myeloma.

Detailed description:

Arms:
arm 1: Participants in the dose-escalation cohort received 300 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. arm 2: Participants in the dose-escalation cohort received 600 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. arm 3: Participants in the dose-escalation cohort received 900 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. arm 4: Participants in the dose-escalation cohort received 1200 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. arm 5: Participants in the safety expansion cohort received 1200 mg of venetoclax daily on Days 1 - 21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. arm 6: Participants with t(11;14) translocation multiple myeloma received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years). arm 7: The Phase 2 cohort further explored the efficacy of venetoclax in combination with dexamethasone in relapsed or refractory participants with t(11;14) translocation multiple myeloma. Participants received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years).

Interventions: intervention 1: Venetoclax intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. intervention 2: Tablets were administered by mouth per the dexamethasone prescribing information.

Protocol document:
Prot_000.pdf: 
Venetoclax (ABT-199)
M13-367 Protocol Amendment 12
EudraCT 2012-000589-38
1
1.0
Title Page
Clinical Study Protocol M13-367
A Phase 1/2 Study Evaluating the Safety and 
Pharmacokinetics of ABT-199 in Subjects with 
Relapsed or Refractory Multiple Myeloma
Incorporating Administrative Change 1, and 
Amendments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
AbbVie Investigational 
  Product:
Venetoclax (ABT-199)
Date:
17 February 2021
Development Phase:
1/2
EudraCT:
2012-000589-38
Study Design:
This is an open-label study designed to determine the safety, 
pharmacokinetics, maximum tolerated dose, and the recommended 
Phase 2 dose of ABT-199 in subjects with relapsed or refractory 
multiple myeloma.
Investigator:
Investigator information on file at AbbVie.
Sponsor:
AbbVie*
Collaborative Partners Genentech, Inc.
Sponsor/Emergency 
  Contact:
, MD
Medical Director, TA Oncology
Pharmacyclics Switzerland 
GmbH
An AbbVie Company
Mühlentalstrasse 36
CH-8200 Schaffhausen
Located in Europe:
Phone:
Emergency 24-hour Number:  
Email: 
  
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
 
NCT01794520


Venetoclax (ABT-199)
M13-367 Protocol Amendment 12
EudraCT 2012-000589-38
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
11 April 2012
Administration Change 1
17 October 2012
Amendment 1
16 November 2012
Amendment 2
22 March 2013
Amendment 3
03 March 2014
Amendment 4
01 December 2014
Amendment 5
23 April 2016
Amendment 6
05 October 2017
Amendment 7
11 January 2018
Amendment 8
30 May 2018
Amendment 9 
15 March 2019
Amendment 10
24 September 2019
Amendment 11
03 November 2020
The purpose of this amendment is to:
●
Update to Section 5.1 Overall Study Design and Plan:  Description
Rationale:  To clarify subjects will continue on treatment until the end of study 
provided they continue to tolerate Venetoclax, have no evidence of disease 
progression, and do not meet any criteria for subject discontinuation 
(Section 5.4.1)
●
Update to Section 13.0 Completion of the Study
Rationale:  To clarify end of study is the end of study is defined as the date of 
the last subject's last visit, including Safety Follow Up.
 


Venetoclax (ABT-199)
M13-367 Protocol Amendment 12
EudraCT 2012-000589-38
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1.2
Synopsis
AbbVie
Protocol Number:  M13-367
Name of Study Drug:  Venetoclax (ABT-199)
Phase of Development:  1/2
Name of Active Ingredient:  Not available
Date of Protocol Synopsis:  17 February 2021
Protocol Title:  A Phase 1/2 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects 
with Relapsed or Refractory Multiple Myeloma
Objectives:
Phase 1 Portion (Dose Escalation, Safety Expansion and Venetoclax-Dexamethasone (VenDex) 
Combination: 
The primary objectives are to assess the safety profile, characterize pharmacokinetics (PK), determine 
the dosing schedule, the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RPTD) 
of venetoclax monotherapy when administered in subjects with relapsed or refractory multiple myeloma 
(MM).  This study will also assess the safety profile and PK of venetoclax in combination with 
dexamethasone in subjects with t(11;14)-positive MM.  The secondary objectives are to evaluate the 
preliminary efficacy data regarding the effect of venetoclax monotherapy or combined with 
dexamethasone on objective response rate (ORR), time to response (TTR), time to disease progression 
(TTP), and duration of response (DOR).  
Phase 2 Portion (VenDex Expansion): 
The primary objective of the Phase 2 portion is to further evaluate the ORR and very good partial 
response or better rate (VGPR+) in subjects with t(11;14)-positive multiple myeloma.  The secondary 
objectives are to monitor safety, progression free survival (PFS), DOR, TTR, TTP, and overall survival 
(OS) and to evaluate Patient Reported Outcomes (PRO) including Worst Pain (Brief Pain Inventory –
Short Form [BPI-SF]), Physical Functioning and Global Health Status/Quality of Life (GHS/QoL) 
(European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 
[EORTC QLQ-C30]), and Fatigue (Patient Reported Outcomes Measurement Information System 
[PROMIS] Cancer Fatigue Short Form [SF]).  The tertiary objectives of the Phase 2 portion are to assess 
other PRO endpoints (remaining subscales/items from BPI-SF, EORTC QLQ-C30, European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma 
Module [EORTC QLQ-MY20], and Euroqol EQ-5D-5L.
The exploratory objectives for both portions are to evaluate pharmacodynamic and predictive 
biomarkers for association with PK, safety, and efficacy.  In addition, minimal residual disease (MRD) 
will be assessed in the bone marrow by next generation sequencing (NGS).
Investigators:  Multicenter
Study Sites:  Approximately 32 sites.
Study Population:  Relapsed/refractory multiple myeloma subjects.
Number of Subjects to be Enrolled:  Approximately 166 – 186 (86 subjects in the Phase 1 portion and 
approximately 80 – 100 subjects in the Phase 2 portion)
 


Venetoclax (ABT-199)
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Methodology:
This is a Phase 1/2, open-label, multicenter study evaluating the safety and PK profile of venetoclax 
under a once daily dosing schedule.  This study will consist of 2 distinct portions (Phase 1 and Phase 2).  
The Phase 1 portion includes dose escalation, safety expansion, venetoclax-dexamethasone (VenDex) 
combination.  The dose escalation cohort of the study will evaluate the safety and pharmacokinetic 
profile of venetoclax in approximately 30 subjects, with the objective of defining dose limiting toxicities 
(DLTs) and the MTD.  The safety expansion cohort will evaluate venetoclax at the MTD defined in the 
dose escalation portion in approximately 36 additional subjects in order to further define the toxicity 
profile, test biomarker correlates, and better inform the RPTD determination for subjects with MM.  The 
VenDex combination cohort will evaluate the safety and efficacy of venetoclax at the RPTD in 
combination with dexamethasone in approximately 20 subjects with t(11;14)-positive MM.  The Phase 2 
portion is an expansion cohort of the VenDex combination and will further evaluate the efficacy of 
approximately 80 – 100 additional relapsed or refractory subjects with t(11;14)-positive MM.  
Investigators and/or qualified site staff will assess the ORR and VGPR+ rate per IMWG criteria.
Survival information (i.e., alive or deceased, and if deceased, the date and cause of death) and post 
treatment information will be collected approximately every 12 weeks (or as needed to allow for more 
frequent data collection) until death, the subject is lost to follow-up, the subject withdraws consent, or 
the study is terminated by AbbVie, whichever occurs first.
Non-treatment emergent death (those occurring > 30 days after the final dose of study drug) information 
will also be collected.  Subject must request to be withdrawn specifically from survival follow-up.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Subject must be ≥ 18 years of age.
2.
Subject has an ECOG performance score of ≤ 1.

For subjects in the Phase 2 portion:  ECOG performance score of ≤ 2.
3.
Diagnosis of multiple myeloma which requires treatment and has been previously treated with:

For subjects in the Dose Escalation cohort of the study:
o
≥ 1 prior line of therapy.  Induction therapy followed by stem cell transplant and 
maintenance therapy will be considered as a single line of therapy.

For subjects in the Safety Expansion cohort of the study:
o
Have received treatment with a proteasome inhibitor and an immunomodulatory (IMiD®) 
agent (e.g., thalidomide, lenalidomide, pomalidomide).  Induction therapy followed by 
stem cell transplant and maintenance therapy will be considered as a single line of therapy.

For subjects in the Venetoclax-Dexamethasone (VenDex) Combination cohort of the study:
o
Have received treatment with a proteasome inhibitor and an immunomodulatory (IMiD®) 
agent (e.g., thalidomide, lenalidomide, pomalidomide).  Induction therapy followed by 
stem cell transplant and maintenance therapy will be considered as a single line of therapy, 
AND
o
Have MM positive for the t(11;14) translocation, as determined by an analytically 
validated fluorescence in situ hybridization (FISH) assay per the central laboratory testing.
 


Venetoclax (ABT-199)
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):

For subjects in the Phase 2 cohort of the study: 
o
Have MM positive for the t(11;14) translocation, as determined by an analytically 
validated fluorescence in situ hybridization (FISH) assay per central laboratory testing 
(enrollment with local t(11;14)-positive FISH results will be considered at the discretion of 
the TA MD).  
AND
o
Subject must have evidence of disease progression on or within 60 days of the last dose of 
the most recent previous treatment regimen based on the IMWG criteria, 
AND
o
Subject must have previously received at least 2 lines of therapy, including an 
immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor 
(bortezomib, carfilzomib or ixazomib), daratumumab, and glucocorticoids.  

For United States (US) Subjects:  Daratumumab combination regimen must be one of 
the prior lines of therapy (for this study, daratumumab plus corticosteroids will not be 
considered a combination regimen)

For Non-US Subjects:  Either daratumumab monotherapy or daratumumab 
combination therapy is acceptable.  Daratumumab monotherapy will be limited to 
approximately 20 percent of the total number of Phase 2 subjects.
4.
Subject must have measurable disease at Screening, defined as any of the following:

Serum monoclonal protein ≥ 1.0 g/dL (≥ 10 g/L) by protein electrophoresis,

≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis, or

Serum immunoglobulin free light chain (FLC) ≥ 10 mg/dL provided serum FLC ratio is 
abnormal.
5.
Subjects with a history of autologous or allogenic stem cell transplantation must have adequate 
peripheral blood counts independent of any growth factor support, and have recovered from any 
transplant-related toxicity(s) and be:

100 days post-autologous transplant (prior to first dose of study drug), or

≥ 6 months post-allogenic transplant (prior to first dose of study drug) and not have active 
graft-versus-host disease (GVHD), i.e., requiring treatment.
 


Venetoclax (ABT-199)
M13-367 Protocol Amendment 12
EudraCT 2012-000589-38
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
6.
Subjects must meet the following laboratory parameters, per laboratory reference range, at least 
once during screening period:

ANC ≥ 1000/µL 
Subjects may use growth factor support to achieve ANC eligibility criteria.  

AST and ALT ≤3 × upper limit of normal range (ULN)

Calculated creatinine clearance ≥ 30 mL/min using a modified Cockcroft-Gault calculation or a 
24-hour urine collection for Creatinine Clearance:
eCCr
=
(140 – Age) ● weight (kg) ● [0.85 if Female]
72 ●Serum Creatinine (mg/dL)
OR, if serum creatinine is in µmol/L:
eCCr
=
(140 – Age) ● weight (kg) ● [1.23 if Male, 1.04 if Female]
Serum Creatinine (µmol/L)

Platelet count ≥30,000 mm3, independent of transfusion for 2 weeks

Hemoglobin ≥ 8.0 g/dL, subjects may receive blood transfusion to achieve hemoglobin 
eligibility criteria per investigator discretion.

Total bilirubin ≤1.5 × ULN 
Subjects with Gilbert's Syndrome may have bilirubin > 1.5 × ULN.
 


Venetoclax (ABT-199)
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Subject exhibits evidence of other clinically significant uncontrolled condition(s), including, but not 
limited to: 

Acute infection within 14 days prior to first dose of study drug requiring antibiotic, antifungal, 
or antiviral therapy

Diagnosis of fever and neutropenia within 1 week prior to first dose of study drug.
2.
Subject has a cardiovascular disability status of New York Heart Association Class ≥ 3. 
3.
Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, 
immunologic, cardiovascular or hepatic disease within the last 6 months that, in the opinion of the 
investigator, would adversely affect his/her participation in the study.
4.
Subject has a history of other active malignancies other than multiple myeloma within the past 
3 years prior to study entry, with the following exceptions:

Adequately treated in situ carcinoma of the cervix uteri;

Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;

Localized prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen 
(PSA) levels off treatment

Previous malignancy confined and surgically resected (or treated with other modalities) with 
curative intent.
5.
Known Human Immunodeficiency Viral (HIV) infection.  
6.
Active hepatitis B or C infection based on screening blood testing.  
7.
Subject is receiving other ongoing anti-myeloma therapy.
8.
Subject has received any of the following within 7 days prior to the first dose of study drug:

Strong or moderate CYP3A inhibitors, or

Strong or moderate CYP3A inducers.
 


Venetoclax (ABT-199)
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Investigational Products:
Venetoclax (ABT-199):  10 mg, 50 mg, and 100 mg Tablets
Dexamethasone (For subjects enrolled to the VenDex combination 
and Phase 2 cohorts):  4 mg tablets
Non-Investigational Product:
Dexamethasone (For subjects enrolled to the dose escalation and 
safety expansion cohorts)
Doses:
All subjects will begin dosing with a lead-in period with step-wise 
dose escalation to the designated cohort dose during the dose 
escalation and safety expansion portions.
Subjects in the first cohort will begin the lead-in period with a starting 
dose of 50 mg and will step up in increments anticipated to be at least 
50 mg to a designated cohort dose level of 300 mg.  Based on 
additional clinical data from the enrolled subjects, the starting dose for 
the lead-in period may be further reduced to less than 50 mg.
In the first dose-escalation cohort, the first dose for the second subject 
will not be administered until at least 1 week after the first dose of the 
first subject.  Staggered enrollment may continue for subsequent 
cohorts.
In subsequent cohorts, modifications in the lead-in period may occur 
based on tolerability.  Increases or decreases in the lead-in period 
starting dose and/or changes in the dosing increments may be 
implemented.  For example, the starting dose of 50 mg in subsequent 
cohorts may be lowered; dose escalation may then occur in smaller 
increments.  The lead-in period may be eliminated if toxicities such as 
clinically significant metabolic abnormalities of tumor lysis syndrome 
(TLS) are not observed.
A lower starting dose and/or modifications to the lead-in regimen may 
be implemented for individual subject(s) at particularly high risk for 
TLS.
The venetoclax designated cohort dose will begin at 300 mg/day and 
escalate to the MTD with a minimum of 3 subjects at each dose level.  
Designated cohort dose escalation or de-escalation decisions to the 
next designated cohort dose will be made after subjects have 
completed the lead-in period (if applicable) plus one cycle (21 days) 
at the designated cohort dose.  Escalation of designated cohort dose 
will occur in increments of 100 mg unless data indicate smaller 
increments are required.  De-escalation will occur in increments of 
50 mg unless data indicate other increments are required.  Decisions 
will be informed by subject tolerability and safety data.
During dose escalation and safety expansion portions, upon 
assessment of progressive disease, investigators may add 
dexamethasone dosed orally starting at 40 mg using label guidelines.  
Dexamethasone will be dosed on Days 1, 8, and 15 of each 21-day 
cycle.
 


Venetoclax (ABT-199)
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Doses (Continued):
During the VenDex combination and Phase 2 cohorts, a lead-in period 
with step wise dose escalation will not be implemented.  Subjects will 
take venetoclax RPTD of 800 mg daily (QD) in combination with 
dexamethasone.  Dexamethasone (40 mg) will be dosed orally (PO) 
on Days 1, 8, and 15 of each 21-day cycle.  All subjects who are 
≥75 years old may start dexamethasone at a 20 mg dose.
Mode of Administration:
Oral (PO)
Duration of Treatment:  Anticipated duration is 10 months.
Criteria for Evaluation:
Efficacy Assessment:  Phase 1 Portion subjects will be evaluated for preliminary efficacy using the 
International Uniform Response Criteria for Multiple Myeloma (IMWG, 2011); Phase 2 Portion subjects 
will be evaluated for efficacy using IMWG 2016 response criteria.  
PROs will be evaluated using BPI-SF, EORTC QLQ-C30, European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20), 
PROMIS Cancer Fatigue SF, and EuroQoL EQ-5D-5L (EQ-5D-5L).
Pharmacokinetic Assessment:  Intensive pharmacokinetic samples will be collected for venetoclax in 
the dose escalation cohort.  Sparse pharmacokinetic samples will be collected for venetoclax in the dose 
escalation, safety expansion, VenDex combination and Phase 2 cohorts.  For the intensive 
pharmacokinetic days, values for the pharmacokinetic parameters of venetoclax, including the maximum 
observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax) and the area under the plasma 
concentration-time curve (AUC) over a 24-hour dose interval (AUC0-24) will be determined using 
noncompartmental methods.  Additional parameters may be calculated if useful in the interpretation of 
the data.
Biomarkers:  Biospecimens (blood, serum, plasma, bone marrow aspirate and bone marrow core biopsy 
tissue) will be collected to investigate biomarkers.  Types of biomarkers analyzed may include:  BCL-2 
family member expression, chromosomal abnormalities (IgH translocations, amplifications, or 
deletions), and MRD.  Additional biomarkers analyzed may include nucleic acids, proteins, lipids or 
metabolites.  The samples may be analyzed as part of a multi-study assessment of factors involved in the 
response to therapy or the disease state.  Results may or may not be included in the clinical study report.
Safety Assessment:  Adverse event monitoring, vital signs, physical examination, 12-lead ECG, 
multiple gated acquisition scan (MUGA)/2D echocardiogram, and laboratory assessments.  Guidelines 
for the management for TLS are provided.
Statistical Methods:  3+3 design (for dose escalation purposes)
Efficacy:  The following efficacy endpoints will be assessed:  ORR, VGPR+, PFS, DOR, TTR, TTP, 
and OS.
Pharmacokinetic:  An analysis will be performed on PK variables for single and multiple doses to 
simultaneously explore for demographic variables that explain some of the variability in 
pharmacokinetics and to address questions of dose proportionality and linear kinetics.  Additional 
analyses, e.g., time to reach steady state, will be performed if useful and appropriate.
Safety:  A safety analysis will be performed for all subjects participating in the study unless otherwise 
indicated.  For the study as a whole, adverse events will be evaluated and summarized.  Laboratory test 
results and vital signs will be explored for trends and summarized as appropriate.
 


Venetoclax (ABT-199)
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ALT
Alanine aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate aminotransferase
BPI-SF
Brief Pain Inventory – Short Form
BUN
Blood Urea Nitrogen
C
Cycle
CFR
Code of Federal Regulations
CHF
Congestive Heart Failure
CR
Complete Response
COVID-19
Coronavirus Disease-2019
CSF
Colony Stimulating Factors
CTCAE
Common Terminology Criteria for Adverse Events
CYP1A2
Cytochrome P450 1A2
CYP2B6
Cytochrome P450 2B6
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
CYP3A
Cytochrome P450 3A
D
Day
DLBCL
Diffuse Large B-Cell Lymphoma
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
DTP
Direct-to-patient
EBMT
European Society for Blood and Marrow Transplantation
EBV
Epstein Barr Virus
EC
Ethics Committee
ECG
Electrocardiogram
 


Venetoclax (ABT-199)
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ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDTA
Edetic Acid (Ethylenediaminetetraacetic Acid)
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core
EORTC QLQ-MY20
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Multiple Myeloma Module
EQ-5D-5L
EuroQol EQ-5D-5L
FFPE
Formalin-Fixed, Paraffin-Embedded
FISH
Fluorescence In Situ Hybridization
FL
Follicular Lymphoma
FLC
Free Light Chain
GCP
Good Clinical Practice
GVHD
Graft-Versus-Host Disease
HAV-IgM
Hepatitis A Virus Immunoglobulin M
HBsAg
Hepatitis B Surface Antigen
HCV Ab
Hepatitis C Virus Antibody
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
Hr
Hour
HRQoL
Heath-related Quality of Life
HSV
Herpes Simplex Virus
IBW
Ideal Body Weight
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IF
Immunofixation
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMiD®
Immunomodulatory Thalidomide Derivative Compound
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IV
Intravenous
Kg
Kilogram
 


Venetoclax (ABT-199)
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LDH
Lactate Dehydrogenase
MCHC
Mean Corpuscular Hemoglobin Concentration
MCL
Mantle Cell Lymphoma
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
µg
Microgram
Mg
Milligram
Min
Minute
mL
Milliliter
MM
Multiple Myeloma
MPV
Mean Platelet Volume
MR
Minimal Response
MRD
Minimal Residual Disease
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition Scan
NCI
National Cancer Institute
NGS
Next Generation Sequencing
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-Free Survival
PG
Pharmacogenetic
PK
Pharmacokinetic
PR
Partial Response
PRO
Patient Reported Outcomes
PROMIS
Patient Reported Outcomes Measurement Information System
PT
Prothrombin Time
QD
Once Daily
QoL
Quality of Life
QTc
QT Interval Corrected for Heart Rate
QTcB
QT Interval Corrected for Heart Rate by Bazett's Formula
RBC
Red Blood Cell
RNA
Ribonucleic Acid
RS
Richter's Syndrome
 


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SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
sβ2M
Serum β2 microglobulin
sCR
Stringent Complete Response
SCT
Stem Cell Transplant
SD
Stable Disease
sFLC
Serum Free Light Chains
SPD
Sum of the Product of the Diameters
SPEP
Serum Protein Electrophoresis
sQI
Serum Quantitative Immunoglobulins
SST
Serum Separator Tube
TA MD
Therapeutic Area Medical Director
TLS
Tumor Lysis Syndrome
TTP
Time to Disease Progression
TTR
Time to Response
ULN
Upper Limit of Normal Range
UPEP
Urine Protein Electrophoresis
US
United States
VenDex
Venetoclax and Dexamethasone
VGPR
Very Good Partial Response
VGPR+
Very Good Partial Response or better
VZV
Varicella Zoster Virus
WBC
White Blood Cell
WOCBP
Women Of Childbearing Potential
Pharmacokinetic and Statistical Abbreviations
AUC
Area Under the Plasma Concentration-Time Curve
AUCt
Area Under the Plasma Concentration-Time Curve from Time Zero to Time 
of Last Measurable Concentration
AUC∞
Area Under the Plasma Concentration-Time Curve from Time Zero to 
Infinity
β
Beta
Cmax
Maximum Observed Plasma Concentration
Tmax
Time to Maximum Observed Plasma Concentration
 


Venetoclax (ABT-199)
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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................3
1.3
List of Abbreviations and Definition of Terms........................................10
2.0
Table of Contents...................................................................14
3.0
Introduction ...........................................................................21
3.1
Multiple Myeloma (MM).........................................................................21
3.2
Bcl-2 Family of Proteins in Multiple Myeloma.......................................22
3.3
Pharmacology, Preclinical Data and Initial Clinical Data .......................22
3.4
Benefits and Risks....................................................................................30
3.5
Differences Statement..............................................................................32
4.0
Study Objectives....................................................................32
5.0
Investigational Plan...............................................................33
5.1
Overall Study Design and Plan:  Description ..........................................33
5.2
Selection of Study Population..................................................................43
5.2.1
Inclusion Criteria .....................................................................................43
5.2.2
Exclusion Criteria ....................................................................................47
5.2.3
Determination of the Number of Prior Lines of Therapy and 
Refractoriness to Prior Therapies.............................................................49
5.2.4
Prior and Concomitant Therapy...............................................................50
5.2.4.1
Pretreatment Guidance.............................................................................50
5.2.4.2
Allowed Treatments.................................................................................52
5.2.4.3
Excluded and Cautionary Medications ....................................................53
5.2.4.4
Dose Modifications for Moderate and Strong CYP3A Inhibitors 
Used with Venetoclax..............................................................................55
5.2.5
Contraception Recommendations ............................................................56
5.3
Efficacy, Pharmacokinetic, Biomarker, and Exploratory Research 
and Safety Assessments/Variables...........................................................57
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................57
5.3.1.1
Study Procedures .....................................................................................74
5.3.1.2
Confinement...........................................................................................102
 


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5.3.1.3
Meals and Dietary Requirements...........................................................102
5.3.1.4
Collection and Handling of Biomarker and Exploratory Research 
Samples..................................................................................................102
5.3.1.5
Samples for Mandatory Biomarker Analysis.........................................103
5.3.1.6
Samples for Exploratory Research.........................................................106
5.3.2
Drug Concentration Measurements .......................................................108
5.3.2.1
Collection of Samples for Analysis .......................................................108
5.3.2.2
Handling/Processing of Samples ...........................................................110
5.3.2.3
Disposition of Samples ..........................................................................110
5.3.2.4
Measurement Methods...........................................................................110
5.3.3
Efficacy Variables..................................................................................111
5.3.3.1
IMWG Criteria for Tumor Response.....................................................111
5.3.3.2
Evaluation of Disease ............................................................................112
5.3.4
Safety Variables.....................................................................................113
5.3.5
Pharmacokinetic Variables ....................................................................113
5.3.6
Biomarker and Exploratory Research Variables....................................113
5.4
Removal of Subjects from Therapy or Assessment...............................115
5.4.1
Discontinuation of Individual Subjects..................................................115
5.4.2
Discontinuation of Entire Study.............................................................118
5.5
Treatments..............................................................................................119
5.5.1
Treatments Administered.......................................................................119
5.5.2
Identity of Investigational Product.........................................................122
5.5.2.1
Packaging and Labeling.........................................................................123
5.5.2.2
Storage and Disposition of Study Drug .................................................123
5.5.3
Method of Assigning Subjects to Treatment Groups.............................123
5.5.4
Selection and Timing of Dose for Each Subject....................................123
5.5.5
Blinding..................................................................................................124
5.5.6
Treatment Compliance...........................................................................124
5.5.7
Drug Accountability...............................................................................124
5.5.8
Safety Review Committee .....................................................................125
5.6
Discussion and Justification of Study Design........................................125
5.6.1
Discussion of Study Design and Choice of Control Groups..................125
5.6.2
Appropriateness of Measurements.........................................................125
 


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5.6.3
Suitability of Subject Population ...........................................................125
5.6.4
Selection of Doses in the Study .............................................................126
6.0
Complaints ...........................................................................127
6.1
Medical Complaints...............................................................................127
6.1.1
Definitions..............................................................................................128
6.1.1.1
Adverse Event........................................................................................128
6.1.1.2
Serious Adverse Events .........................................................................129
6.1.2
Adverse Event Severity..........................................................................131
6.1.3
Adverse Events Expected Due to Study Related Endpoints..................132
6.1.3.1
Deaths ....................................................................................................132
6.1.3.2
Lack of Efficacy or Worsening of Disease ............................................133
6.1.4
Relationship to Study Drug....................................................................133
6.1.5
Adverse Event Collection Period...........................................................133
6.1.6
Adverse Event Reporting.......................................................................135
6.1.7
Pregnancy...............................................................................................137
6.1.8
Toxicity Management ............................................................................138
6.1.8.1
Definition – Dose Limiting Toxicity (DLT)..........................................138
6.1.8.2
Management of Infection and Lymphopenia.........................................140
6.1.8.3
Management of Neutropenia..................................................................141
6.1.8.4
Management of Tumor Lysis Syndrome ...............................................141
6.1.8.5
Guidelines for Dose Modifications and Treatment................................143
6.1.8.6
Dose Modifications or Delays for Venetoclax Toxicities......................144
6.1.9
Management of Decreased Spermatogenesis.........................................147
6.1.10
Toxicities Related to Dexamethasone....................................................147
6.1.11
Determination of the MTD ....................................................................148
6.1.12
Determination of the RPTD...................................................................149
6.2
Product Complaint .................................................................................149
6.2.1
Definition ...............................................................................................149
6.2.2
Reporting................................................................................................150
7.0
Protocol Deviations..............................................................150
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................152
8.1
Statistical Analysis Plans .......................................................................152
 


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8.1.1
Definition of Analysis Population .........................................................152
8.1.2
Baseline Characteristics.........................................................................152
8.1.3
Pharmacokinetics ...................................................................................152
8.1.3.1
Tabulations and Summary Statistics......................................................152
8.1.3.2
Model and Tests.....................................................................................152
8.1.3.3
Missing Values and Model Violations...................................................153
8.1.4
Efficacy Endpoints.................................................................................154
8.1.4.1
Objective Response Rate and Very Good Partial Response or 
Better Rate .............................................................................................154
8.1.4.2
Time to Disease Progression..................................................................154
8.1.4.3
Duration of Response.............................................................................155
8.1.4.4
Progression-Free Survival......................................................................155
8.1.4.5
Overall Survival.....................................................................................156
8.1.4.6
Time to Response...................................................................................156
8.1.5
Statistical Analysis of Efficacy..............................................................156
8.1.5.1
Phase 2 Efficacy Subgroup Analysis .....................................................158
8.1.6
Statistical Analysis of Safety .................................................................158
8.1.6.1
Duration of Study Drug Exposure .........................................................158
8.1.6.2
Adverse Events ......................................................................................158
8.1.6.3
Serious Adverse Events .........................................................................159
8.1.6.4
Deaths ....................................................................................................159
8.1.6.5
Longitudinal Analyses of Laboratory and Vital Signs Data..................159
8.1.6.6
Analyses of Laboratory Data Using NCI CTCAE.................................159
8.1.6.7
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values.................................................................160
8.1.7
Biomarkers and Exploratory Research Variables ..................................160
8.2
Determination of Sample Size ...............................................................160
9.0
Ethics.....................................................................................161
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................161
9.2
Ethical Conduct of the Study .................................................................162
9.3
Subject Information and Consent...........................................................163
 


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10.0
Source Documents and Case Report Form 
Completion ...........................................................................164
10.1
Source Documents .................................................................................164
10.2
Case Report Forms.................................................................................165
11.0
Data Quality Assurance ......................................................167
12.0
Use of Information...............................................................168
13.0
Completion of the Study .....................................................169
14.0
Investigator's Agreement....................................................170
15.0
Reference List ......................................................................171
List of Tables
Table 1.
Lead-In Doses to Designated Cohort Doses ............................................37
Table 2.
Dose Escalation Guidelines .....................................................................38
Table 3.
Excluded and Cautionary Medications/Food...........................................54
Table 4.
Dose Modifications for Venetoclax:  Moderate and Strong 
CYP3A Inhibitor Use...............................................................................55
Table 5.
Study Activities for Phase 1 Portion:  Screening Through Cycle 3 
Day 1........................................................................................................58
Table 6.
Study Activities for Phase 2 Portion:  Screening Through 
Cycle 10+.................................................................................................63
Table 7.
Final Visit and Follow-Up Activities for Phase 2 Portion.......................66
Table 8.
Schedule of Pharmacokinetic Blood Collection for Venetoclax .............68
Table 9.
Biomarker and Exploratory Research Sampling – Phase 1 Portion.........70
Table 10.
Biomarker and Exploratory Research Sampling – Phase 2 Portion.........72
Table 11.
Patient-Reported Outcome Assessments .................................................81
Table 12.
Clinical Laboratory Tests – Phase 1 Portion............................................92
Table 13.
Clinical Laboratory Tests – Phase 2 Portion............................................94
Table 14.
Assessments for IMWG Response Criteria (Phase 1 Portion).................96
Table 15.
Assessments for IMWG Response Criteria (Phase 2 Portion).................97
Table 16.
Identity of Investigational Product.........................................................122
Table 17.
Identity of Non-Investigational Product ................................................122
Table 18.
Venetoclax Monotherapy Dose Levels..................................................144
 


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Table 19.
Venetoclax Combined with Dexamethasone Dose Levels ....................145
Table 20.
Hematological and Non-Hematological Toxicities Related to 
Venetoclax .............................................................................................146
Table 21.
Dose Reductions for Dexamethasone ....................................................147
Table 22.
Treatment Guidelines for Toxicity Related to Dexamethasone.............148
Table 23.
Event and Censoring Date Used in TTP................................................154
Table 24.
Event and Censoring Date Used in DOR...............................................155
Table 25.
Event and Censoring Date Used in PFS ................................................156
List of Figures
Figure 1.
Overall Study Design...............................................................................34
Figure 2.
Dosing Schedule for Lead-In to Designated Cohort Dose:  Dose 
Escalation Cohorts ...................................................................................35
Figure 3.
Safety Expansion Cohort Dosing, if a Lead-in Period is Required .........40
Figure 4.
Safety Expansion Cohort Dosing, if a Lead-in Period is Not 
Required...................................................................................................40
Figure 5.
VenDex Combination Cohort Dosing Schedule, Without Lead-In 
Period .......................................................................................................42
Figure 6.
Adverse Event Collection ......................................................................134
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................175
Appendix B.
List of Protocol Signatories....................................................................177
Appendix C.
Sample List of Cautionary Medications.................................................178
Appendix D.
Sample Meal Description.......................................................................180
Appendix E.
IMWG Response Criteria for Multiple Myeloma..................................181
Appendix F.
Howard Definition of Tumor Lysis Syndrome......................................187
Appendix G.
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS) in 
Multiple Myeloma Subjects...................................................................188
Appendix H.
Adverse Events Commonly Associated with MM Study 
Population or Progression of MM..........................................................193
 


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Appendix I.
Corticosteroid Conversion Table ...........................................................195
 


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3.0
Introduction
3.1
Multiple Myeloma (MM)
Multiple myeloma is an incurable malignancy arising from post germinal center, 
terminally differentiated plasma cells, characterized by an excess of monotypic plasma 
cells in the bone marrow, resulting in elevated levels of monoclonal immunoglobulins (Ig) 
in the serum and/or urine.1  Common clinical sequelae include lytic bone lesions, 
fractures, myelosuppression, and renal failure.  In the United States of America, the 
estimated annual diagnosed incidence is 16,000, with approximately 50,000 prevalent 
cases.  In Europe, the estimated annual diagnosed incidence is 21,611 with approximately 
54,536 prevalent cases.2  Multiple myeloma accounts for 10% of all hematologic 
malignancies and 1% of all malignancies.  Advances in high-dose chemotherapy and stem 
cell transplantation have improved overall survival and event-free disease periods in 
patients with MM, but relapses are inevitable.3,4  New therapeutic agents, such as 
bortezomib and thalidomide analogues (IMiD®), have shown promising clinical benefit in 
patients with relapsed or refractory disease.  Current treatments include combination 
chemotherapy with regimens using melphalan (Alkeran®), bortezomib (Velcade®), 
thalidomide (Thalomid®), and lenalidomide (Revlimid®) with and without corticosteroids.  
Younger patients are consolidated with high-dose therapy (ablative chemotherapy or 
radiation) with autologous stem cell transplantation.  In addition, newer agents with 
encouraging single agent activity are currently in clinical trials for the relapsed/refractory 
population.  Treatment of subjects with carlfilzomib, a new generation proteasome 
inhibitor, has resulted in a response rate of about 25% in subjects who received a prior 
IMiD® and Velcade®.5  Pomalidomide, a new generation immunomodulatory drug, in 
combination with dexamethasone resulted in a similar response rate in MM subjects 
refractory to both an IMiD® and Velcade®.6  Despite these therapeutic advances, MM 
remains essentially incurable and is associated with high morbidity and mortality.7
 


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3.2
Bcl-2 Family of Proteins in Multiple Myeloma
There are two main pathways of apoptosis or programmed cell death, namely the 
extrinsic, or death receptor-mediated pathway, and the intrinsic, or mitochondrial 
pathway.  The intrinsic pathway is regulated by a delicate balance between anti-apoptotic 
(Bcl-2, Bcl-xL, Bcl-w, Bfl-1/A1, and Mcl-1) and pro-apoptotic (Bax, Bak, Bid, Bcl-xS, 
Bad, Bik, Bim, and Hrk) members of the Bcl-2 family.  Anti-apoptotic Bcl-2 family 
members are localized in the mitochondrial outer membrane, nuclear membrane, or the 
endoplasmic reticulum, while most of the pro-apoptotic members are in the cytosol or 
localized to the cytoskeleton.  Normally, Bax and Bak are sequestered by the 
anti-apoptotic proteins Bcl-2, Bcl-xL, and/or Mcl-1 and prevented from translocating to 
mitochondria.  However, various damaging stimuli can result in their liberation and 
translocation to the mitochondrial outer membrane, leading to an increase in 
mitochondrial permeability, the release of cytochrome c, and activation of caspase 9 
through its binding to Apaf-1.  This in turn leads to activation of effector caspases like 
caspase 3 and cellular apoptosis.  Plasma cells are typically geared towards long-term 
survival and have low apoptotic rates, likely due to high levels of anti-apoptotic proteins 
such as Bcl-2.  Dysregulation of apoptotic pathways in these cells, often via Bcl-2 
overexpression, is thought to play a major role in the development and progression of 
multiple myeloma.  Antagonizing Bcl-2 function to induce apoptosis is thus a compelling 
therapeutic approach in multiple myeloma.
All information related to the venetoclax clinical pharmacology and clinical data 
(including clinical data with venetoclax in multiple myeloma) can be found in the most 
current version of the Investigator's Brochure.
3.3
Pharmacology, Preclinical Data and Initial Clinical Data
ABT-199 (Venetoclax) Activity and Preclinical Pharmacokinetic Profile
ABT-199 (Venetoclax) is a novel, orally bioavailable small molecule inhibitor of Bcl-2 
(Ki < 0.10 nM) with much lower affinity for Bcl-xL and Bcl-w (> 480-fold and 
> 2,000-fold lower affinity, respectively).  In vitro, venetocalx has demonstrated broad 
 


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cell killing activity against hematopoietic tumor cell lines including B-cell follicular 
lymphomas (FL), mantle cell lymphomas (MCL), diffuse large B-cell lymphomas 
(DLBCL), acute myeloid leukemias (AML), and multiple myelomas (MM).  Venetoclax 
was especially potent against FL and DLBCL cell lines expressing high levels of Bcl-2 
due to the t(14;18) translocation.  The sensitivity of MM cell lines correlated most closely 
with their Bcl-2/Mcl-1 mRNA expression ratio, with the most sensitive cell lines 
expressing high levels of Bcl-2 relative to Mcl-1, a known resistance factor for Bcl-2 
inhibitors.  Multiple myloma cell lines bearing the t(11;14) translocation were particularly 
sensitive to venetoclax (6 of 8 cell lines with an LD50 < 100 nM, median LD50 = 10 nM).  
Similar trends were observed for MM primary samples treated ex vivo with venetoclax, 
with four of five t(11;14)-positive samples being especially sensitive (LD50 < 100 nM).8
The pharmacokinetic behavior of venetoclax was evaluated in multiple animal species.  In 
mouse, rat, monkey and dog the pharmacodynamic profile was characterized by low 
plasma clearance and low volumes of distribution.  Half-lives ranged from 2.2 hours in 
monkey to 12 hours in dog.  Food had a marked effect on the oral bioavailability in dogs.
Venetoclax has high protein binding to human, rat, dog, and monkey plasma proteins 
(> 99.9%).  In rats, venetoclax was widely distributed into liver, kidneys, spleen, heart, 
lungs, small intestine, and white fat, but was poorly distributed in testes, brain, muscle, 
and bone.  Metabolism was the major route of elimination with biliary excretion of the 
parent drug playing the secondary role in rats.  Venetoclax showed moderate metabolic 
stability in vitro hepatic systems across species tested, except for low to moderate stability 
in dog hepatocytes.
In vitro, venetoclax was metabolized by CYP3A4; it was not a potent inhibitor of 
CYP3A4, CYP1A2, CYP2B6, CYP2C19, or CYP2D6 (IC50 > 30 µM); it did not induce 
CYP3A4 or CYP1A2 at concentrations up to 10 µM.  Venetoclax is a substrate for P-gp 
and BCRP.  Studies in Oatp1a/b cluster KO mice indicated that venetoclax may be an 
OATP substrate.  Active uptake of venetoclax or M27 was not observed in cells 
overexpressing OATP1B1, OATP1B3 or OCT1.  Venetoclax is a P-gp, BCRP and 
OATP1B1 inhibitor in vitro.
 


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All information related to the venetoclax clinical pharmacology and clinical data 
(including clinical data with venetoclax in multiple myeloma) can be found in the most 
current version of the Investigator's Brochure.29
Venetoclax Preclinical Toxicology
Venetoclax has been assessed in repeated-dose general toxicology studies, and in genetic, 
developmental/reproductive, and safety pharmacology studies.
Repeated-dose oral toxicity studies with venetoclax were conducted in mice and dogs.  
GLP-compliant definitive toxicity studies consisted of IND-enabling studies in mice and 
dogs with 4 weeks of dosing followed by a 4-week (dose-free) recovery period; a 2-week 
toxicity study in dogs that focused on lymphocyte recovery over an extended (18-week) 
recovery period; and chronic toxicity studies in mice (6 months) and dogs (9 months).  No 
recovery periods were included in the chronic toxicity studies.  The maximum venetoclax 
plasma exposures (mean AUC0-24 h) achieved in the 4-week studies were 92 µg•hr/mL (at 
600 mg/kg/day) in mice and 572 µg•hr/mL (at 150 mg/kg/day) in dogs.  In the chronic 
toxicity studies, AUCs reached 34.1 µh•h/mL (at 300 mg/kg/day) in mice and 
139 µh•h/mL (at 20 mg/kg/day) in dogs.
The primary toxicities associated with venetoclax administration included effects on the 
hematologic system (decreased lymphocytes and erythrocytes) in mice and dogs; the male 
dog reproductive system (testicular germ cell depletion); and embryofetal toxicity in mice.
In mice and dogs, venetoclax produced robust decreases in lymphocytes in the peripheral 
blood (of up to 75% in mice and up to 81% in dogs) and in lymphoid tissues.  In dogs, the 
recovery of lymphocyte counts (total lymphocytes, CD4+ and CD8+ T cells and mature 
B cells) was prolonged, requiring up to 18 weeks after completion of 2 weeks of dosing.  
B cells were the most sensitive lymphocyte subtype based on the magnitude of decrease 
and/or the length of time required for recovery.  Decreases of lymphocytes in lymphoid 
tissues were reversible in mice and reversible to partially reversible in dogs.  
 


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venetoclax-related decreases in lymphocytes in blood and lymphoid tissues are considered 
pharmacologically-mediated and non-adverse.9
Venetoclax effects on red blood cell mass parameters principally consisted dose-related 
decreases of hematocrit and hemoglobin in mice and dogs; these effects were adverse only 
at the highest dosages in the 4-week mouse and dog studies and were reversible.  Effects 
on the white and red cell counts are readily monitored in clinical trial subjects.
No effects of venetoclax have been identified in female reproductive tissues in mice or 
dogs in general toxicology studies.  However, in dogs venetoclax produced adverse, 
non-reversible, non-dose related microscopic findings of testicular germ cell depletion at 
all dosages tested; however, there were no testicular effects in mice.  The testicular effecs 
may be related to venetoclax pharmacology, as one or more members of the Bcl-2 family 
of proteins play a role in spermatogenesis.10-12  The translatability of the testicular 
findings in dogs to humans is unknown.  In view of the potential treatment benefits of 
venetoclax, this finding is anticipated not to impact the treatment of subjects with relapsed 
or refractory multiple myeloma.
Venetoclax resulted in increased postimplantation loss and decreased fetal body weights 
in the mouse embryofetal development study at the highest dosage administered 
(150 mg/kg/day); the no-observed-adverse-effect-level (NOAEL) was defined at the 
mid-dose of 50 mg/kg/day.  Venetoclax was not teratogenic, and there were no other 
effects on development or fertility.
Venetoclax produced loss of hair pigmentation in dogs (reversibility has not been 
assessed).  Evidence from Bcl-2 knockout mouse (Bcl-2 -/-) studies indicates that hair 
hypopigmentation is consistent with the pharmacological effect of Bcl-2 functional loss, 
and occurs due to loss of hair follicle melanocytes dependent on Bcl-2 for survival.13  A 
dedicated physical exam of the skin and extensive ophthalmic exams determined that 
pigmentation of the skin and in the eye (particularly, the iris and fundus) of the dog 
appeared unaffected.
 


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Other effects of venetoclax included single cell necrosis in various epithelial tissues in 
dogs (i.e., gallbladder, stomach, exocrine pancreas, and epididymides) that was of 
minimal magnitude and produced no loss of mucosal integrity; and increased pigment in 
Kupffer cells or macrophages in the liver and gallbladder of dogs.  None of the effects 
were considered to be adverse, and all were reversible.
Dogs at the high dose of 150 mg/kg/day in the 4-week study had clinical signs of swelling 
of the skin on the ears, head (cranial area), and forepaws and/or hindpaws.  Most but not 
all animals (8 of 10 dogs) were affected.  The clinical signs were mild to moderate in 
severity, transient and sporadic in occurrence, and were absent during the recovery period.  
The swelling reactions were observed after the first dose in 3 dogs, and therefore not 
consistent with drug-induced immediate (IgE-mediated, Type I) hypersensitivity; 
however, other immune-mediated mechanisms could be involved.  Although the basis for 
the swelling reactions was not established, there were no signs of anaphylaxis.  Clinical 
signs of swelling were not observed at the lower dosages of venetoclax evaluated in 
chronic toxicity studies in mice or dogs.  Any occurrences of swelling reactions in 
subjects can be monitored and treated.
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax.
Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the CNS/neurobehavioral or respiratory studies in mice at oral doses up to and 
including the highest dose of 600 mg/kg.  No effects on corrected QT interval (QTc) were 
observed up to a maximum plasma concentration of 46 µg/mL in dogs.  In conscious 
dogs, venetoclax did not produce any cardiovascular effects up to and including the 
highest oral dose of 150 mg/kg (maximum observed plasma concentration, 
Cmax = 16 µg/mL).  In the anesthetized dog at higher plasma concentrations, venetoclax 
produced mild reductions in myocardial contractility (–6% to –13%) and cardiac output 
(–11% to –19%) at plasma concentrations of ≥ 16 µg/mL and ≥ 32 µg/mL, respectively.  
These concentrations are greater than the plasma concentration of venetoclax in oncology 
subjects (e.g., 2.18 µg/mL at the 400 mg dose).
 


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On the basis of nonclinical safety pharmacology and toxicology evaluations of 
venetoclax, and on the basis of nonclinical and human studies of related antiapoptotic 
Bcl-2 family protein inhibitors, potential mechanism-based toxicities may include 
lymphopenia and neutropenia,14 signs of tumor lysis, reduction in red cell mass, decreased 
spermatogenesis, skin swelling and hair hypopigmentation.  The potential for 
development of hair color change in humans is unknown.  No adverse events of changes 
in hair color, skin pigmentation, or eye color have been reported in the venetoclax clinical 
studies to date.  Although no effects of venetoclax on female reproductive tissues have 
been observed in general repeat-dose toxicology studies, embryofetal toxicity studies in 
animals have identified a fetal toxicity risk.
Thrombocytopenia has not been observed in toxicology studies in mice and dogs.  These 
findings are consistent with venetoclax as a Bcl-2 specific (Bcl-xL sparing) inhibitor.  
Consequently, thrombocytopenia is not expected to be a dose limiting toxicity (DLT) 
clinically.
In vitro studies have shown that venetoclax is metabolized primarily by CYP3A4; thus, 
coadministration of venetoclax with drugs that inhibit CYP3A4 (such as ketoconazole) is 
predicted to cause a significant increase in the exposure of venetoclax and will be 
undertaken with dose modifications as outlined in Section 5.2.4.4.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can 
be found in the Investigator's Brochure.15-17,29
Venetoclax Clinical Data
Venetoclax is being investigated in Phase 1 to Phase 3 clinical oncology studies 
conducted as monotherapy or in combination with a variety of compounds for the 
treatment of hematologic malignancies including MM, chronic lymphocytic leukemia 
(CLL), small lymphocytic leukemia (SLL), NHL, acute myeloid leukemia (AML), and 
myelodysplastic syndrome (MDS).  Data are available from drug-drug interaction studies 
 


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of venetoclax and ketoconazole, rifampin, and warfarin digoxin, ritonavir, and 
azythromycin.
As of 28 November 2018, on the basis of open-label and unblinded data available in the 
clinical databases for company-sponsored studies with unblinded data in the venetoclax 
oncology development program, a total of 2543 adult subjects (1313 CLL/SLL, 
361 AML, 218 MM, 570 NHL, and 59 MDS, 20 ALL, 1 rhabdomyocarcoma, and 1 Evans 
tumor) in the pooled analysis dataset across all monotherapy and combination therapy 
oncology studies in the venetoclax development program have been exposed to at least 
1 dose of venetoclax.  An additional 20 pediatric subjects (< 18 years of age; 5 ALL, 
10 AML, 3 neuroblastoma, 2 other solid tumors) have been exposed to at least 1 dose of 
venetoclax. 
Overall for MM, when treated with venetoclax as a single agent or in combination with 
other therapies, most subjects experience at least 1 adverse event.  Overall 78% of 
subjects experience ≥ grade 3 adverse events, and the most common events were 
cytopenias.  Forty-four percent (44%) of subjects experienced SAEs.  Findings from the 
analysis based on the FAIRs were consistent with the findings from the analysis based on 
the subject incidence rates.  All of the adverse events reported in the current MM studies 
are consistent with underlying disease or concomitant medical conditions, as well as other 
combination agents used to treat MM patients.  Neutropenia and infections reported in 
subjects with MM treated with venetoclax are consistent with the expected safety profile 
of venetoclax.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology of 
venetoclax can be found in the Investigator's Brochure.15-17,29  
The BELLINI study, a global, Phase 3, multicenter, randomized, double-blind study of 
bortezomib and dexamethasone in combination with either venetoclax or placebo in 
subjects with relapsed or refractory multiple myeloma who are sensitive or naïve to 
proteasome inhibitors, was unblinded as per protocol for the final analysis of the primary 
efficacy endpoint.  As of the data cutoff date of 26 November 2018, 194 patients were 
 


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randomized to the venetoclax arm, and 97 to the placebo arm (2:1 randomization).  The 
BELLINI study met its primary endpoint of progression-free survival (22.4 versus 
11.5 months, HR 0.63, 95% CI:  0.44 – 0.90) and showed statistically significant 
improvements in ORR (82% vs 68%) and VGPR or better (59% vs 36%) in the 
venetoclax arm compared to the control arm.  However, there were 51 deaths in the safety 
analysis set, 40 (20.7%) in the venetoclax arm and 11 (11.5%) in the placebo arm (the 
median OS has not been reached in either arm).  The imbalance was predominantly seen 
in the treatment-emergent deaths, which are those occurring on therapy or within 30 days 
after the last dose of therapy.  Among the 14 treatment-emergent deaths reported, 
13 (6.7%) were in the venetoclax arm and 1 (1.0%) in placebo arm.  Of the 13 treatment-
emergent deaths on the venetoclax arm, 8 were attributed by investigator to an event of 
infection, more than half of them also in the setting of refractory or progressive disease.  
Although the majority of infection-related deaths occurred within 180 days of starting 
study treatment, some have occurred later, even after a year or more on treatment.  A 
higher rate of Grade 3 or 4 neutropenia was seen in the venetoclax arm compared to 
placebo, but an association of infection-related deaths with neutropenia has not been 
established at this point.  Among the 37 non-treatment emergent deaths (those occurring 
more than 30 days after the last dose of study treatment), 27 (14.0%) were in the 
venetoclax arm (6 of them attributed to infection, 3.1%), and 10 (10.4%) in the placebo 
arm (2 of them attributed to infection, 2.1%).  After the data cutoff of 26 November 2018, 
additional deaths were reported in the BELLINI trial.  As of 01 March 2019, there were 
65 deaths in the safety analysis set, 48 (24.7%) in Venetoclax arm and 17 (17.5%) in the 
placebo arm.  
All information related to the venetoclax clinical pharmacology and clinical data 
(including clinical data with venetoclax in multiple myeloma) can be found in the most 
current version of the Investigator's Brochure.
Venetoclax and Dexamethasone Combination
Preclinical data support studying venetoclax in relapsed or refractory MM subjects, in 
particular, those with a Bcl-2 profile (high Bcl-2/low Mcl-1) which is more frequently 
 


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observed in MM bearing the t(11;14) translocation.8  Noteworthy, recent published data 
also demonstrate that dexamethasone highly sensitizes multiple myeloma cell lines and 
primary samples to venetoclax by increasing Bim and Bcl-2 expression.  Dexamethasone 
appears to shift Bim binding towards Bcl-2 instead of Mcl-1 resulting in increased 
sensitivity to venetoclax, even in cell lines with prior resistance to Bcl-2 inhibition.18  The 
addition of dexamethasone to venetoclax could be clinically beneficial for subjects with 
multiple myeloma expressing higher levels of resistance factors such as Mcl-1.
All information related to the venetoclax clinical pharmacology and clinical data 
(including clinical data with venetoclax in multiple myeloma) can be found in the most 
current version of the Investigator's Brochure.
3.4
Benefits and Risks
Based on data available, there is observed anti-tumor activity in hematological 
malignancies (such as CLL, NHL, AML and MM) subjects receiving venetoclax.  In 
addition, the safety profile is acceptable in treating advanced cancer patients.  Ongoing 
monitoring for safety will continue as outlined in the Risk Assessment.  Therefore, the 
overall risk benefit profile supports further investigation of venetoclax in cancer patients.
Based on supportive safety and efficacy data from ongoing Phase 1/2 studies when treated 
with venetoclax as a single agent or in combination with other therapies, subjects enrolled 
in this study are anticipated to benefit from the combined treatment with dexamethasone 
based on their pro-apoptotic effects in myeloma cells.
Since the antitumorigenic effects of venetoclax and dexamethasone on myeloma cells are 
via distinctive mechanisms of action, the combination of these 2 drugs is anticipated to 
result in an enhanced therapeutic effect that could potentially benefit patients with MM.  
The goal of the Phase 2 portion of the study is to determine the efficacy and safety profile 
of venetoclax and dexamethasone combination therapy in patients with t(11;14)-positive 
MM.
 


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Following the analysis of the BELLINI study (see Section 3.3) guidance for dose 
interruption/reduction following a Grade ≥ 3 or serious infection in subjects receiving 
venetoclax have been implemented (Section 6.1.8.3 and Section 6.1.8.4)
The safety profile of venetoclax as a monotherapy or in combination with dexamethasone 
in patients with R/R MM has been favorable and consistent with its mechanism of action 
and the background disease in this population.  Based on nonclinical toxicology and 
clinical studies with venetoclax, toxicities may include lymphopenia, neutropenia, 
thrombocytopenia, anemia, and gastrointestinal adverse events.  The safety and efficacy 
data to date of venetoclax in combination with dexamethasone from the Phase 1 portion of 
the study supports further evaluation of this combination in subjects with R/R MM.
For further details on venetoclax, please see findings from completed studies including 
safety data in the most current venetoclax Investigator Brochure29 and the dexamethasone 
package insert.
Based on the BELLINI data referenced above, the FDA placed Study M13-367 on partial 
clinical hold on 14 March 2019.  A total of 117 subjects have been enrolled (Phase 1:  86; 
Phase 2:  31) to Study M13-367.  No new subjects will be enrolled into the 
Study M13-367.  Subjects who are currently receiving venetoclax monotherapy or 
venetoclax and dexamethasone in combination will be allowed to continue study 
treatment per protocol if the investigator believes the subject is continuing to receive 
clinical benefit.  For subjects who choose to continue study treatment, study procedures 
have been modified as described in Table 6 and throughout protocol.  Additionally, 
pneumococcal and influenza vaccinations requirements applicable for subjects on study 
treatment have been implemented, as well as recommendations for subjects in follow up
(please refer to Section 5.2.4.1).
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Subjects receiving venetoclax may be at 
an increased risk for COVID-19 infection or experience serious illness if infected.  
Management of these adverse events will be made on a case-by-case basis with 
 


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consideration of benefit/risk.  However, based on the population and disease being studied 
and the anticipation that COVID-19 related risks are not expected to differ substantially 
between study subjects and the broader population of subjects receiving treatment for R/R 
multiple myeloma, no change to the benefit/risk balance for subjects in this study is 
expected.
3.5
Differences Statement
One Phase 1 clinical trial investigating the safety, pharmacokinetics, maximum tolerated 
dose, and recommended Phase 2 dose (RPTD) of venetoclax monotherapy in subjects 
with relapsed or refractory chronic lymphocytic leukemia and non-Hodgkin's lymphoma 
is underway.  This is the first Phase 1 protocol of venetoclax monotherapy in subjects 
with relapsed or refractory multiple myeloma.  In addition, one Phase 1 clinical trial 
investigating the safety, pharmacokinetics, maximum tolerated dose, and RPTD of 
venetoclax in combination with bortezomib and dexamethasone as standard therapy in 
subjects with relapsed or refractory multiple myeloma is underway.
4.0
Study Objectives
Phase 1 Portion (Dose Escalation, Safety Expansion and Venetoclax-Dexamethasone 
Combination): 
The primary objectives are to assess the safety profile, characterize pharmacokinetics 
(PK), determine the dosing schedule, the maximum tolerated dose (MTD), and the 
recommended Phase 2 dose (RPTD) of venetoclax monotherapy when administered in 
subjects with relapsed or refractory multiple myeloma.  This study will also assess the 
safety profile and PK of venetoclax in combination with dexamethasone in subjects with 
t(11;14)-positive multiple myeloma.  The secondary objectives are to evaluate the 
preliminary efficacy data regarding the effect of venetoclax monotherapy or combined 
with dexamethasone on overall response rate (ORR), time to response (TTR), time to 
disease progression (TTP), and duration of response (DOR).  
 


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The Phase 2 Portion (Venetoclax-Dexamethasone Expansion):
The primary objective of the Phase 2 portion is to further evaluate the ORR and very good 
partial response or better rate (VGPR+) in subjects with t(11;14)-positive multiple 
myeloma, with the secondary objectives to monitor safety and evaluate progression-free 
survival (PFS), DOR, TTR, TTP, and overall survival (OS) and to evaluate patient 
reported outcomes (PRO) including Worst Pain (Brief Pain Inventory – Short Form 
[BPI-SF]), Physical Functioning and Global Health Status (GHS)/Quality of Life (QoL) 
(European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core [EORTC QLQ-C30]), and Fatigue (Patient Reported Outcomes 
Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF]).  The 
tertiary objectives of the Phase 2 portion are to assess other PRO endpoints (remaining 
subscales/items from BPI-SF, EORTC QLQ-C30, European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 
[EORTC QLQ-MY20], and Euroqol EQ-5D-5L).
The exploratory objectives for all study portions are to evaluate pharmacodynamic and 
predictive biomarkers for association with PK, safety, and efficacy.  In addition, minimal 
residual disease (MRD) will be assessed in the bone marrow by next generation 
sequencing (NGS).
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 1/2, open-label, multicenter study evaluating the safety and PK of 
venetoclax when administered in male and female subjects with relapsed or refractory 
MM.  The study is designed to enroll approximately 166 – 186 subjects.  Subjects in this 
study will be enrolled at approximately 32 research sites globally.  This study is 
sponsored by AbbVie in collaboration with Roche/Genentech.
This study will consist of 2 distinct portions (Phase 1 and Phase 2).  The Phase 1 portion 
includes dose escalation, safety expansion, and VenDex combination cohorts.  The 
 


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first cohort of the study will evaluate the safety and pharmacokinetics profile of 
venetoclax, to be administered in approximately 30 subjects following a dose escalation 
scheme, with the objective of defining the dose limiting toxicity (DLT) and the MTD.
The second cohort of the study is a safety expansion cohort that will further evaluate 
venetoclax safety at the MTD (or RPTD) and explore Bcl-2 family expression profile in 
approximately 36 subjects.  
The third cohort of the study is a (VenDex) combination cohort that will evaluate 
venetoclax safety and efficacy at the RPTD in combination with dexamethasone in 
approximately 20 subjects with t(11;14)-positive MM.
The Phase 2 portion of the study is an expansion of the combination cohort that will 
further evaluate ORR and VGPR+ of venetoclax and dexamethasone in approximately 
80 –100 relapsed or refractory subjects with t(11;14)-positive MM.  Disease assessment 
for each post-baseline IMWG assessment will be performed by the investigator.
The overall study design is shown in Figure 1.
Figure 1.
Overall Study Design
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 




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dose level of 300 mg.  Subjects will continue to receive the same starting dose of 
Venetoclax once daily for 1 week starting on Lead-in Day 1.  If, after approximately 
1 week, subjects have absence or resolution of metabolic abnormalities comprising TLS 
and do not experience a DLT (refer to Section 6.1.8.1), the dose level will be subsequently
increased in increments anticipated to be at least 50 mg per week until the designated 
cohort dose level is achieved.  The decision to escalate will be made by AbbVie following 
discussion between the investigator and the AbbVie TA MD.
In the first dose escalation cohort, the Lead-in Day 1 dose for the second subject will not 
be administered until at least 1 week following the Lead-in Day 1 dose of the first subject.  
Staggered enrollment may continue for subsequent cohorts if decided by AbbVie, 
following discussion between the investigators and the AbbVie TA MD.
Each dose of venetoclax will be taken orally with approximately 240 mL of water within 
30 minutes after the completion of a low-fat breakfast.
On days that pre-dose PK sampling is required, venetoclax dosing will occur in the clinic 
to facilitate PK sampling following the completion of a low-fat breakfast.  For subjects in 
the Dose Escalation cohorts, dosing will occur in the clinic to facilitate PK sampling 
following the completion of a standard low-fat breakfast on the intensive PK day, 
Cycle 2 Day 1.
Dose Modification and Escalation Guidelines
In subsequent cohorts, modifications in the lead-in period may occur based on tolerability.  
Increases or decreases in the lead-in period starting dose and/or changes in the dosing 
increments may be implemented.  For example, the starting dose of 50 mg in subsequent 
cohorts may be lowered; dose escalation may then occur in smaller increments.  The 
lead-in period may be eliminated if clinically significant metabolic abnormalities of TLS 
are not observed.  Decisions to modify the lead-in period will be made by AbbVie 
following discussion between the investigators and AbbVie TA MD.  Lead-in doses to the 
designated cohort doses for Cohorts 1 to 3 are depicted in Table 1.
 


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Table 1.
Lead-In Doses to Designated Cohort Doses
Cohort
Starting Dose* (mg)
(Lead-in Week 1)
Step 2 (mg) * 
(Lead-in Week 2)
Designated Cohort Dose 
(mg)
1
50
100
300
2
100**
300
600
3
300**
600
900
4
400**
800
1200
*
Starting dose and/or Step 2 may be removed in cohorts subsequent to Cohort 1 if no metabolic abnormalities of 
TLS are observed in the prior cohort.
**
Higher starting dose would only occur if metabolic abnormalities of TLS are not observed at lower doses.
A lower starting dose and/or modifications to the lead-in regimen may be implemented for 
individual subject(s) at particularly high risk for TLS (refer to Management of Tumor 
Lysis Syndrome, Section 6.1.8.4).  The decision to modify the lead-in period dosing 
regimen for an individual subject will be made by AbbVie following discussion between 
the investigator and AbbVie TA MD and communicated to the IRB/EC, as appropriate.
Designated cohort dose escalation or de-escalation decisions to the next designated cohort 
dose will be made after subjects have completed the lead-in period plus one cycle 
(21 days) at the designated cohort dose.  Escalation of designated cohort dose will occur 
in multiples of 100 mg but may occur in other increments as determined by available data.  
De-escalation will occur in increments of 50 mg unless data indicate other increments are 
required.  Decisions will be informed by subject tolerability and safety data.  Escalation or 
de-escalation of the designated cohort dose will be determined by AbbVie following 
discussion between the investigators and AbbVie TA MD.
A minimum of 3 subjects will be enrolled per cohort.  Additional subjects may be enrolled 
at a current dose level at the discretion of the AbbVie medical monitor.  Dose escalation 
decisions may be made following the completion of the lead-in period (if applicable) plus 
one cycle (21 days) of dosing at the designated cohort dose for the subjects in the intended 
cohort (e.g., first three evaluable).  Available data from all subjects receiving study drug 
will be considered in dose escalation decisions.  Adverse events occurring after this 
defined period and PK assessment may also be considered in dose escalation decisions.
 


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If continuous dosing is not feasible, a lower dose or alternative dosing schedules may be 
employed.  Alternative doses and schedules will be determined after discussions between 
the investigators and the AbbVie TA MD, based on factors such as pharmacokinetic data, 
recovery periods for observed DLTs and toxicity data.
Escalation of venetoclax to the next designated cohort dose level will proceed if all 
assigned subjects in the intended cohort (e.g., first three evaluable) complete the lead-in 
period plus one cycle (21 days) at the designated cohort dose without experiencing a DLT 
(refer to Section 6.1.8.1).  If one (1) subject within any dose level experiences a DLT, up 
to 6 subjects will be enrolled at that dose level.  Additional subjects may be enrolled at the 
current dose level at the discretion of the AbbVie TA MD.  If < 33% of the subjects 
enrolled at a dose level experience a DLT, then escalation of the designated cohort dose 
may continue.  If ≥33% of the subjects enrolled at a dose level experience a DLT, dose 
escalation will stop and the previous lead-in period and designated cohort dosing regimen 
will be considered the MTD or dose de-escalation of the designated cohort dose, and/or a 
modified lead-in period may be explored if MTD is not declared.
Dose escalation guidelines are summarized in Table 2.
Table 2.
Dose Escalation Guidelines
Number of Subjects with DLT
Dose Escalation
0 of 3
Begin enrollment in the next dose level 
1 of 3
Enroll 6 subjects in current dose level
1 of 6 or n < 33%
Begin enrollment in the next dose level
≥ 2 of 6 or n ≥ 33%
Previous dose determined as the MTD or dose de-escalation
Note:
If a DLT of TLS occurs during the lead-in period, it will affect dosing decisions in the lead-in period.  
(Refer to Section 6.1.8.1, Definition – Dose Limiting Toxicity).
If dose de-escalation or modification of the lead-in period occur and < 33% of subjects 
enrolled experience a DLT at the reduced designated cohort dose and/or the modified 
lead-in period regimen, this dosing regimen will be declared the MTD.  If ≥ 33% of the 
subjects enrolled at the reduced designated cohort dose and/or the modified lead-in period 
 


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regimen still experience a DLT, dose de-escalation of the designated cohort dose and/or 
modified lead-in period regimen will continue to be explored.
The MTD will be defined as the highest designated cohort dose level (and corresponding 
lead-in period regimen, if applicable) at which < 33% of the subjects enrolled experience 
a DLT.
Transition from Dose Escalation to Safety Expansion Portion
Once the MTD is determined, enrollment into the dose escalation portion of the study will 
end.  The dose level for the safety expansion portion will be communicated to all 
participating investigators prior to the start of enrollment.  Subjects from the dose 
escalation portion of the study are not eligible for enrollment in the safety expansion 
portion of the study.
Safety Expansion Cohort
Once the MTD is declared, a cohort of approximately 36 additional subjects with relapsed 
or refractory MM will be enrolled at the MTD, or RPTD, in order to further define the 
toxicity profile and better inform the RPTD determination for subjects with MM.  It is 
expected, based on a prevalence rate of about 40%, that approximately 14 of 36 subjects 
will overexpress Bcl-2 and have low Bcl-xL.
To mitigate the risk for TLS observed, subjects will receive TLS prophylaxis prior to and 
during treatment (refer to Management of Tumor Lysis Syndrome, Section 6.1.8.4).  TLS 
prophylaxis and subject management guidelines may be modified or removed based on 
results from the dose escalation portion.
The dosing schedule for the safety expansion cohort, if a lead-in period is required, is 
depicted in Figure 3.  The dosing schedule for the safety expansion portion, if a lead-in 
period is not required, is depicted in Figure 4.
 


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Figure 3.
Safety Expansion Cohort Dosing, if a Lead-in Period is Required
*
Week 2 of the Lead-in dosing may be applicable based on safety data.
Figure 4.
Safety Expansion Cohort Dosing, if a Lead-in Period is Not 
Required
If, during the safety expansion cohort of the study, toxicities are observed during the 
lead-in period (if applicable) plus one cycle (21 days) at the designated cohort dose at a 
frequency higher than the definition of MTD (> 33%), a lower dose or alternative dosing 
schedules may be examined.  The alternative dose and schedule will be determined by 
AbbVie after discussion between the investigators and the AbbVie TA MD.
During the dose escalation and safety expansion cohorts, upon assessment of progressive 
disease and discussion with AbbVie TA MD, the investigator may add dexamethasone 
treatment starting at 40 mg (PO) orally on Days 1, 8, and 15 of each 21-day cycle per the 
dexamethasone prescribing information.  All subjects who are ≥ 75 years old may start 
dexamethasone at a 20 mg dose.
 
 
  
  
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 


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Intrasubject Dose Escalation
During the dose escalation cohort, in order to maximize the collection of information at 
relevant doses and to minimize the exposure of individuals to suboptimal doses, subjects 
may progressively escalate their current dose to the highest cleared venetoclax dose level 
or any dose below.  Individuals will need to complete at least 2 cycles at their designated 
cohort dose (or current dose) level prior to any escalation as determined by investigator 
and the AbbVie TA MD.
TLS prophylaxis and management will be implemented at each dose escalation.  For 
subjects who dose escalate.  TLS prophylaxis and management will be discussed between 
the AbbVie TA MD and investigator.  Refer to Section 6.1.8.4 Management of Tumor 
Lysis Syndrome for additional information.
Venetoclax-Dexamethasone Combination Cohort
The combination cohort will explore the safety and efficacy of venetoclax in combination 
with dexamethasone in approximately 20 subjects with t(11;14)-positive MM.  Subjects 
will receive venetoclax daily (Day1 – 21) at the RPTD with dexamethasone (40 mg PO) 
on Days 1, 8, and 15 of each 21-day cycle, per the dexamethasone prescribing 
information.  All subjects who are ≥75 years old may start dexamethasone at a 20 mg 
dose.
During the VenDex combination cohort, a lead-in period will not be employed.  The 
dosing schedule for the VenDex combination portion is depicted in Figure 5.
 


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Figure 5.
VenDex Combination Cohort Dosing Schedule, Without Lead-In 
Period
Phase 2 Portion:
The Phase 2 cohort will further explore the efficacy of venetoclax in combination with 
dexamethasone in approximately 80 – 100 relapsed or refractory subjects with t(11;14)-
positive MM.  Subjects will receive venetoclax daily (Day 1 – 21) with dexamethasone 
orally Day 1, 8, and 15 per the prescribing information.  
Subjects enrolled in the VenDex combination and Phase 2 cohorts may discontinue 
dexamethasone due to toxicity or intolerability, and may continue receiving venetoclax 
once daily as monotherapy.  Subjects will continue study treatment until the end of the 
study provided they continue to tolerate venetoclax, have no evidence of disease 
progression, and do not meet any criteria for subject discontinuation (Section 5.4.1).
Option to Continue Venetoclax Treatment
All subjects will continue receiving study drug until the end of study provided they 
continue to tolerate venetoclax, have no evidence of disease progression and do not meet 
any of the criteria for subject discontinuation (Section 5.4.1).
 
   
  
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 


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5.2
Selection of Study Population
Subjects will undergo screening procedures within approximately 21 days prior to initial 
study drug administration, with the exception of the skeletal survey which must be 
completed within approximately 30 days prior to planned study drug administration.  
Adult male and female subjects who meet the inclusion criteria and who do not meet any 
of the exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Subject must be ≥ 18 years of age.
2.
Subject has an ECOG performance score of ≤ 1.
●
For subjects in the Phase 2 portion:  ECOG performance score of ≤ 2
3.
Diagnosis of multiple myeloma that requires treatment and has been previously 
treated with:
●
For subjects in the Dose Escalation cohort of the study:
○
≥ 1 prior line of therapy.  Induction therapy followed by stem cell 
transplant and maintenance therapy will be considered as a single line of 
therapy.
●
For subjects in the Safety Expansion cohort of the study:
○
Have received treatment with a proteasome inhibitor and an 
immunomodulatory (IMiD®) agent (e.g., thalidomide, lenalidomide, 
pomalidomide).  Induction therapy followed by stem cell transplant and 
maintenance therapy will be considered as a single line of therapy.
●
For subjects in the VenDex Combination cohort:
○
Have received treatment with a proteasome inhibitor and an 
immunomodulatory (IMiD®) agent (e.g., thalidomide, lenalidomide, 
pomalidomide), AND
 


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○
Have MM positive for t(11;14) translocation as determined by an 
analytically validated fluorescence in-situ hybridization (FISH) assay per 
the central laboratory testing
●
For subjects in the Phase 2 cohort:
○
Have MM positive for the t(11;14) translocation, as determined by an 
analytically validated fluorescence in situ hybridization (FISH) assay per 
the central laboratory testing (enrollment with local t(11;14)-positive FISH 
results only will be considered at the discretion of the TA MD)
AND
○
Subject must have evidence of disease progression on or within 60 days of 
the last dose of the most recent previous treatment regimen based on the 
IMWG criteria, AND
○
Subject must have previously received at least 2 lines of therapy, including 
an immunomodulatory drug (lenalidomide or pomalidomide), a 
proteasome inhibitor (bortezomib, carfilzomib or ixazomib), daratumumab, 
and glucocorticoids.  
●
For US subjects:  Daratumumab combination regimen must be one of 
the prior lines of therapy (for this study, daratumumab plus 
corticosteroids will not be considered a combination regimen)
●
For Non-US Subjects: Either daratumumab monotherapy or 
combination therapy is acceptable.  Daratumumab monotherapy will be 
limited to approximately 20 percent of the total number of Phase 2 
subjects.
4.
Subject must have had measurable disease at Screening, defined as any of the 
following:
●
Serum monoclonal protein ≥1.0 g/dL (≥10 g/L) by protein electrophoresis, or
●
≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis, or
●
Serum immunoglobulin free light chain (FLC) ≥10 mg/dL provided serum 
FLC ratio is abnormal.
 


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5.
Subjects with a history of autologous or allogenic stem cell transplantation must 
have adequate peripheral blood counts independent of any growth factor support, 
and have recovered from any transplant related toxicity(s) and be:
●
> 100 days post-autologous transplant (prior to first dose of study drug), or
●
≥ 6 months post-allogenic transplant (prior to first dose of study drug) and not 
have active graft-versus-host disease (GVHD), i.e., requiring treatment.
6.
Subjects must meet the following laboratory parameters, per laboratory reference 
range, at least once during the screening period:
●
Absolute neutrophil count (ANC) ≥1000/µL,
Subjects may use growth factor support to achieve ANC eligibility criteria.  
●
AST and ALT ≤3 × upper limit of normal range (ULN),
●
Calculated creatinine clearance ≥ 30 mL/min using a modified Cockcroft-
Gault calculation or a 24-hour urine collection for Creatinine Clearance:
eCCr
=
(140 – Age) ● weight (kg) ● [0.85 if Female]
72 ●Serum Creatinine (mg/dL)
OR, if serum creatinine is in µmol/L:
eCCr
=
(140 – Age) ● weight (kg) ● [1.23 if Male, 1.04 if Female]
Serum Creatinine (µmol/L)
●
Platelet count ≥30,000 mm3, independent of transfusion for 2 weeks
●
Hemoglobin ≥ 8.0 g/dL, subjects may receive blood transfusion to achieve 
hemoglobin eligibility criteria per investigator discretion.
●
Total bilirubin ≤1.5 × ULN
Subjects with Gilbert's Syndrome may have bilirubin > 1.5 × ULN.
7.
If female, subject must be:
●
Postmenopausal defined as:
○
Age > 55 years with no menses for 12 or more months without an 
alternative medical cause. 
 


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○
Age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingestomy, 
or hysterectomy).
OR
●
A Women of Childbearing Potential (WOCP) practicing at least one protocol 
specified method of birth control (Section 5.2.5) starting at Cycle 1 Day 1 (or 
earlier) through at least 30 days after last dose of study drug.  
8.
Females of childbearing potential (must have negative results for pregnancy test 
performed:
●
At Screening, on a serum sample obtained within 21 days prior to the 
first study drug administration, and
●
Prior to dosing, on a urine sample obtained on the first day of study drug 
dosing, if it has been > 7 days since obtaining the serum pregnancy test results.
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined above) at Screening do not require pregnancy 
testing.  
9.
This criterion has been removed.
10.
Must voluntarily sign and date an informed consent, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of 
any screening or study-specific procedures.
Rationale for Inclusion Criteria
(1 – 4)  To select the subject population
(5, 6)  For the safety of the subjects
(7 – 9)  The impact of venetoclax on pregnancy is unknown
 


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(10)  In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject exhibits evidence of other clinically significant uncontrolled condition(s), 
including, but not limited to:  
●
Acute infection within 14 days prior to first dose of study drug requiring 
antibiotic, antifungal, or antiviral therapy
●
Diagnosis of fever and neutropenia within 1 week prior to first dose of study 
drug.
2.
Subject has a cardiovascular disability status of New York Heart Association Class 
≥ 3.
3.
Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, cardiovascular or hepatic disease within the last 6 months 
that, in the opinion of the investigator, would adversely affect his/her participation 
in the study.
4.
Subject has a history of other active malignancies other than multiple myeloma 
within the past 3 years prior to study entry, with the following exceptions:
●
Adequately treated in situ carcinoma of the cervix uteri,
●
Basal cell carcinoma of the skin or localized squamous cell carcinoma of the 
skin,
●
Localized prostate cancer Gleason grade 6 or lower AND with stable Prostate 
Specific Antigen (PSA) levels off treatment
●
Previous malignancy confined and surgically resected (or treated with other 
modalities) with curative intent.
5.
Known Human Immunodeficiency Viral (HIV) infection
6.
Active hepatitis B or C infection based on screening blood testing.  
 


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7.
Subject is receiving other ongoing anti-myeloma therapy.
8.
Subject has received any of the following within 7 days prior to the first dose of 
study drug:
●
Strong or moderate CYP3A inhibitors, or
●
Strong or moderate CYP3A inducers.
9.
Subject has received any of the following within 14 days prior to the first dose of 
study drug or has not recovered to less than a Grade 2 clinically significant adverse 
effect(s)/toxicity(s) of the previous therapy:  any anti-myeloma therapy including 
chemotherapy, radiotherapy, or investigational therapy, including targeted small 
molecule agents.
10.
This criterion has been removed.
11.
Subject has received prior treatment with a BCL-2 family inhibitor.
12.
This criterion has been removed.
13.
Subject is pregnant, parturient, or breastfeeding; deprived of freedom by judicial or 
administrative decision; hospitalized and unable to provide consent, or otherwise 
unable to provide consent.
14.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit within 3 days prior to the 
first dose of study drug.
15.
Subject has received immunization with live vaccine within 60 days of dosing.
16.
Recent corticosteroid therapy at a cumulative dose equivalent to > 140 mg of 
prednisone or a single dose equivalent to ≥ 40 mg of dexamethasone within 
2 weeks prior to the first dose of study drug.
Rationale for Exclusion Criteria
(1 – 2, 4, 7)  To select the appropriate subject population
 


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(3, 5, 6, 8 – 11, 14, 15, 16)  For the safety of the subjects
(13)  The impact of venetoclax on pregnancy is unknown
5.2.3
Determination of the Number of Prior Lines of Therapy and 
Refractoriness to Prior Therapies
A line of therapy consists of at least: 
●
1 complete cycle of a single agent; or
●
A regimen consisting of combination of several drugs; or
●
A planned sequential therapy of various regimens.20
A treatment is considered a new line of therapy if any of the following 3 conditions are 
met:
●
Start of a new line of treatment after discontinuation of a previous line: If a 
treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy.  A regimen is considered 
to have been discontinued if all the drugs in that given regimen have been 
stopped.  A regimen is not considered to have been discontinued if only some 
of the drugs of the regimen, but not all, have been discontinued.
●
The unplanned addition or substitution of 1 or more drugs in an existing 
regimen:  Unplanned addition of a new drug or switching to a different drug 
(or combination of drugs) due to any reason is considered a new line of 
therapy.
●
Stem Cell Transplant (SCT):  In patients undergoing > 1 SCT, except in the 
case of a planned tandem SCT with a predefined interval (such as 3 months), 
each SCT (autologous or allogeneic) should be considered a new line of 
therapy regardless of whether the conditioning regimen used is the same or 
different.  Data on type of SCT should also be captured.
 


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Definition of Refractory Myeloma to a Prior Therapy
In this study, a subject will be considered refractory to a prior line of therapy if any of the 
following criteria are met:
●
Subject has not achieved at least a minimum response, as defined per European 
Society for Blood and Marrow Transplantation (EBMT) or IMWG response 
criteria, while on that primary or salvage therapy.
●
Subject has progressive disease while on that primary or salvage therapy, or 
within 60 days of last dose of the therapy.
5.2.4
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary from 
3 weeks prior to study drug administration until 30 days following the last dose of study 
drug, the name of the medication, dosage information including dose, route and 
frequency, date(s) of administration including start and end dates, and reason for use must 
be recorded on the appropriate electronic case report form (eCRF).  The AbbVie TA MD 
identified in Section 7.0 should be contacted if there are any questions regarding 
concomitant or prior therapy(ies).
Information regarding potential drug interactions with venetoclax can be located in the 
most current Venetoclax Investigator's Brochure.
5.2.4.1
Pretreatment Guidance
Anti-infective Prophylaxis
It is recommended that subjects should receive anti-infective prophylaxis 
(e.g., amoxicillin/clavulanic acid, levofloxacin, or equivalent per institutional guidelines) 
at least during the first 90 days of study, when Grade 4 neutropenia develops (ANC 
< 500 cells/uL) and continued until the neutropenia improves to Grade 3 or better (ANC 
> 500 cells/uL), and upon disease progression for at least 30 days, unless contraindicated 
 


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per investigator discretion.  Furthermore, it is recommended that subjects deemed at high 
risk of infection receive immunoglobulin replacement therapy (i.e., IVIG) per institutional 
guidelines or at the Investigator's discretion.  Pneumocystis prophylaxis is allowed per 
institutional guidelines or at the Investigator's discretion.
●
The use of antibiotics that are moderate or strong CYP3A4 inhibitors 
(Section 5.2.4.3 and Appendix C) should be avoided or used with caution and 
with the appropriate venetoclax dose modification (Table 4) as per protocol.
Pneumococcal and Influenza Vaccination
All subjects MUST be vaccinated against pneumococcus and receive a yearly influenza 
vaccination (live attenuated vaccines are not allowed), while on study treatment.  It is 
mandated that pneumococcal and yearly influenza vaccinations be administered after 
signing the updated informed consent for all subjects who have not previously received 
the influenza and/or pneumococcal vaccine within the recommended time frame per local 
and/or institutional vaccination guidelines, unless contraindicated, not available, or not 
applicable per local standard of care.
It is recommended that subjects in Progression Follow-up and/or Survival Follow-up 
remain vaccinated against pneumococcus and receive a yearly influenza vaccination at the 
discretion of the investigator.
Please refer to local label and/or institutional guidelines for additional information (e.g., 
vaccination/booster schedules) and contraindications regarding pneumococcal and 
influenza vaccinations.  Local and/or institutional vaccination references must be recorded 
in the site source documents.
Pneumococcal and Influenza vaccination information must be recorded in the appropriate 
eCRF.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications:
A delay in pneumococcal and/or influenza vaccination may take place per PI discretion if 
the subject tests positive for SARS-CoV-2 until such time that the subject has clinically 
recovered from COVID-19 or per institutional guidelines. In all other cases 
pneumococcal and/or Influenza vaccinations should continue as scheduled per protocol.
Tumor Lysis Syndrome Prophylaxis
There is a potential for TLS in subjects affected by hematologic malignancies.  Refer to 
Section 6.1.8.4, Management of Tumor Lysis Syndrome for required TLS prophylaxis.  
5.2.4.2
Allowed Treatments
The following concomitant medications are allowed during study treatment.  Please refer 
to Table 3 for a list of excluded and cautionary medications due to potential drug drug 
interaction (DDI) when considering the use of the following:
●
Hormonal contraceptives (examples include birth control pills, vaginal rings, 
or patches), associated with inhibition of ovulation for at least 3 months prior 
to taking study drug.
●
Colony stimulating factors (granulocyte colony-stimulating factor [G-CSF], 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) will be allowed 
per American Society of Clinical Oncology (ASCO) guidelines.21,40
●
Bisphosphonates intravenous (IV) or PO as indicated per Institutional 
guidelines.
●
Oral proton-pump inhibitor (lansoprazole, omeprazole, esomeprazole, etc.) as 
prophylactic therapy for peptic ulcer disease during treatment with 
dexamethasone.
●
Antimicrobial (including anti-fungal) prophylaxis.
●
Anticoagulants to prevent or treat thromboembolic events. 
●
Best supportive care and treatment (e.g., antiemetics, antibiotics, transfusions, 
nutritional support, pain control, etc.).
 


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●
Only low dose corticosteroids (e.g., prednisone ≤ 10 mg PO QD or its 
equivalent), inhaled steroids and topical preparations for reasons other than 
multiple myeloma (e.g., asthma) are allowed during study treatment.  Systemic 
corticosteroids > 10 mg PO QD of prednisone (or its equivalent) should not be 
given on the same day as dexamethasone is administered.  Systemic 
corticosteroids > 10 mg PO QD of prednisone (or its equivalent) are allowed 
when dexamethasone has not been interrupted provided that the dose of 
prednisone (or its equivalent) was given for less than 7 days and the 
cumulative dose was < 120 mg.  For additional guidance and to determine the 
equivalent dose of systemic corticosteroid, refer to Appendix I, Corticosteroid 
Conversion Table.
●
Surgery and radiation:
○
Localized radiation therapy to a site of pre-existing disease may be 
permitted while on study.  Following approval by the AbbVie TA MD or 
designee (refer to Section 7.0), the subject may initiate or continue with 
protocol therapy without interruption during the course of palliative 
radiation therapy if the Investigator believes that the risk of excessive bone 
marrow suppression or other toxicity is acceptable, and it is in the best 
interest of the subject to do so.
○
If the subject develops a definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas that meets the criteria for progressive 
disease, treatment must be discontinued for progressive disease regardless 
of whether radiation therapy is initiated.
○
Kyphoplasty, vertebroplasty, or emergency orthopedic surgery is 
permitted.
○
Use of radiotherapy or surgical intervention must be recorded on the Case 
Report Form.
5.2.4.3
Excluded and Cautionary Medications
General guidelines regarding excluded, cautionary and allowed medications/food are 
summarized in Table 3.
 


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Table 3.
Excluded and Cautionary Medications/Food
Excluded Food (From 3 Days Prior to Study Administration Until Last Day of Treatment)

Grapefruit and grapefruit products

Seville Oranges (including marmalade containing Seville oranges)

Starfruit
Excluded Medications

Any systemic anti-myeloma therapies other than dexamethasone and venetoclax while on study 
treatment.

Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent.

Immunization with live vaccines.
Cautionary, Additional Guidance Noted 

Strong and Moderate CYP3A inhibitors 
Consider alternative medications.  If subject requires use of these medications, use with caution and 
reduce the venetoclax dose by 50% for moderate inhibitors and 75% fold for strong inhibitors 
during co-administration.  Patients should be monitored more closely for signs of toxicities and the 
dose may need to be further adjusted.  Please Section 5.2.4.4 for additional details.
After discontinuation of CYP3A inhibitor, wait for 3 days before venetoclax dose is increased back 
to the previous dose level.

Strong and Moderate CYP3A inducers
Consider alternative medications.  If subject requires use of these medications, use with caution and 
contact AbbVie TA MD or designee (refer to Section 6.1.6) for guidance.
Cautionary

Warfarin*

P-gp substrates

BCRP substrates

OATP1B1/1B3 substrates

P-gp inhibitors

BCRP inhibitors

High Dose Corticoidsteroids^
*
Closely monitor the international normalized ratio (INR).
^
Refer to Appendix I for additional guidance.
A sample list of excluded medications and cautionary medications that fall into the 
categories within Section 5.2.4 can be found in Appendix C.  It is not possible to produce 
a 100% exhaustive list of medications that fall into these categories, so if in question, 
please refer to the appropriate product label.
 


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If the investigator determines that such a medication is medically necessary, the 
investigator will notify the AbbVie TA MD and discuss the investigator's use of these 
medications and the investigator's plans to medically monitor the potential study subject 
under consideration.
5.2.4.4
Dose Modifications for Moderate and Strong CYP3A 
Inhibitors Used with Venetoclax
Use of venetoclax with moderate or strong CYP3A inhibitors should be avoided and the 
investigator should consider alternative medications.  If the administration of a moderate 
or strong CYP3A is necessary based on the investigator's clinical judgment, then 
venetoclax dose should be reduced during the period it is co-administered with a moderate 
or strong CYP3A inhibitors.  Dose reductions for venetoclax dose levels used with 
moderate and strong CYP3A inhibitors are provided on Table 4.  Subjects should be 
monitored more closely for signs of toxicities and the dose may need to be further 
reduced.  Guidelines in Table 18, Table 19 and Table 20 should also be followed for 
venetoclax-toxicity related dose reductions when moderate or strong CYP3A inhibitors 
are concomitantly administered.  After discontinuation of CYP3A inhibitor, wait for 3 
days before venetoclax dose is increased back to previous dose level.
Table 4.
Dose Modifications for Venetoclax:  Moderate and Strong CYP3A 
Inhibitor Use
Dose with No Moderate or 
Strong CYP3A Inhibitor
With Moderate CYP3A Inhibitor
With Strong CYP3A Inhibitor
1200 mg QD
600 mg QD
300 mg QD
800 or 900 mg QD
400 mg QD
200 mg QD
600 mg QD
300 mg QD
100 mg QD
400 mg QD
200 mg QD
100 mg QD
300 mg QD
100 mg QD
Interrupt venetoclax temporarily
200 mg QD
100 mg QD
Interrupt venetoclax temporarily
100 mg QD
Interrupt venetoclax temporarily
Interrupt venetoclax temporarily
 


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5.2.5
Contraception Recommendations
While participating in this research study, female subjects should not become pregnant or 
breastfeed.
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential 
(WOCB), practicing at least one of the following highly effective methods of birth 
control, on Day 1 (or earlier) through at least 30 days.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to first dose of study drug.  Also, barrier method 
must be used during this study from initial study drug administration to 
30 days after the last dose of study drug as drug-drug interaction with 
venetoclax upon the hormonal contraception is unknown.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
first dose of study drug.  Also, barrier method must be used during this study 
from initial study drug administration to 30 days after the last dose of study 
drug as drug-drug interaction with venetoclax upon the hormonal 
contraception is unknown.
●
Bilateral tubal occlusion/ligation at least 1 month before study participation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure at least 1 month before 
study participation.
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
 


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(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
5.3
Efficacy, Pharmacokinetic, Biomarker, and Exploratory 
Research and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
 


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Table 5.
Study Activities for Phase 1 Portion:  Screening Through Cycle 3 Day 1
Screeninga
Lead-in (if applicable)
Cycle 1
Cycle 2
Cycle 
3
Not applicable for VenDex 
Combination Cohort
Event↓                                      
Day→
1
2
8^
1
2
3
8, 15
1
2
8, 15
1
Informed Consent
X
Medical/Oncology History
X
X
X
Concomitant Medications, Vaccinations and 
Adverse Experiences
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X (+ height)
X*
SD*
X*
SD*
X*
SD*
X*
Vital Signsb
X
Xb
0 hr
Xb
Xb
0 hr
X‡
X‡
X‡
X*
ECOG Performance status
X
X*
X*
X*
X*
X*
Cardiac Assessments (ECG and MUGA)c
X
Pregnancy Test*
Serum
Urined*
Urined*
Chemistrye
X
0 hr‡
0 hr
0 hr‡
0 hr‡
0 hr
X‡
X‡
X‡
X*
Hematologye
X
0 hr‡
0 hr
0 hr‡
0 hr‡
0 hr
X‡
X‡
X‡
X*
Coagulation and Urinalysis
X
X*
X*
X*
X*
Viral Serologies
X
Viral Polymerase Chain Reaction
X
Lymphocyte Enumeration
X
X*
X*
Assessments for IMWG Response Criteriaf
X
X*
 


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Table 5.
Study Activities for Phase 1 Portion:  Screening Through Cycle 3 Day 1 (Continued)
Screeninga
Lead-in (if applicable)
Cycle 1
Cycle 2
Cycle 
3
Not applicable for VenDex 
Combination Cohort
Event↓                                      
Day→
1
2
8^
1
2
3
8, 15
1
2
8, 15
1
Skeletal Surveyg
Xa,g
Plasmacytoma Evaluation
X
X*
Bone Marrow Aspirate and Biopsyh
X
PK/Biomarker/Exploratory Research Sample 
Collectionsi
Xa,i
X
X
X
X
X
X
X
X
TLS Prophylaxisj
X
X
X
Subject Diary and Study Drug 
Dispensation/Collection
X
X
X
X
X
Clinical Disease Progression Assessment
X
X
0 hr = pre-dose within 4 hours prior to dosing; ‡ = within 24 hours prior to the scheduled visit; * = within 72 hours before or after scheduled visit; SD = Symptom-Directed; 
^= Lead-in Day 15 procedures, if implemented, are the same as Lead-in Day 8.  Unless otherwise specified, study visits may occur within 4 days from anticipated date for 
operational or logistical purposes
 


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Table 5.
Study Activities for Phase 1 Portion:  Cycle 4 Day 1 Through Follow-up (Continued)
Event↓                                        
Day→
Cycle 4 
and Every 
Cyclek
Cycle 5
Cycle 7
Cycle 9 
and Every 
4th Cyclek
Intrasubject 
Dose 
Escalationj
Confirmation 
of Responsek
Final 
Visitk
Safety 
Follow-upk
1
1
1
1
Informed Consent
Medical/Oncology History
Concomitant Medications, Vaccinations and Adverse 
Experiences
X
X
X
X
X
X
X
Physical Examination
X*
X*
X*
X*
X*
X*
Vital Signsb
X*
X*
X*
X*
Xb
X*
X*
ECOG Performance status
X*
X*
X*
X*
X*
X*
Cardiac Assessments (ECG and MUGA)c
X*
Urine Pregnancy Test*
X*
X*
X*
X*
X*
X*
Chemistrye
X*
X*
X*
X*
X
X*
X*
X
Hematologye
X*
X*
X*
X*
X
X*
X*
Coagulation and Urinalysis
X*
X*
X*
X*
X*
X*
Viral Serologiesl
X*
Viral Polymerase Chain Reaction
Lymphocyte Enumeration
X*
X*
X*
Assessments for IMWG Response Criteriaf
X*
X*
X*
X*
Skeletal Surveyg
Plasmacytoma Evaluation
X*
X*
X*
X*
Bone Marrow Aspirate and Biopsyh
X
X
X*
 


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Table 5.
Study Activities for Phase 1 Portion:  Cycle 4 Day 1 Through Follow-up (Continued)
Event↓                                        
Day→
Cycle 4 
and Every 
Cyclek
Cycle 5
Cycle 7
Cycle 9 
and Every 
4th Cyclek
Intrasubject 
Dose 
Escalationj
Confirmation 
of Responsek
Final 
Visitk
Safety 
Follow-upk
1
1
1
1
PK/Biomarker/Exploratory Research Sample 
Collectionsi
X
X
X
X
CR, sCR only
X
TLS Prophylaxisj
X
Subject Diary and Study Drug 
Dispensation/Collection
X
X
X
X
X
Clinical Disease Progression Assessment
X
X
X
X
X
0 hr = pre-dose within 4 hours prior to dosing; ‡ = within 24 hours prior to the scheduled visit; * = within 72 hours before or after scheduled visit; CR = Complete Response; 
sCR = Stringent Complete Response; SD = Symptom-Directed; ^= Lead-in Day 15 procedures, if implemented, are the same as Lead-in Day 8.  Unless otherwise specified, study 
visits may occur within 4 days from anticipated date for operational or logistical purposes
a.
Screening procedures must be performed within approximately 21 days of first dose of study drug, except for skeletal survey which must be performed within approximately 
3 months prior to first dose.
b.
Vital signs are to be evaluated prior to each laboratory collection for TLS prophylaxis and management.
c.
2D Echo allowed if multiple gated acquisition (MUGA) scan cannot be obtained; however, MUGA is preferred.
d.
Urine pregnancy testing must be completed prior to first dose of study drug (Lead-in Day 1 or Cycle 1 Day 1) for women of childbearing potential if it has been > 7 days since 
Screening serum pregnancy test result.
e.
Hematology and chemistry labs:

Will be performed per the requirements of Section 6.1.8.4, Management of Tumor Lysis Syndrome. 

Lead-in Day 1 through Cycle 1 Day 3 and Intra-subject Dose Escalation testing must be performed ±20 minutes of the indicated timepoint except for zero-hour labs 
(0 hr) must be performed within 4 hours prior to dosing, unless otherwise indicated.  All labs should be performed immediately and assessed by the investigator real time 
to ensure appropriate subject management.
 


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Table 5.
Study Activities for Phase 1 Portion:  Cycle 4 Day 1 Through Follow-up (Continued)

Cycle 1 Day 8 through Cycle 2 testing may be performed predose within 24 hours prior to the scheduled visit.  

Cycle 3 Day 1 through end of study labs may be performed predose within 72 hours before or after the scheduled visit.

Refer to Table 12 for listing of specific tests required and for handling procedure that must be followed to avoid ex vivo uric acid degradation in the presence of 
rasburicase.  Reticulocyte counts only required at Screening, Lead-in Day 1 (if applicable), Day 1 of each Cycle and Final Visit.  Serum β2 microglobulin (sβ2M) and 
C-reactive Protein (CRP) are only required at Screening.  Amylase and lipase are only required at Screening, Cycle 3 Day 1, and Final Visit/Time of Relapse.  
Cholesterol and triglycerides are only required at Screening and Final Visit.

Additional hematology and chemistry labs may be performed as clinically necessary.
f.
Refer to Table 14, Assessments for IMWG Response Criteria for details on timing and requirements for specific procedures.  IMWG labs may be completed up to 1 week 
prior to the scheduled assessment day, in order to allow time for the labs to be resulted prior the actual assessment visit.
g.
Skeletal survey consists of lateral radiograph of skull, antero-posterior and lateral views of spine, antero-posterior views of pelvis, ribs, femora, tibiae, fibulae, humeri, ulnae, 
and radii.  Skeletal survey is not required to assess response unless clinically indicated.  Results obtained within approximately 3 months prior to planned first dose (Lead-in 
Day 1 or Cycle 1 Day 1) may be used at Screening.
h.
Bone Marrow Biopsy/Aspirate:

Due to differences in bone marrow core biopsy collection methodology between the sites in the US and France, the core biopsy collection will be considered an optional 
procedure for subjects enrolled in France for the dose escalation phase but mandatory at Screening in the safety expansion and VenDex combination cohorts.  Samples 
should be split for biomarkers whenever possible.

Screening samples:  When possible, fresh samples should be obtained within 21 days prior to the first dose of study drug and should be obtained after all other eligibility 
criteria have been met.

Timing of Cycle 5 Day 1 sample may be requested earlier if a CR or sCR is suspected.

sCR or CR confirmatory bone marrow aspirate must include immunophenotyping.  A bone marrow biopsy is mandatory in the circumstance that an aspirate sample is not 
available (e.g., due to a dry tap).
i.
Refer to Table 8, Pharmacokinetic Sampling and Table 9, Biomarker and Exploratory Research Sampling, for details of specific collections.
j.
TLS prophylaxis may be initiated in all subjects starting 72 hours prior to the first dose of venetoclax and prior to each dose escalation per the guidelines in Section 6.1.8.4.  
For subjects who intrasubject dose escalate, TLS prophylaxis and management will be discussed between AbbVie TA MD and investigator.  Refer to Section 5.1 Intrasubject 
Dose Escalation.
k.
Allowed modifications to study activities due to COVID-19 are described under the individual study procedures in Section 5.3.1.1.
l.
SARS-CoV-2 test (preferred molecular testing e.g., PCR) if clinically indicated per Investigator's discretion (done locally).
 












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Table 8.
Schedule of Pharmacokinetic Blood Collection for Venetoclax
Collection Times
Not applicable for VenDex 
Combination Cohort
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 2
Day 2
Cycles 3, 5, 7, 
9
Day 1
Intrasubject 
Dose 
Escalation**
Lead-in
Day 1*
Lead-in
Day 8*
Dose Escalation Cohort
8† hr 
post-dose
8† hr post-dose
8† hr post-dose
0 (pre-dose), 2, 4, 
6, 8 hrs post-dose
24 hours post 
Cycle 2 Day 1 
dose (pre-dose of
Cycle 2 Day 2)
0 (pre-dose)
8† hr post-dose 
(optional) and at 
the next 
scheduled study 
visit 0 hr 
(pre-dose)
Safety Expansion 
Cohort
8† hr 
post-dose
8† hr post-dose
8† hr post-dose
0 (pre-dose)
N/A
0 (pre-dose)
8† hr post-dose 
(optional) and at 
the next 
scheduled study 
visit 0 hr 
(pre-dose)
VenDex Combination 
Cohort
N/A
N/A
8† hr post dose
0 (pre-dose)
N/A
0 (pre-dose)
N/A
Phase 2 Cohort
N/A
N/A
N/A
0 (pre-dose)
N/A
0 (pre-dose)
Cycles 3, 5, and 
7 only
N/A
* = applicable when a Lead-in period is implemented.  ** = This is only for subjects who are escalating above their designated cohort dose (or current dose) to a higher dose level 
during dose escalation portion.  Refer to Section 5.1 Intra-Subject Dose Escalation.  An 8 hour post-dose collection may be performed on the day of the escalation, if possible.  At 
the next scheduled study visit, a sample will be collected at 0 hour (pre-dose).
N/A = No PK samples will be collected.    † = The 8 hour post-dose PK sample may be collected up to 1 hour earlier, if necessary to facilitate sample processing.
 


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Table 8.
Schedule of Pharmacokinetic Blood Collection for Venetoclax (Continued)
Notes:

All "pre-dose" samples are relative to venetoclax administration.

Subjects will take a low-fat breakfast prior to all study drug administration.  Dose Escalation subjects will take a standard low-fat breakfast prior to study drug 
administration on intensive PK sample collection day Cycle 2 Day 1.

The date and time (to the nearest minute) of each study drug dose taken and whether or not the dose was taken within 30 minutes after completing breakfast will be 
recorded on the eCRF for every scheduled PK day and for the 2 days prior to every scheduled PK day:

If a dose escalation is planned for an individual subject after clearing the designated cohort dose, dosing time and breakfast completion will be recorded for the 2 days 
prior to the escalation.  Subjects may only escalate beyond their assigned designated cohort dose (or current dose) on Day 1 of a cycle with prior approval of the AbbVie 
TA MD.
 


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Table 9.
Biomarker and Exploratory Research Sampling – Phase 1 Portion
Sample Collections
(Sample Type)
Sample 
Type
Screening 
(Preferred) OR 
Prior 
to First Dose
Lead-In 
Day 2a
Cycle 1
Days 1 
and 2
Cycle 3
Day 1
Cycle 5
Day 1
Cycle 9 
and every 
4th Cycle
Day 1e
Confirmation 
of CR, sCRe
Time of 
Relapse 
(Preferred) OR 
Final Visite
Pharmacogenetics
Optional sample, additional consent 
required
Blood
4 mL
Serum Markers (pre-dose)
Blood
5 mL
3.5 mL
3.5 mL
3.5 mL
3.5 mL
3.5 mLf
3.5 mL
Plasma Markers (pre-dose)
Blood
6 mL
3 mL
3 mL
3 mLf
3 mL
Minimal Residual Disease (MRD) 
Assessment
Aspirate
1 mL
3 mL
3 mL
Cytogenetics/FISH
Aspirate
3 mLb
2 mLb,d
2 mLb
Bcl-2 Family Member Analysis
Aspirate
8 mLb
4 mLb,d
4 mLb
In Vitro Sensitivity of MM Cells
Optional samples, France only
Aspirate
3 mLb
BH3 Profiling
Optional samples, US only
Aspirate
1 mLb
1 mLb
Bcl-2 family member Protein Analysis
Optional samples:  France (dose 
escalation – all time points; safety 
expansion/venetoclax-dexamethasone 
combination – C5D1 and relapse/Final 
Visit)
FFPE core 
biopsyb,c
FFPE coreb,c
FFPE 
coreb,c,d
FFPE coreb,c
sCR = Stringent Complete Response; CR = Complete Response; FFPE = Formalin-fixed paraffin-embedded
 


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Table 9.
Biomarker and Exploratory Research Sampling – Phase 1 Portion (Continued)
a.
Lead-in Day 2 (if applicable) sample only to be collected if subject is being seen for laboratory monitoring and sample collection is feasible.  Not applicable for subjects who 
enroll to the venetoclax-dexamethasone combination portion.  
b.
Bone marrow aspirate and core samples should be split from samples obtained for IMWG criteria assessment whenever possible.
c.
Due to differences in bone marrow core biopsy collection methodology between the sites in the US and France, the core biopsy collection will be considered an optional 
procedure for subjects enrolled in France for the dose escalation phase but mandatory at Screening in the safety expansion and venetoclax-dexamethasone portion.
d.
If the Cycle 5 Day 1 bone marrow aspirate and biopsy are completed early based on observed response data (e.g., sCR or CR is suspected), those samples should not be split 
for use in biomarker testing and a second aspirate and biopsy should not be collected at the Cycle 5 Day 1 time point.
e.
Allowed modifications due to COVID-19 are described under the individual study procedures in Section 5.3.1.1.
f.
No additional collections following implementation of Protocol Amendment 12.
 


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Table 10.
Biomarker and Exploratory Research Sampling – Phase 2 Portion
Sample Collections (Sample Type)
Screening
C1D1
Cycles 2 – 5 Day 1
Confirmation of 
sCR/CRa
6 Months Post-
Confirmation of 
sCR/CRa
12 Months Post-
Confirmation of 
sCR/CRa
Final Visita
PERIPHERAL BLOOD 
SAMPLES
Samples should be collected pre-dose.  
Pharmacogenetics
(Optional sample)
X
Immuno-phenotyping
(US only)
4 mL
4 mL
4 mLb
Immuno-sequencing
(US only)
4 mL 
4 mL
4 mL
Serum Markers
3.5 mL
3.5 mL
3.5 mL
3.5 mL
Plasma Markers
3 mL
3 mL
3 mL
3 mL
BONE MARROW CORE 
BIOPSY SAMPLES
When possible, samples should be assessed for IWMG first, and split for biomarker analysis.  Fresh samples are preferred, however, 
samples collected within 12 weeks prior to first dose of study drug that are representative of the subject's current disease, without 
intervening treatment will be accepted.  Core block or tissue slides are acceptable.
Bcl-2 family member Protein 
Analysis
X
X (Optional)
 


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Table 10.
Biomarker and Exploratory Research Sampling – Phase 2 Portion (Continued)
Sample Collections (Sample Type)
Screening
C1D1
Cycles 2 – 5 Day 1
Confirmation of 
sCR/CRa
6 Months Post-
Confirmation of 
sCR/CRa
12 Months Post-
Confirmation of 
sCR/CRa
Final Visita
BONE MARROW ASPIRATE 
SAMPLES
Samples should be assessed for IWMG first, and split for biomarker analysis.  At Screening, fresh samples should be obtained within 
21 days prior to first dose of study drug and when possible, should be obtained after all other eligibility criteria have been met.
Minimal Residual Disease (MRD) 
Assessment
3 mL
3 mL
3 mL
3 mL
Bcl-2 Family Member Analysis
12 mL
12 mL (Optional)
Cytogenetics/FISH
3 mL
3 mL (Optional)b
Translational Research
3 mL
3 mL (Optional)b
a.
Allowed modifications due to COVID-19 are described under the individual study procedures in Section 5.3.1.1.
b.
No additional collections following implementation of Protocol Amendment 11.
 


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5.3.1.1
Study Procedures
Unless otherwise stated, the baseline measurement for any given variable will be defined 
as the last value obtained for the variable prior to the first dose of study drug.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Every effort should be made to 
ensure the safety of subjects and site staff, while maintaining the integrity of the study.  
General COVID-19 study execution guidance and COVID-19 pandemic-related 
acceptable protocol modifications are provided in the following sections of the protocol if 
visits cannot be conducted onsite due to travel restrictions or other pandemic-related 
reasons:
●
Section 3.4 Benefits and Risks
●
Section 5.2.4.1 – Pretreatment Requirements Pneumococcal and Influenza 
Vaccination 
●
Section 5.3.1 Efficacy and Safety Measurements Assessed and Flow Chart
●
Section 5.3.1.1 Study Procedures
○
Informed Consent
○
Concomitant Medications and Adverse Experiences
○
Physical Examination
○
Vital Signs
○
ECOG
○
Cardiac Assessments
○
Clinical Laboratory Tests
○
Skeletal Survey
○
Plasmacytoma Evaluation
○
IMWG Testings
○
Subject Diaries
○
Progression of Disease
 


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○
Biomarker testings
○
Virology -SARS-CoV-2 test (preferred molecular testing e.g., PCR)
●
Section 5.4.1 Discontinuation of Individual Subjects
●
Section 5.5.1 Treatments
●
Section 5.5.6 Treatment Compliance
●
Section 6.1.6 Adverse Event Reporting
●
Section 7.0 Protocol Deviation
●
Section 9.2 Ethical Conduct of the Study
●
Section 11.0 Data Quality Assurance
Screening procedures must be performed within approximately 21 days prior to study 
drug administration.  Skeletal survey results obtained within < 30 days prior to planned 
first dose of study drug may be used for Screening.
For subjects enrolled to the VenDex combination and Phase 2 cohorts, a lead-in period 
will not be employed.
Informed Consent
Signed informed consent will be obtained from the subject before any study-specific 
procedures are undertaken or before any prohibited medications are withheld from the 
subject in order to participate in this study.  Informed consent is also required for optional 
exploratory research sampling.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations. 
All informed consent procedures must be documented within the subject's source 
documents.
 


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Medical and Oncology History
The following will be collected during the Screening Visit and updated prior to first dose 
of study drug (Lead-in Day 1 or Cycle 1 Day 1):
●
Complete medical history, including documentation of any clinically 
significant medical condition
●
History of tobacco and alcohol use
●
Detailed oncology history, including:
○
Histology
○
Date of cancer diagnosis
○
Stage/Grade
○
Any surgical procedures
○
Prior treatments administered (including dates, type of modality, response 
to treatment and reason for treatment discontinuation)
○
Refractory or relapsed status must be assessed and documented per the 
definitions in Section 5.2.3
●
Detailed prior and concomitant medication usage including dates of usage and 
dosing information for all medications and supplements taken
On the first day of dosing (Lead-in Day 1 or Cycle 1 Day 1) any additional medical 
history that is observed after signing of the informed consent but prior to initial 
venetoclax admininistration and considered not related to study required procedures will 
be recorded in the subject's medical history.
Concomitant Medications and Adverse Experiences
Medication (prescription or over-the-counter, including vitamins and herbal supplements) 
will be recorded beginning with the Screening Visit and continuing until 30 days 
following the last dose of study drug.
On the first day of dosing (Lead-in Day 1 or Cycle 1 Day 1), any serious adverse events 
observed from the time of signing the informed consent but prior to initial venetoclax 
 


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administration will be reported, if considered by the Investigator to be causally related to 
study-required procedures.  At each visit, including the Final Visit and the 30-day Safety 
Follow-up Visit, the subject's medical history will be reviewed and any changes from 
baseline will be recorded on the adverse event eCRF.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, concomitant medication and AE assessments visits may 
be conducted via phone or video conference. Additional guidance for the reporting of 
COVID-19 adverse events (including the capture of specific signs/symptoms of infection 
and testing results) can be found in Section 6.1.6.
Physical Examination
A physical examination (including weight) will be performed according to Table 5, 
Table 6, and Table 7 as applicable.
Physical examinations may be performed within 72 hours before or after the scheduled 
visit day.
A symptom-directed physical examination will be performed when necessary.
Any clinically significant physical examination changes after dosing will be recorded as 
adverse events.
COVID-19 Pandemic-Related Acceptable Protocol Modifications:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  If subjects are unable to be assessed by the study site, physical exam 
(including body weight) may be performed by another licensed practitioner.
 


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Vital Signs
Body temperature (oral or tympanic), blood pressure, and pulse will be measured after the 
subject has been sitting at least 3 minutes according to Table 5, Table 6, and Table 7 as 
applicable.
Vital signs may be performed within 72 hours before or after the visit day, unless 
otherwise specified.
COVID-19 Pandemic-Related Acceptable Protocol Modifications:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  If subjects are unable to be assessed by the study site, vital signs (including 
body weight) may be collected by the subject or caregiver as needed.
ECOG Performance Status
The ECOG22 performance status will be assessed according to Table 5, Table 6, and 
Table 7 as applicable.
ECOG performance status may be performed within 72 hours before or after the visit day.
Grade
Description
0
Fully active, able to carry on all predisease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications:
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  If subjects are unable to be assessed by the study site, ECOG performance 
status may be performed by another licensed practitioner.
Patient-Reported Outcome (PRO) Assessments (Phase 2 Portion Only)
PRO assessments include BPI-SF, EORTC QLQ-C30, EORTC QLC MY20, PROMIS 
Cancer Fatigue SF, and EQ-5D-5L.  These assessments will be collected per Table 6 and 
Table 7 throughout the trial.  Subjects may complete all baseline PRO assessments within 
72 hours prior to the first dose of venetoclax.  It is required that PRO assessments be 
completed prior to any other clinical assessments and prior to dosing for subsequent cycle 
visits.  With the implementation of Protocol Amendment 10 PRO Assessments will no 
longer be collected.
BPI-SF
The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or 
intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in 
patients with cancer pain.32  The four pain severity items assess pain at its "worst," "least," 
"average," and "now" (current pain).  For these items, patients are asked to rate their pain 
on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you 
can imagine).  The BPI "worst" pain severity item has been shown to be reliable and valid 
for use as a single item.33  The BPI-SF also includes questions to measure the interference 
of pain in the patient's daily life, including general activity, mood, ability to walk, normal 
work both outside the home and housework, relations to other people, sleep, as well as 
enjoyment of life.  For these items, patients are asked to describe the extent to which pain 
has interfered on an 11-point numeric rating scale with anchors of 0 (does not interfere) to 
10 (completely interferes).
 


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EORTC QLQ-C30
HRQoL and symptoms will be assessed with the EORTC-QLQ-C30 version 3.34  The 
QLQ-C30 is a 30-item subject self report questionnaire composed of both multi-item and 
single scales, including five functional scales (physical, role, emotional, social, and 
cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health 
status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).  Subjects rate items on a four-point 
scale, with 1 as "not at all" and 4 as "very much."  The QLQ-C30 was developed and 
validated for use in a cancer patient population, and its reliability and validity is highly 
consistent across different language cultural groups.
EORTC QLQ-MY20
The EORTC QLQ-MY20 was developed as an additional module for the QLQ-C30 and is 
composed of 20 multiple myeloma specific items.35  The QLQ-MY20 includes scales for 
disease symptoms, side effects of treatment, future perspective, and body image.  Values 
for each scale range from 0 to 100.  Subjects rate items on a four-point scale, with 1 as 
"not at all" and 4 as "very much."  The QLQ-MY20 is a reliable and valid instrument for 
measuring quality of life in myeloma patients.
PROMIS Cancer Fatigue SF
The PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.36  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Cancer Fatigue SF that has been developed 
for use in oncology populations.37,38  PROMIS Cancer Fatigue SF is a seven item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days.  All 
questions employ the following five response options:  1 = Not at all, 2 = A little bit, 
3 = Somewhat, 4 = Quite a bit, and 5 = Very much.
 


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EQ-5D-5L
The EQ-5D-5L is a generic preference instrument that has been validated in numerous 
populations.39  The EQ-5D-5L has five dimensions:  mobility, self care, usual activities, 
pain/discomfort and anxiety/depression.  These dimensions are measured on a five level 
scale:  no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.
Table 11.
Patient-Reported Outcome Assessments
Administration Order
Test
Administration Time
1
BPI-SF
Approximately 5 minutes
2
PROMIS Cancer Fatigue SF
Approximately 5 minutes
3
EORTC QLQ-C30
Approximately 12 minutes
4
EORTC QLQ-MY20
Approximately 5 minutes
5
EQ-5D-5L
Approximately 5 minutes
Total Admin Time:  Approximately 
32 minutes
Cardiac Assessments
Cardiac assessments will include 12-lead electrocardiogram and multiple gated 
acquisition scan (MUGA, preferred) or 2D echocardiogram according to Table 5, Table 6, 
and Table 7, as applicable.  Data from the cardiac assessments will be entered into EDC 
eCRF within 5 days of report availability.
12-Lead Electrocardiogram
A 12-lead resting ECG will be obtained according to Table 5, Table 6, and Table 7 as 
applicable.
An appropriately qualified physician at the study site (local reader) will read all ECGs.  
The local reading of the ECG will be used by the investigator for subject safety 
assessments, including adverse event determination and management, dose escalation, and 
 


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termination of subjects from the study.  The local reader will write on the ECG tracing 
global interpretation as either:
●
normal ECG
●
abnormal ECG - not clinically significant
●
abnormal ECG - clinically significant
●
unable to evaluate
The reader will then sign and date the ECG.  Any reports that are abnormal clinically 
significant will be faxed to the Oncology Safety Management Team via the contact 
information provided in Section 6.1.6 within 5 business days.  The corrected QT interval 
measurement (Bazett QTcB) will be documented in the eCRF only if the local reader 
selects the "prolonged QT" box for an abnormal ECG.  Correction by the Bazett formula 
(QTcB) is suggested for logistical reasons and for consistency across sites; however, 
correction by other methods may be acceptable based on consultation with AbbVie TA 
MD.  A copy of any other ECGs will sent to AbbVie, if requested.  The original ECG 
tracing will be retained in the subject's records at the study site.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the ECG cannot be performed at the study site due to study modifications 
related to the COVID-19 pandemic, the ECG may be completed at other centers providing 
the modality/technique is equivalent.
Multiple Gated Acquisition Scan (MUGA)
A MUGA scan will be performed according to Table 5, as applicable.
If a MUGA scan cannot be performed, a 2D echocardiogram with doppler may be 
performed.  Subjects may have either a MUGA or echocardiogram performed; however, 
MUGA is the preferred method and it is preferred that the same method of assessment 
(MUGA or 2D echocardiogram) is used throughout the study for a given subject.  A 
MUGA scan (or 2D echocardiogram) is not required for the Phase 2 portion.
 


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A qualified physician will sign and date the MUGA/echocardiogram reports and 
determine if any findings outside normal physiological variation are clinically significant 
(in consultation with a cardiologist, if necessary).  If any findings outside normal 
physiological variation are clinically significant, this will be documented on the 
appropriate eCRF and the report will be faxed to the AbbVie Oncology Safety 
Management Team via the contact information in Section 6.1.6 within 5 days of obtaining 
the report, unless otherwise noted.  If necessary, AbbVie may request that copies of other 
MUGA/echocardiogram reports be sent in for further analysis by AbbVie.
The original MUGA/echocardiogram report with physician assessment will be retained in 
the subject's records at the study site.  Repeat MUGAs/echocardiograms will be 
performed whenever clinically necessary.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
MUGA or 2D ECHO (if MUGA scan cannot be done) may be done at other centers 
providing modality/technique is equivalent.
Clinical Laboratory Tests
Local laboratories will be utilized to process and provide results for all clinical laboratory 
tests except IMWG assessments, viral PCR, and viral serologies, which will be performed 
at a central laboratory.  For the Phase 1 portion, IMWG assessment samples may also be 
collected and sent to the local laboratory at Screening.  Phase 2 subjects must have all 
IMWG assessment samples collected and sent to the central laboratory.  Viral PCR 
and/or viral serologies may be performed locally if approved by AbbVie.
Screening labs must be completed within 21 days prior to the subject's first dose of 
venetoclax.  
Lead-in Day 1, if applicable, or Cycle 1 Day 1 through Cycle 1 Day 2 testing must be 
performed ±20 minutes of the indicated timepoint except for 0 hr pre-dose labs which 
must be performed within 4 hours prior to dosing, unless otherwise indicated.  All labs for 
 


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Lead-in Day 1, if applicable, or Cycle 1 Day 1 through Cycle 1 Day 2 should be 
performed immediately and assessed by the investigator real-time.
Cycle 1 Day 8 through Cycle 2 labs must be completed within 72 hours prior to the 
subject's scheduled visit.
All laboratory testing starting with Cycle 3 may be performed within ±72 hours of the 
scheduled visit day unless otherwise specified.
Local laboratory results should be entered into the eCRF as directed.  Laboratory normal 
ranges for local laboratories will be provided to the AbbVie Clinical Team as requested.
All local laboratory measurements will be entered into the eCRF within 5 days of report 
availability, unless the report reflects a Grade 3 or 4 test result in which case the results 
will be entered immediately into the eCRF within 24 hours of report availability.
Pregnancy Test
For female subjects of childbearing potential, pregnancy testing will be performed 
according to Table 5, Table 6, and Table 7 as applicable.
Female subjects considered not of childbearing potential must meet any of the following 
criteria:
●
Postmenopausal, age > 55 years with no menses for 12 or more months 
without an alternative medical cause.
●
Postmenopausal, age ≤ 55 years with no menses for 12 or more months 
without an alternative medical cause AND an FSH level > 40 IU/L.
●
Permanently surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy).
●
Females who have not experienced menarche (at least one menstrual period).
 


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Chemistry and Hematology
Chemistry and hematology testing are to be performed within the specified windows 
according to Table 5, Table 6, and Table 7 as applicable.
If subject is taking rasburicase, the special sample handling procedure outlined in 
Table 12 and Table 13 must be followed to avoid ex vivo uric acid degradation in the 
presence of rasburicase.
If laboratory abnormalities consistent with TLS are observed, see Appendix G.  
Recommendations for Initial Management of Electrolyte Imbalances and Prevention of 
Tumor Lysis Syndrome (TLS) in Multiple Myeloma Subjects for procedures to follow.
Phase 1 Portion: Reticulocyte count only required at Screening, Lead-in Day 1, Day 1 of 
each Cycle and Final Visit.  Serum β2 microglobulin (sβ2), C-reactive protein (CRP) are 
only required at Screening.  Cholesterol and triglycerides are only required at Screening 
and Final Visit.  Amylase and lipase are only required at Screening, Cycle 3 Day 1 and 
Final Visit.
Phase 2 Portion:  Reticulocyte count, CRP, cholesterol and triglycerides are not required.  
Serum β2 microglobulin (sβ2), amylase and lipase are only required at Screening and as 
clinically indicated.
Chemistry tests should be performed under fasting conditions, if possible.
Coagulation
PT/aPTT samples will be performed according to Table 5, Table 6, and Table 7 as 
applicable.
Urinalysis
Urinalysis will be performed according to Table 5.
 


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Viral Serologies
Samples will be collected to identify hepatitis A (HAV-IgM), hepatitis B (HBsAg, 
anti-HBs, total anti-HBc, IgM anti-HBc), hepatitis C (HCV) antibody or RNA, 
cytomegalovirus* (IgM and IgG), varicella zoster* virus (IgM and IgG), herpes simplex* 
virus (HSV 1 IgG, HSV 2 IgG), and Epstein-Barr* virus (IgM and IgG), at the following 
time points:
●
Screening or prior to the first dose of study drug (Lead-in Day 1 or Cycle 1 
Day 1)
●
As needed throughout study
*
These samples will not be collected for subjects screening or enrolled to the VenDex 
combination and Phase 2 cohorts of the study.
Viral serology samples are to be collected and sent to the central laboratory for testing.  
If prior agreement is reached between the investigative site and AbbVie, the viral serology 
testing may be performed locally.
SARS-CoV-2 serology testing (preferred molecular testing e.g., PCR) to be done at any
timepoint if clinically indicated, per Investigator's decision.  Testing will be performed 
locally.
Viral Polymerase Chain Reaction
Polymerase chain reaction (PCR) samples will be collected to identify herpes simplex* 
virus (HSV) Type 1 and 2 DNA*, Cytomegalovirus DNA*, Epstein-Barr virus DNA*, 
Herpesvirus 6 DNA (HHV-6)*, Herpesvirus 7 DNA (HHV-7)*, Herpesvirus 8 DNA 
(HHV-8)*, Adenovirus DNA*, Enterovirus RNA*, BK* and JC virus DNA*, and 
Parvovirus B19 DNA* at the following time points:
●
Screening
●
As needed throughout the study
 


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*
These samples will not be collected for subjects screening and enrolled to the VenDex 
combination and Phase 2 cohorts of the study.
Viral polymerase chain reaction (PCR) samples are to be collected and sent to the central 
laboratory for archiving and will only be analyzed if needed due to manifestations of 
possible infections during the treatment period.  If prior agreement is reached between the 
investigative site and AbbVie, the viral PCR sample may be stored and tested 
(if necessary) locally.
SARS-CoV-2 testing (molecular testing e.g., PCR) to be done at any timepoint if 
clinically indicated, per Investigator's decision.  Testing will be performed locally.
Lymphocyte Enumeration
Lymphocyte enumeration to identify B- and T-cell lymphocyte subpopulations will be 
performed according to Table 5.
B- and T-cell lymphocyte subpopulations:
●
T-cells (CD3)
●
B-cells (CD19)
●
Natural killer (CD16 + CD56)
●
Helper T-cells (CD4)
●
T-suppressor or T-cytotoxic cells (CD8)
●
Other lymphocyte studies
Lymphocyte enumerations may be performed within 72 hours of the scheduled visit.
Lymphocyte enumeration will not be collected for Phase 2 cohort subjects.
Assessments for IMWG Response Criteria
Analysis of serum protein immunofixation, serum protein electrophoresis (SPEP), serum 
quantitative immunoglobulins (sQI), serum free light chains (sFLC), urine protein 
immunofixation, urine protein electrophoresis (UPEP), plasmacytoma evaluation (if 
 


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applicable), skeletal survey, and bone marrow aspirate and biopsy, will be utilized for 
disease assessment.  Subjects will be evaluated against the International Myeloma 
Working Group (IMWG)23-25,30 criteria for disease response.
Disease assessments will be performed and submitted to the central laboratory for 
reporting according to Table 5, Table 6, and Table 7 as applicable.  Phase 2 subjects must
have all IMWG response assessments based on the central laboratory results.
Response criteria definitions are outlined in Appendix E.
All response categories (i.e., sCR, CR, VGPR, PR, MR, and PD) require 2 consecutive 
assessments for confirmation made at any time before declaring response/PD and the 
institution of any new therapy (no minimum interval between the 2 consecutive 
assessments is required, and the assessments can be done the same day).  However, 
to confirm response or PD, 2 discrete samples are required and testing cannot be 
based upon the splitting of a single sample.  Only one bone marrow assessment is 
required.  All response categories sCR, CR, VGPR, PR, MR, and SD also require no 
known evidence of progressive or new bone lesions if radiographic studies were 
performed.  Radiographic studies are not required to satisfy these response requirements, 
unless plasmacytoma is present at baseline.  Any soft tissue plasmacytoma documented at 
baseline must undergo serial monitoring as per Table 5, Table 6, and Table 7.
The following laboratory tests are required for the assessment of disease response and 
may be performed up to 1 week prior to the scheduled assessment visit day.
Serum Protein Immunofixation, Serum Protein Electrophoresis (SPEP)
Blood samples for serum protein immunofixation and SPEP testing will be collected for 
all subjects according to Table 14 and Table 15 as applicable.
Serum Quantitative Immunoglobulins (sQI)
Blood samples for sQI testing will be collected for all subjects according to Table 14 and 
Table 15 as applicable.
 


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Serum Free Light Chains (sFLC)
Blood samples for serum free light chain testing will be collected for all subjects 
according to Table 14 and Table 15 as applicable.
Subjects with measurable disease in either SPEP and/or UPEP will be assessed for 
response only based on these two tests and not by the FLC assay.  FLC response criteria 
are only applicable to subjects without measurable disease in the serum or urine and to 
fulfill the requirements of sCR.
Urine Protein Immunofixation and Urine Protein Electrophoresis (UPEP), 24-hr 
Urine
24-hr urine samples for urine protein immunofixation and UPEP testing will be collected 
for all subjects according to Table 14 and Table 15 as applicable.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible.
Skeletal Survey
A skeletal survey will be comprised of the following:
●
Lateral radiograph of skull
●
Antero-posterior and lateral views of the spine
●
Antero-posterior views of pelvis, ribs, femora, tibiae, fibulae, humeri, ulnae 
and radii
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the skeletal survey cannot be performed at the study site due to study 
modifications related to the COVID-19 pandemic, the skeletal survey may be completed 
at other centers providing the modality/technique is equivalent.
Plasmacytoma Evaluation
Plasmacytoma evaluation via physical examination or radiography (if clinically indicated) 
should be completed according to Table 5, Table 6, and Table 7 as applicable:
Plasmacytoma evaluations may be performed within 72 hours before or after the visit day.  
The frequency of plasmacytoma evaluation by radiography may be altered per discussion 
between the investigator and AbbVie TA MD.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the imaging for plasmacytoma assessment cannot be performed at the study 
site due to study modifications related to the COVID-19 pandemic, the imaging may be 
completed at other centers providing the modality/technique is equivalent.
Bone Marrow Aspirate and Biopsy
Bone marrow aspirate and biopsy should be completed according to Table 5, Table 6, 
Table 7, Table 9 and Table 10, as applicable.
Due to differences in bone marrow core biopsy collection procedures between the sites in 
the US and France, the core biopsy collection will be considered an optional procedure for 
subjects enrolled in France during the dose escalation portion.  During the safety 
expansion and VenDex combination, the core biopsy collection is required for all sites 
(US and France).  During the Phase 2 cohort, the core biopsy will be collected per 
Section 5.3.1.5.
All aspirate collections are required.  Bone marrow aspirates and biopsies performed as 
standard of care throughout the study should also be captured on an eCRF.
 


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A sufficient bone marrow aspirate or biopsy must be collected for clinical assessment 
(pathology, plasma cell % and kappa (κ)/lambda (λ) for clonality) performed by a local 
laboratory as well as for shipment of a portion to AbbVie (or designee) for the biomarker 
analyses (refer to Section 5.3.6).  Samples should be assessed for IMWG first and then 
split for biomarker analysis.
Assessment of bone marrow for percentage of plasma cells is required within 21 days 
before first dose of study drug, for baseline assessment (screening visit) and while on 
study to confirm CR (i.e., subjects who become immunofixation negative) or at time of 
suspected disease progression, if clinically indicated.
Bone marrow plasma cell clonality must also be evaluated at the time of CR (< 5% 
plasma cells) to assess for sCR, if applicable.  Flow cytometry is preferred over 
immunohistochemistry (IHC) for assessment of clonality by kappa (κ) and lambda (λ) 
staining.  Flow cytometry will be performed only to assess for sCR locally per institution 
standard practice.  If local flow cytometry to assess clonality is not available at the time of 
CR, a core biopsy and/or clot section should be evaluated by IHC staining for kappa (κ) or 
lambda (λ) or light chain restriction.  To confirm a CR, a second confirmation bone 
marrow analysis for CR is not needed.
A bone marrow aspirate collection is mandatory at screening and to confirm sCR/CR.  At 
screening, fresh samples should be obtained within 21 days of first dose of study, and, 
when possible, should be obtained after all other eligibility criteria have been met.  For 
Phase 2, a bone marrow aspirate is optional at time of study drug discontinuation or 
disease progression.
Bone marrow core biopsy (fixed formalin paraffin embedded [FFPE] core) should be also 
collected, unless not recommended per institutional guidelines.  However, a bone marrow 
biopsy is mandatory in the circumstance that an aspirate sample is not available (e.g., due 
to a dry tap).  Fresh biopsies are preferred but archived tissue is acceptable if 
representative of current disease and if collected within the previous 12 weeks without 
intervening treatment.  Core block or tissue slides are acceptable.  Bone marrow core 
 


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biopsies are optional to confirm sCR, CR, or at the time of treatment completion or 
disease progression.
Table 12.
Clinical Laboratory Tests – Phase 1 Portion
Hematology
Chemistrya
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Mean platelet volume (MPV)
Mean corpuscular hemoglobin 
(MCH)
Mean corpuscular volume 
(MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Reticulocyte count (Screening, 
Lead-in Day 1 (if applicable), 
Day 1 of each Cycle and 
Final Visit only)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acidb
Cholesterol (Screening and Final
Visit only)
Total protein
Glucose
Triglycerides (Screening and 
Final Visit only)
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Amylase (Screening, 
Cycle 3 Day 1 and Final Visit
only)
Lipase (Screening, 
Cycle 3 Day 1 and Final Visit
only)
Serum β2 microglobulin (sβ2M) 
(Screening only) 
C-reactive protein (CRP) 
(Screening only)
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination
(as indicated)
Testing for Response 
Assessment
Serum protein immunofixation 
Serum protein electrophoresis 
(SPEP)
Serum quantitative 
immunoglobulins (sQI)
Serum free light chains (sFLC)
Urine protein immunofixation
(24-hr urine)
Urine protein electrophoresis 
(UPEP) (24-hr urine)
Lymphocyte Enumeration
Coagulation
T-cells (CD3)
B-cells (CD19)
Natural killer (CD16 + CD56)
Helper T-cells (CD4)
T-suppressor or T-cytotoxic cells
(CD8)
Other lymphocyte studies
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
 


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Table 12.
Clinical Laboratory Tests – Phase 1 Portion (Continued)
Viral PCRc
Viral Serologies
Herpes simplex virus (HSV), 
Type 1 and 2 DNA 
Cytomegalovirus DNA 
Epstein-Barr virus DNA
Herpesvirus 6 (HHV-6) DNA
Herpesvirus 7 (HHV-7) DNA
Herpesvirus 8 (HHV-8) DNA
Adenovirus DNA 
Enterovirus RNA 
BK and JC virus DNA 
Parvovirus B19 DNA
SARS-CoV-2d testing (at local 
lab)
Hepatitis A (HAV-IgM)
Hepatitis B (HBsAg, anti-HBs,
total anti-HBc, IgM 
anti-HBc)
Hepatitis C (HCV antibody or
RNA)
Cytomegalovirusc (IgM, IgG)
Varicella zoster virusc (IgM, 
IgG)
Herpes simplex virusc (HSV 1
IgG, HSV 2 IgG)
Epstein-Barr virusc (IgM, IgG)
SARS-CoV-2 serology testingd
(PCR preferred) at local lab
a.
Chemistry tests should be obtained under fasting conditions, if possible.
b.
At room temperature, rasburicase causes enzymatic degradation of the uric acid in blood/plasma/serum samples 
potentially resulting in spuriously low plasma uric acid assay readings.  The following special sample handling 
procedure must be followed to avoid ex vivo uric acid degradation if the subject has taken rasburicase.  
Uric acid must be analyzed in plasma.  Blood must be collected into pre-chilled tubes containing heparin 
anticoagulant.  Immediately immerse plasma samples for uric acid measurement in an ice water bath.  Plasma 
samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C).  Finally, the plasma must be 
maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
c.
Tests are not required for subjects enrolled to the VenDex combination cohort of the study.
d.
SARS-CoV-2 testing performed at local lab for all Phase 1 and 2 subjects on study treatment, as clinically 
indicated per Investigator's discretion.
 


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Table 13.
Clinical Laboratory Tests – Phase 2 Portion
Hematology – Local Lab
Chemistrya – Local Lab
Testing for Response 
Assessment – Central Lab
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable) 
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acidb
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Amylase (Screening, and as 
clinically indicated)
Lipase (Screening, and as 
clinically indicated)
Serum β2 microglobulin (sβ2M) 
(Screening only) 
Serum protein immunofixation 
Serum protein electrophoresis 
(SPEP)
Serum quantitative 
immunoglobulins (sQI)
Serum free light chains (sFLC)
Urine protein immunofixation
(24-hr urine)
Urine protein electrophoresis 
(UPEP) (24-hr urine)
Coagulation – Local Lab
Viral Serologies –
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
Central Lab:
Hepatitis B (HBsAg, anti-HBs,
total anti-HBc, IgM 
anti-HBc)
Hepatitis C (HCV antibody or
RNA)
Local Lab:
SARS-CoV-2 serology testing 
(PCR preferred) 
Viral PCR – Local Lab
SARS-CoV-2c testing
a.
Chemistry tests should be obtained under fasting conditions, if possible.
b.
At room temperature, rasburicase causes enzymatic degradation of the uric acid in blood/plasma/serum samples 
potentially resulting in spuriously low plasma uric acid assay readings.  The following special sample handling 
procedure must be followed to avoid ex vivo uric acid degradation if the subject has taken rasburicase.  
Uric acid must be analyzed in plasma.  Blood must be collected into pre-chilled tubes containing heparin 
anticoagulant.  Immediately immerse plasma samples for uric acid measurement in an ice water bath.  Plasma 
samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C).  Finally, the plasma must be 
maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
c.
SARS-CoV-2 testing performed at local lab for all Phase 1 and 2 subjects on study treatment, as clinically 
indicated per Investigator's discretion.
For any laboratory test value outside the reference range that the investigator considers 
clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
 


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●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
A laboratory test value that requires a subject to be discontinued from the study, 
necessitates therapeutic medical intervention, meets protocol specific criteria (see 
Section 6.1.8 regarding toxicity management), and/or the investigator considers clinically 
significant will be recorded as an adverse event.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible.
 


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Table 14.
Assessments for IMWG Response Criteria (Phase 1 Portion)
Screening
Cycle 3
Day 1
Cycle 5
Day 1
Cycle 9 Day 1 
and every 
4th Cycle 
To Confirm 
sCR, CR or 
VGPR
Final 
Visit
Serum protein immunofixation
X
S
S
S
X
S
Serum protein electrophoresis
X
S
S
S
X
S
Serum quantitative 
immunoglobulins
X
S
S
S
S
Serum free light chains
X
O
O
O
X – sCR only
O
Urine protein immunofixation
X
U
U
U
X
U
Urine protein electrophoresis
X
U
U
U
X
U
Skeletal Survey
X
Plasmacytoma Evaluation
X
X
X
X
X – sCR or CR 
only
X
Bone Marrow Aspirate and 
Biopsy*
X
X
X± – sCR or 
CR only
X
sCR = Stringent complete response; CR = Complete response; VGPR = Very good partial response
S = Collect only for subjects with monoclonal protein in Screening serum.
U = Collect only for subjects with monoclonal protein in Screening urine.
X = Collect for all subjects.
O = Collect for subjects without monoclonal protein in Screening serum or urine.
*
Due to differences in bone marrow core biopsy collection procedures between the sites in the US and France, the 
core biopsy collection will be considered an optional procedure for subjects enrolled in France during the dose 
escalation portion.  During the safety expansion and venetoclax-dexamethasone combination, the core biopsy 
collection is required for all sites (US and France).
±
A bone marrow core biopsy collection is not required to confirm sCR or CR, unless it is performed at Cycle 5, 
Day 1 (or earlier based on observed response data).  However, a bone marrow biopsy is mandatory in the 
circumstance that an aspirate sample is not available (e.g., due to a dry tap).
Note:
IMWG labs may be collected up to 1 week prior to scheduled assessment visit.
Cross reference:  Durie 2007,24 Rajkumar 201125
 


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Table 15.
Assessments for IMWG Response Criteria (Phase 2 Portion)
Screening
Cycle 1 
Day 1a
Day 1 of Each 
Subsequent 
Cycle
To Confirm 
sCR or CR
At 
Suspected 
PD
Final Visit 
or Follow-
Up
Serum protein 
electrophoresis
X
X
X
X
X
X
Serum protein 
immunofixation
X
X
X
X
X
X
Serum quantitative 
immunoglobulinsd
X
X
X
X
X
X
Serum free light chains
X
O
O
X
X
O
Urine protein 
immunofixation
X
X
X
X
X
X
Urine protein 
electrophoresis
X
X
X
X
X
X
Skeletal survey
X
As clinically indicated
Plasmacytoma 
evaluation
If clinically 
indicated
If plasmacytoma is palpable on physical exam, then this 
should be documented every cycle.  Subjects with history of 
plasmacytoma only evaluable radiologic assessment should 
have CT or MRI or PET-CT (CT component) performed every 
3 months.  Otherwise, as clinically indicated.
Bone marrow aspirate 
and biopsyc
X
X
Xb
Xb
CR = Complete Response; sCR = Stringent Complete Response
X
Collect for all subjects.
O
Collect only for subjects without measurable M-protein in Screening serum or urine.
a.
For Cycle 1 Day 1, screening results or assessments may be used if done within 7 days of Cycle 1 Day 1.
b.
Collection of bone marrow sample at PD or Final Visit is optional.
c.
Bone marrow biopsy should be collected, unless not recommended per Institutional guidelines.  A core biopsy is 
not required to confirm sCR or CR, only an aspirate is required.  A core biopsy is mandatory in the circumstance 
that an aspirate sample is not available (e.g., due to a dry tap).
d.
For IgA or IgD Myeloma, serum Immunoglobulins are preferred for disease assessments.
Cross reference:  Kumar 201630
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from visiting the study site for the collection and shipping of 
IMWG laboratory assessments to the central laboratory, a local laboratory, hospital, or 
 


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other facility may be used to manage subject disease assessment of IMWG (Serum M-
Protein, Urine M-Protein, Serum Free Light Chains, Serum quantitative 
immunoglobulins).  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible. For Phase 1 subjects local IMWG assessments are 
allowable per protocol prior to the COVID-19 Pandemic.
TLS Prophylaxis
TLS prophylaxis will be initiated in all subjects starting 72 hours prior to the first dose of 
venetoclax, prior to each dose escalation of venetoclax, and prior to the first dose of 
venetoclax with dexamethasone, per the guidelines in Section 6.1.8.4.
Subject Diaries
Subject diaries will be provided at Lead-in Day 1 (if applicable), weekly throughout 
Lead-in period (if applicable), Cycle 1 Day 1, and Day 1 of each cycle thereafter.
Subjects will be instructed to record the date and time each dose of study drug is taken 
(indicating if any doses of study drug are missed) and time of breakfast completion.  The 
date and time (to the nearest minute) of each study drug taken and whether or not the dose 
was taken within 30 minutes after completing breakfast will be recorded on the eCRF on 
the scheduled PK days and for 2 days prior to every scheduled PK day.
Subjects will also be instructed to record adverse events and concomitant medications in 
the subject diaries.
Subject diaries should be reviewed at each study visit.  Subject diaries will be collected 
from subjects weekly throughout the Lead-in period (if applicable) and on Day 1 of every 
cycle.  The diaries are to be returned to the site, reviewed by study staff at visits where 
study drug is dispensed to the subject, and appropriately filed with the subject's source 
documents for this study.
 


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Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, subject diaries can be couriered to subjects along with 
study drug. AEs, Concomitant medications and dosing compliance listed in the diaries 
shall be verbally shared with site if a phone or video conference visit occurs Diaries
should be returned to the study site when the subject is able to visit the site next, and 
appropriately filed with the subject's source documents for this study.
Clinical Disease Progression Assessment
Subjects will be assessed for clinical disease progression according to Table 5, Table 6, 
Table 7 as applicable.  Two consecutive laboratory assessments for confirmation of PD 
made at any time before the start of new therapy are required per IMWG criteria.  The 
second assessment may be taken immediately if PD is suspected.  If PD is suspected by 
rising serum or urine M-protein (or FLC in subjects without measurable disease), 
2 consecutive assessments from laboratory readings should be obtained.
If PD is suspected by clinical symptoms, a plasmacytoma evaluation and/or skeletal 
survey should be obtained, as clinically indicated, and compared with baseline 
assessments to determine whether a new bone lesion or plasmacytoma has developed or 
an existing lesion or plasmacytoma has worsened.  SPEP and UPEP are also required.
The following assessments are not sufficient to determine PD:
●
Rising serum FLC if disease is measurable in the serum, urine, or both.
○
Serum FLC can be used to determine PD according to the IMWG criteria only for 
subjects without measurable serum and urine M-protein.
●
Clinical relapse based on indicators that are not part of the IMWG criteria for 
PD (e.g., decrease in hemoglobin, hypercalcemia, increase in serum creatinine, 
hyperviscosity), and relapse from CR should not be considered PD.
●
General worsening of the subject's condition.  If a subject's condition has 
deteriorated to a point that remaining on protocol therapy is not an option, 
every effort should be made to document PD by at least one of the following 
 


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assessments prior to the initiation of new therapy:  SPEP, UPEP, bone marrow 
biopsy, plasmacytoma evaluation, or skeletal survey.
Investigators are requested not to discontinue subjects from treatment for presumed lack 
of response after only 1 cycle of study treatment.
Dexamethasone Dosing for PD Subjects During Dose Escalation and Safety 
Expansion Portions
Subjects enrolled to dose escalation and safety expansion cohorts of the study, upon 
assessment of progressive disease per IMWG criteria and discussion with AbbVie TA 
MD, the investigator may add dexamethasone treatment starting at 40 mg orally on 
Days 1, 8, and 15 of each 21-day cycle per the dexamethasone prescribing information.  
All subjects who are ≥75 years old may start dexamethasone at a 20 mg dose.
Progressive Disease Assessment
Phase 2 cohort subjects that discontinue the study treatment for reasons other than PD, 
even after receiving new anti-multiple myeloma treatment, will be assessed for disease 
progression (IMWG assessment) every 4 weeks (± 1 week) for 1 year following the last 
dose of study treatment, and then every 12 weeks (± 1 week) thereafter until PD.  After 
PD, the subject will continue to be followed for Overall Survival.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the subject cannot visit the study site for central laboratory and/or research 
sample collection for reasons related to the COVID-19 pandemic, a local accredited 
laboratory may be used to manage subject disease assessment.  Local lab results should be 
obtained along with reference ranges and kept within the subjects' source documentation.  
Local lab results should be reviewed by the investigator as soon as possible.  Additionally, 
the study site should contact the subject by phone or video conference to assess for post-
study myeloma therapy as per Table 7.  This discussion shall be documented in the source 
notes.
 


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Overall Survival Assessments
For the Phase 2 portion, after study treatment and at the time of disease progression, 
subjects will be followed for overall survival.  Survival information (i.e., the date, cause 
of death and any relevant clinical information leading to death) and post-study myeloma 
therapy (i.e., transplantation, regimens, dates of initiation and completion, etc) will be 
collected every 12 weeks (± 2 weeks) (or as needed to allow for more frequent data 
collection) until death, or for 24 months after the last subject's first dose whichever occurs 
first.  Survival information may be obtained via telephone calls and/or clinical visits 
starting at the time of disease progression or after Final Visit.  All Phase 2 subjects will be 
followed for survival information unless the subject requests to be withdrawn specifically 
from this study survival follow-up; this request must be documented in the subject's 
medical record and signed by the Investigator.  In such instances, sites may enter 
confirmation of death using source documentation from publicly available records such as 
death certificates or funeral notices.  
For subjects to be considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, 2 telephone calls 
must be made, and 1 certified letter must be sent and documented in the subject's source 
documentation.
Non-Treatment Emergent Death Collection
After the end of the AE reporting period (i.e., in this instance > 30 days after the final 
dose of study drug), all deaths, including any relevant clinical information leading to the 
death, regardless of cause, should be reported through use of the Non-Treatment 
Emergent Death eCRFs.
Assignment of Subject Numbers
Subjects will be assigned unique consecutive subject numbers at Screening via IRT, as 
described in Section 5.5.3.  The results of all screening evaluations must be within 
clinically acceptable limits, upon review by the investigator, before a subject can be 
 


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administered study drug.  Subjects will not be enrolled in the study if laboratory or other 
screening results are unacceptable.
5.3.1.2
Confinement
Subjects will not be confined during this study but, may be hospitalized for TLS 
prophylaxis treatment and observation.
5.3.1.3
Meals and Dietary Requirements
Subjects will self-administer venetoclax orally with approximately 240 mL of water 
within 30 minutes after the completion of a low-fat breakfast once daily.  Dose Escalation 
portion subjects will consume a standard low-fat breakfast prior to study drug 
administration on intensive PK sample collection day Cycle 2 Day 1; a sample of a 
standard low-fat meal description is provided in Appendix D.  All subjects may not 
consume the following:
●
Grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or star fruit within the 3-day period prior to the 
first study drug administration and until the last day of treatment is completed 
due to possible CYP3A mediated metabolic interaction.
Meal information (e.g., whether or not the dose was taken within 30 minutes after 
completing breakfast or whether grapefruit products were consumed within the past 
3 days) will be recorded.
5.3.1.4
Collection and Handling of Biomarker and Exploratory 
Research Samples
Blood, serum, plasma, bone marrow aspirate and bone marrow core biopsy tissue will be 
collected per Table 9 and Table 10.  Subjects will also have the option to provide samples 
for exploratory research.  Subjects may still participate in the main study even if they 
decide not to participate in the optional exploratory research.  Samples may be utilized to 
evaluate known and/or novel markers (nucleic acids, peptides/proteins and/or metabolites) 
 


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of disease status, related conditions or to evaluate the association with pharmacokinetics, 
safety or efficacy.  All samples should be prepared, labeled, and shipped as outlined in the 
study-specific laboratory manual.  The biomarker rationale will be discussed in the 
Biomarker and Exploratory Research Variables Section (Section 5.3.6).
AbbVie (or people or companies working with AbbVie) will store the biomarker and 
exploratory research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) or this disease and related conditions continues, but for no longer than 20 years 
after study completion.  The procedure for obtaining and documenting informed consent 
is discussed in Section 9.3.
5.3.1.5
Samples for Mandatory Biomarker Analysis
A summary table of biomarker sample collections for the Dose Escalation, Safety 
Expansion, and VenDex Combination Cohorts is found in Table 9.  A summary table of 
biomarker sample collections for the Phase 2 portion is found in Table 10.
Blood Collection for Serum Markers
Blood will be collected by venipuncture into an appropriately labeled serum separator 
tube (SST) according to Table 9 and Table 10 as applicable.  
Blood Collection for Plasma Markers
Blood will be collected by venipuncture into an appropriately labeled K2EDTA tube 
according to Table 9 and Table 10 as applicable.
Bone Marrow Aspirate Collection
A sufficient bone marrow aspirate must be collected for clinical assessment as well as for 
biomarker analyses (performed by central/referral laboratory).  Priority of the aspirate 
sample split for biomarker analysis is as follows:
1.
Cytogenetics/FISH
 


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2.
Translational Research (Phase 2 portion only)
3.
Bcl-2 Family Member Analysis
4.
Minimal Residual Disease (MRD) Assessment
5.
In vitro Sensitivity Assay for MM Cells (France only, optional collection), 3 mL at 
Screening only/BH3 Profiling (US only, optional collection), 1 mL at Screening 
and time of relapse (Phase 1 Portion only)
Cytogenetics/Fluorescence In Situ Hybridization (FISH)
Bone marrow aspirate samples will be collected according to Table 9 and Table 10 as 
applicable.
MRD
Bone marrow aspirate samples will be collected according to Table 9 and Table 10 as 
applicable.
Bcl-2 Family Member Analysis
Bone marrow aspirate samples will be collected according to Table 9 and Table 10 as 
applicable.
Pre-Treatment Bone Marrow Core (BMC) Biopsy Tissue Collection 
Bcl-2 Family Member Protein Analysis
A bone marrow core biopsy sample will be collected according to Table 9 and Table 10 as 
applicable.  One of the following forms of pre-therapy tumor tissue (newly collected 
tissue or archived tissue) will be collected at Screening to enable biomarker assessments 
as outlined in the study objectives:
●
Fresh tumor tissue:  Fresh BMC biopsies performed during screening are 
preferred unless not recommended per Institution guidelines.  Tissue should be 
fixed, decalcified, and embedded in paraffin according to institutional 
 


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procedures.  While sending FFPE blocks is preferred, slides prepared by the 
local pathology laboratory are acceptable and should be prepared as described 
in the study-specific laboratory manual.  In addition, a pathology report, with 
all the subject identifying information redacted, should be submitted along 
with the tissue sample.
●
Archived BMC biopsy tissue:  The most recent archived diagnostic specimen 
is acceptable, provided the sample is representative of the subject's current 
disease state at the time of study entry and within 12 weeks prior to first dose 
of study drug.  While sending FFPE blocks is preferred, slides prepared by the 
local pathology laboratory are acceptable and should be prepared and stored as 
described in the study-specific laboratory manual.  In addition, a pathology 
report, with all the subject identifying information redacted, should be 
submitted along with the tissue sample.
Due to differences in bone marrow core biopsy collection methodology between the sites 
in the US and France, the core biopsy collection will be considered an optional procedure 
for subjects enrolled in France in the dose escalation portion, but required at Screening in 
the safety expansion and VenDex combination.  For subjects enrolled in the Phase 2 
portion, the bone marrow biopsy should be collected at screening, unless not 
recommended per institutional guidelines.  This will enable testing by 
immunohistochemistry of key biomarkers (BCL-2, BCL-XL, and MCL-1) that have been 
identified preclinically to be associated with single agent sensitivity to venetoclax.
Blood Collection for Immuno-Phenotyping (US Only, Phase 2 Portion Only)
Blood samples will be collected according to Table 10 as applicable.
Note:  Immuno-Phenotyping sample collection at Final Visit will be discontinued after 
implementation of Protocol Amendment 11.
Blood Collection for Immuno-Sequencing (US Only, Phase 2 Portion Only)
Blood samples will be collected according to Table 10 as applicable.
 


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5.3.1.6
Samples for Exploratory Research
For all subjects in the study that consent to optional exploratory research, blood, bone 
marrow core biopsy and bone marrow aspirate samples will be collected per Table 9 and 
Table 10.  Please contact the AbbVie TA MD or designee if necessary for additional 
information.
Blood Collection for Pharmacogenetic Analysis 
An optional 4 mL whole blood sample for DNA isolation will be collected at Screening or
prior to the first dose of study drug from each subject who consents to provide samples for 
exploratory research.  If the sample is not collected prior to the first dose of study drug, 
the sample may be collected at any time throughout the study.
Final Visit Bone Marrow Core (BMC) Biopsy Tissue Collection
Bcl-2 Family Member Protein Analysis
A bone marrow core biopsy sample may be collected at Final Visit (prior to the initiation 
of a new anti-myeloma treatment) if deemed feasible by the Investigator.  Tissue should 
be fixed, decalcified and embedded in paraffin according to institutional procedures.  
While sending FFPE blocks is preferred, slides prepared by the local pathology laboratory 
are acceptable and should be prepared and stored as described in the study-specific 
laboratory manual.  In addition, a pathology report, with all the subject identifying 
information redacted, should be submitted along with the tissue samples.
Final Visit Bone Marrow Aspirate Collection
Sample may be collected at Final Visit, if deemed feasible by the Investigator.
Priority of the bone marrow aspirate sample split is as follows:
●
Cytogenetics/FISH
●
Translational Research
●
BCL-2 Family Member Analysis
 


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Note:  Cytogenetics/FISH and Translational Research sample collection at Final Visit will 
be discontinued after implementation of Protocol Amendment 11.
In Vitro Sensitivity of MM Cells (France Only, Optional Collection, Phase 1 Portion 
Only)
Bone marrow aspirate samples will be collected according to Table 9 as applicable.
Instructions for collection and processing of the in vitro sensitivity sample are as follows:
●
Collect 2 – 3 mL of bone marrow aspirate into an EDTA tube.
●
Ship ambient on day of collection to:
Dr. 
U892 Equipe 10 
Centre de Recherche Contre le Cancer Nantes/Angers
8, quai Moncousu
44007 Nantes
France
Collection should only be completed if subject agrees and is undergoing aspirate for 
reasons other than in vitro sensitivity sample collection.
BH3 Profiling (US Only, Optional Collection, Phase 1 Portion Only)
Bone marrow aspirate samples will be collected according to Table 9 as applicable.
Collection should only be completed if subject agrees and is undergoing aspirate for 
reasons other than BH3 Profiling sample collection.
BH3 Profiling aspirate samples will be shipped directly from the site to the central 
laboratory per the current laboratory manual.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the subject cannot visit the study site for central laboratory and/or research 
sample collection for reasons related to the COVID-19 pandemic, laboratory and/or 
research samples will not be collected.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Immediately after collection, the blood samples will be inverted several times to ensure 
good mixing of the blood and anticoagulant, and will be placed in an ice bath.
The timing of blood collections will take priority over all other scheduled study activities 
except for dosing.  The order of blood collections will be maintained to the minute such 
that the time intervals relative to the preceding dosing will be the same for all subjects.  
The date and time (to the nearest minute) of each blood sample collection will be recorded 
on the eCRF.
The date and time (to the nearest minute) of each dose of venetoclax and whether or not 
the dose was taken within 30 minutes after the completion of breakfast will be recorded 
on the scheduled PK days and for the last 2 dosess prior to every scheduled PK day.  Sites 
will ensure that all information is captured through source documents (site or subject 
calendar/diary provided by AbbVie).
Blood Samples for Venetoclax Assay
Blood samples (3 mL) for venetoclax assay will be collected by venipuncture into 
evacuated potassium (K2) EDTA tube at the following times:
Dose Escalation Cohort
●
Lead-in Day 1:  8† hours post-dose (if Lead-in period is utilized)
●
Lead-in Day 8:  8† hours post-dose (if Lead-in period is utilized)
●
Cycle 1 Day 1:  8† hours post-dose
 


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●
Cycle 2 Day 1:  0-hour (pre-dose) and at 2, 4, 6, 8† hours post-dose
●
Cycle 2 Day 2:  24 hours post Cycle 2 Day 1 dose (pre-dose of Cycle 2 Day 2)
●
Cycles 3, 5, 7 and 9 Day 1:  0-hour (pre-dose)
●
*Intrasubject dose escalation, if applicable, optional:  
○
8† hours post-escalated dose
○
0-hour (pre-dose) at next scheduled visit 
Safety Expansion Cohort
●
Lead-in Day 1:  8† hours post-dose (if Lead-in period is utilized)
●
Lead-in Day 8:  8† hours post-dose (if Lead-in period is utilized)
●
Cycle 1 Day 1:  8† hours post-dose
●
Cycles 2, 3, 5, 7 and 9 Day 1:  0-hour (pre-dose)
●
*Intrasubject dose escalation, if applicable, optional:
○
8† hours post-escalated dose
○
0-hour (pre-dose) at next scheduled visit 
Venetoclax-Dexamethasone Combination Cohort
●
Cycle 1 Day 1:  8† hours post-dose
●
Cycles 2, 3, 5, 7 and 9 Day 1:  0-hour (pre-dose)
Phase 2 Portion
●
Cycles 2, 3, 5, and 7 Day 1:  0-hour (pre-dose)
†
The 8 hour post-dose PK sample collection may be collected up to 1 hour earlier, if 
necessary, to facilitate sample processing.
*
Refer to Section 5.1 Intrasubject Dose Escalation.
All 0-hr (pre-dose) samples are relative to the start of venetoclax administration.  Refer to 
Table 8 for a schedule of the blood collection for venetoclax assay.
 


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A total of 13 blood samples are planned to be collected per subject for PK analysis in the 
dose escalation cohort.  A total of 8 blood samples are planned to be collected per subject 
for PK analysis in the safety expansion cohort.  A total of 6 blood samples are planned to 
be collected per subject for PK analysis in the VenDex combination cohort.  A total of 
4 blood samples are planned to be collected per subject for PK analysis in the Phase 2 
portion.
5.3.2.2
Handling/Processing of Samples
Blood Samples for Venetoclax PK Assay
Immediately after collection, the blood samples for venetoclax will be inverted 8 to 
10 times to ensure good mixing of the blood and anticoagulant, and will be placed in an 
ice bath.  The blood samples will be centrifuged using a refrigerated centrifuge (2° to 8°C) 
to separate the plasma at 1100 to 1600 × g for 15 minutes within 1 hour of blood 
collection.  The plasma samples will be transferred using plastic pipettes into 
screw-capped polypropylene tubes (cryovials) labeled with the drug number name, assay 
type, type of sample (plasma), the protocol number, the subject number, the study cycle 
and day, and the planned time of sampling relative to dosing and then frozen at –20°C or 
colder.  The entire process should be completed within 2 hours of draw.  Samples should 
be maintained at –20°C or colder until shipped to the central laboratory.
5.3.2.3
Disposition of Samples
The frozen plasma samples for venetoclax assays will be packed in dry ice sufficient to 
last during transport and shipped from the study site to the central laboratory according to 
instructions included in the laboratory manuals for this study.  An inventory of the
samples included will accompany the package.  The central laboratory will be responsible 
for shipping the plasma samples to AbbVie for testing.
5.3.2.4
Measurement Methods
Plasma concentrations of venetoclax will be determined under the supervision of the Drug 
Analysis Department at AbbVie.
 


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5.3.3
Efficacy Variables
In the Phase 1 portion, all efficacy endpoints are secondary, and therefore exploratory in 
nature.  In the Phase 2 portion, confirmatory testing will be conducted for ORR and 
VGPR+, the primary efficacy endpoints.  Secondary efficacy endpoints include PFS, 
DOR, TTR, TTP, OS, and the following PROs:  Worst Pain (BPI-SF), Physical 
Functioning and GHS/QoL (EORTC QLQ-C30), and Fatigue (PROMIS Cancer Fatigue 
SF).  Tertiary efficacy endpoints include the PROs based on the remaining subscales of 
BPI-SF, EORTC QLQ-C30, EORTC QLQ-M20, and EQ-5D-5L.
5.3.3.1
IMWG Criteria for Tumor Response
Subjects with multiple myeloma with measurable disease at baseline will be evaluated 
using the 2011 IMWG criteria23-25 (Phase 1 subjects) or 2016 standard IMWG criteria30
(Phase 2 subjects) provided in Appendix E.
Eligibility:  Only subjects with measurable disease at baseline can have objective 
response evaluated as an end point.  All baseline evaluations should be performed during 
the screening period and prior to the first dose of study drug.
IMWG Criteria
Subjects will be assessed for response using the IMWG response criteria.  All response 
categories require two consecutive assessments made at any time before the institution of 
any new therapy.  All response categories (i.e., stringent complete response, complete 
response, very good partial response, partial response, minimal response, and stable 
disease) also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed.  Radiographic studies are not required to satisfy 
these response requirements.  Response criteria for all categories and subcategories of 
response except CR are applicable only to subjects who have 'measurable' disease defined 
by at least one of the following three measurements:
●
Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L)
●
Urine M-protein ≥ 200 mg/24 hr
 


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●
Serum FLC assay:  involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) provided 
serum FLC ratio is abnormal
COVID-19 Pandemic-Related Acceptable Protocol Modification
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from visiting the study site for the collection and shipping of 
IMWG laboratory assessments to the central laboratory, a local laboratory, hospital, or 
other facility may be used to manage subject disease assessment of IMWG (Serum M-
Protein, Urine M-Protein, Serum Free Light Chains, Serum quantitative 
immunoglobulins).  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible. For Phase 1 subjects local IMWG assessments are 
allowable per protocol prior to the COVID-19 Pandemic.
5.3.3.2
Evaluation of Disease
IMWG response assessments will be reviewed by the Investigator per the 2011 IMWG 
criteria23-25 (Phase 1 subjects) or 2016 standard IMWG criteria30 (Phase 2 subjects) 
provided in (Appendix E).  If the Investigator confirms the subject meets the criteria for 
progressive disease, the subject will be deemed as having met an event of disease 
progression.  For the purposes of this study, the date of progression will be the date on 
which the IMWG assessments were obtained.
Phase 1 portion:  All IMWG laboratory assessments will be performed by the central 
laboratory.  Investigators may choose to submit additional samples to their local 
laboratory for testing.  All local lab results must be entered into the eCRF.  
Phase 2 portion:  All IMWG response assessments are to be based on the central 
laboratory results, with the exception of imaging and bone marrow assessments which are 
performed locally.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from visiting the study site for the collection and shipping of 
IMWG laboratory assessments to the central laboratory, a local laboratory, hospital, or 
other facility may be used to manage subject disease assessment of IMWG (Serum M-
Protein, Urine M-Protein, Serum Free Light Chains, Serum quantitative 
immunoglobulins).  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible. For Phase 1 subjects local IMWG assessments are 
allowable per protocol prior to the COVID-19 Pandemic.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring, vital signs, physical examination, 12-lead ECG, MUGA/2D echocardiogram, 
(Phase 1 portion only), and laboratory assessments.
5.3.5
Pharmacokinetic Variables
Values for the PK parameters of venetoclax, including the maximum observed plasma 
concentration (Cmax), the time to Cmax (peak time, Tmax) and the area under the plasma 
concentration-time curve (AUC) over a 24-hour dose interval (AUC0-24) will be 
determined using noncompartmental methods for doses administered on the intensive PK 
day (i.e., Cycle 2 Day 1 in the dose escalation cohorts).  Additional parameters may be 
calculated if useful in the interpretation of the data.
5.3.6
Biomarker and Exploratory Research Variables
Biospecimens (blood, serum, plasma, bone marrow aspirate and bone marrow core biopsy 
tissue) will be collected to conduct biomarker and exploratory analyses.  The types of 
biomarkers to be analyzed may include, but are not limited to, nucleic acids, proteins, 
lipids or metabolites.  The samples may be analyzed as part of a multi-study assessment of 
factors influencing the subjects' response to the study drug (or drugs of the same or 
 


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similar class) or and progression of the subjects' disease related conditions.  The 
information learned from analyzing these samples may be used to investigate factors 
influencing response to treatment, scientific questions related to MM, and/or in the 
development of new therapies and diagnostic tests, or technologies.  The results from 
these analyses may not be included with the study report.
Biospecimens (serum, plasma, bone marrow aspirate and bone marrow core biopsy tissue) 
will be collected to support biomarker objectives of the study.  These include assessment 
of BCL-2 family member expression at baseline as a predictive biomarker of response.  
BCL-2 family member mRNA expression will be determined by qPCR analysis in 
CD138-enriched samples from bone marrow aspirates.  BCL-2 family member protein 
expression will be evaluated in bone marrow core biopsies by IHC.  Additional biomarker 
objectives include the assessment of FISH markers that are known to be prognostic in 
MM.  These include, but not limited to, t(11;14), t(4;14), t(14;16), del 17p, and +5, +9, or 
+15.  The VenDex combination cohort and Phase 2 portion will evaluate safety and 
efficacy of venetoclax at the RPTD in subjects with t(11;14)-positive MM.  Subjects MM 
tumor cells with the t(11;14) translocation were found to be associated with increased 
sensitivity to venetoclax in preclinical studies of MM.8  t(11;14)-positive samples also 
demonstrated a high median BCL-2/MCL-1 mRNA ratio.8  MRD is an emerging 
component of response assessment in MM subjects.  Exploratory analysis of MRD 
negativity in the bone marrow at 10–4, 10–5 and 10–6 thresholds may be performed.
Additional exploratory evaluations may include biomarkers related to pathway(s) targeted 
by the study drug, those believed to be related to the disease or to drug response 
evaluation or association with genetic factors.  Plasma and serum samples may be 
analyzed for mutational status of circulating tumor DNA and measurement of relevant 
cytokine, chemokine, matrix metalloproteinases and markers of bone turnover 
(formation/resorption).  Blood may also be analyzed by immune cell phenotyping and 
quantification, and T-cell clonality assed by immune-sequencing.  The analyses of tumor 
tissue/cells may include but are not limited to IHC and qPCR-based assays for BCL-2 
family members and other nucleic acids or proteins known to regulate the expression of 
 


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these molecules.  Gene sequencing- and hybridization-based techniques may also be used 
on any of the above specimens for exploratory biomarker research.
Blood samples may also be sequenced and data analyzed for genetic factors contributing 
to the disease or to the subject's response to venetoclax, or other study treatment in terms 
of pharmacokinetics, efficacy, tolerability, and safety.  Such genetic factors may include 
genes for drug metabolizing enzymes, drug transport proteins, genes within the target 
pathway, genes believed to be related to the disease or to drug response.  Some genes 
currently insufficiently characterized or unknown may be understood to be important at 
the time of analysis.  The results are exploratory in nature, and may not be included with 
the study summary.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator will discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including:
●
The investigator believes it is in the best interest of the subject;
●
The subject's response to therapy is unsatisfactory, as evidenced by 
progression of disease while on study drug;
○
However, during dose escalation and safety expansion portion, the subject 
can be considered for venetoclax in combination with dexamenthasone 
upon failing venetoclax monotherapy;
●
The subject's response to combination therapy is unsatisfactory, as evidenced 
by progression of disease while on combination therapy;
●
The subject experiences toxicities related to study drug as clinically significant 
abnormal laboratory results or AEs, which rule out continuation of the study 
drugs, as determined by the investigator or the AbbVie Therapeutic Area 
Medical Director.
 


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●
The subject requires more than 2 dose reductions of venetoclax, in the absence 
of objective response to study treatment;
●
The subject requires radiotherapy, cancer-related surgery as a result of disease
progression, or alternate anti-neoplastic agents during the study period;
●
The subject becomes pregnant or begins breast-feeding;
●
Subject is significantly noncompliant with the study procedures, which would 
put the subject at risk for continued participation in the trial.
All subjects will be included for analysis of safety data.  Subjects who withdraw from the 
study will not be replaced unless they are not evaluable.
During the Phase 1 portion, evaluable subjects are defined as those subjects who:
●
Experience a DLT, or
●
Complete approximately 80% or more of the treatment regimen during the 
DLT assessment period.
In the event that a subject withdraws or is discontinued from the study, the reason(s) for 
the discontinuation from the study and primary reason will be recorded.  Final visit 
procedures per Table 5 and Table 7, as applicable, will be performed as soon as possible 
after discontinuation from the study.  Additional blood samples for drug measurement 
may be collected at the time of discontinuation from subjects who are discontinued due to 
adverse events; the clock time, time in relation to dose, and date the sample was taken will 
be recorded.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
 


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At the end of the subject's participation in the study, the calendars/diaries are to be 
returned to the site and appropriately filed with the subject's source documents for this 
study.
A Safety Follow-up Visit should be performed for all subjects approximately 30 days 
following discontinuation of study drug and then as clinically appropriate for safety 
assessment.  The subject will be followed until a satisfactory clinical resolution of the 
adverse event is achieved.
A separate Safety Follow-up Visit does not need to be performed for subjects who had a 
Final Visit conducted ≥ 30 days after discontinuation of study drug and did not require 
additional adverse event follow-up.  If the subject refuses or is unable to attend the Safety 
Follow-up Visit, this should be noted in the subject's source documentation.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug must be 
discontinued immediately.  The investigator must report a pregnancy within 1 working 
day of the site being aware to one of the AbbVie representatives listed in Section 6.1.6 or 
Section 7.0.
If a subject withdraws from study follow up or withdraws permission for the collection of 
their personal data, the study staff may still use available public records to obtain 
information about survival status only, as appropriate per local regulations.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Additional 
guidance regarding the location of COVID-19 pandemic-related acceptable protocol 
modifications can be found in Section 5.3.1.1.
 


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The investigator should contact the AbbVie TA MD or designee before discontinuing a 
subject from the study for reasons other than those identified above to ensure all 
acceptable mitigation steps have been explored.
All efforts should be made to obtain safety and disease response information at the End of 
Treatment visit prior to the subject initiating another therapy.  If travel restrictions or other 
changes in local regulations in light of the COVID-19 pandemic prevent the subject from 
having blood drawn for laboratory testing at the study site at the End of Treatment and/or 
Safety Follow-Up Visit, if possible, arrange for subjects to have laboratory work done at a 
local lab, hospital, or other facility.  Local lab results should be obtained along with 
reference ranges and kept within the subjects' source documentation.  Local lab results 
should be reviewed by the investigator as soon as possible.  Before starting another MM 
therapy, the site shall make all effort to complete Final Visit and Safety Follow Up Visit 
procedures to obtain safety and disease response information.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  An investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigators by telephone and subsequently provide written instructions for 
study termination.
If, in the judgment of the investigators and AbbVie, the continued exposure to the study 
drug represents a significant risk to subjects, the study will be stopped.  The following 
procedures for discontinuation will be followed:
●
If the sponsor has decided to prematurely discontinue the study, the sponsor 
will promptly notify the investigators in writing as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
 


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●
The investigators must promptly notify the IEC/IRBs and give detailed reasons 
for the discontinuation.
●
The investigators must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
the treatment regimen, if applicable, by other appropriate regimens.
5.5
Treatments
5.5.1
Treatments Administered
Each dose of venetoclax will be taken with approximately 240 mL of water.  On days that 
pre-dose PK sampling is required (refer to Table 8), dosing will occur in the morning at 
the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling.  Dose Escalation 
cohort subjects will take venetoclax within 30 minutes after the completion of a standard
low-fat breakfast (Appendix D) with approximately 240 mL of water on Cycle 2 Day 1.  
On all other dosing days, subjects will be instructed to take venetoclax orally QD within 
30 minutes after the completion of a low-fat breakfast.
In cases of vomiting, no replacement dose is to be given.  In cases where a dose is missed 
or forgotten, the subject should take the dose as soon as possible, ensuring the dose is 
taken within 8 hours of the missed dose with food.  Otherwise, the dose should not be 
taken.
During dose escalation and safety expansion, upon assessment of progressive disease and 
discussion with the AbbVie TA MD, the investigator may add dexamethasone treatment 
starting at 40 mg PO on Days 1, 8, 15 of each 21-day cycle per the dexamethasone 
prescribing information.
During the VenDex combination and Phase 2 cohorts, subjects will receive venetoclax, 
daily (Day 1 – 21), at the RPTD with dexamethasone (40 mg PO) on Days 1, 8, and 15 of 
each 21-day cycle, per the dexamethasone prescribing information.  All subjects who are 
≥ 75 years old may start dexamethasone at a 20 mg dose.  During the VenDex 
combination and Phase 2 cohorts, in cases where a dexamethasone dose is missed or 
 


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forgotten, the subject should take the dose as soon as possible, ensuring the dose is taken 
within 48 hours of the missed dose.  Otherwise, the dose should not be taken.  Subjects 
will be instructed to take each dose of venetoclax orally QD with approximately 240 mL 
of water and within 30 minutes after the completion of breakfast or the subject's first meal 
of the day.  Tablets must be swallowed whole and must not be broken, chewed, or 
crushed.  On days that pre-dose PK sampling is required, dosing will occur at the clinic to 
facilitate PK sampling.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject is unable to come to the study site to pick up their study drug (venetoclax and 
dexamethasone) due to COVID-19, a direct-to-patient (DTP) study drug shipment can be 
made from the study site to the subject if allowed by local regulations.  AbbVie will 
submit any required notifications to the regulatory authority as applicable.  Prior to DTP 
shipping, the study site must confirm it is still safe for the subject to continue on treatment 
via onsite (preferred), phone or video conference visit, or local assessments as permitted 
through COVID-19 Pandemic-Related Acceptable Protocol Modifications.  These 
assessments shall be documented in the source data accordingly.
Study drug may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:
●
Direct-to-patient (DTP) shipment of study drug is allowed by local regulations 
and the relevant ethics committee
●
Study drug can be administered by the subject at home
●
Subject agrees to have the study drug shipped directly to their home
●
Assessment of the following procedures prior to dispensing venetoclax to 
subjects:  AE/CM review, safety labs reviewed [hematology, chemistry, 
Coagulation panel], urine pregnancy testing (women of childbearing potential), 
IMWG disease assessment (central lab collection preferred, local laboratory 
acceptable if not possible to collect centrally), and continuation of TLS 
prophylaxis and infections (as applicable).
 


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●
Instructions will be provided by AbbVie as to how a study site can initiate a 
DTP shipment using Marken, a global vendor selected by AbbVie to provide 
this service when necessary.
○
Marken is the preferred courier for DTP shipping; however, in extenuating 
circumstances, alternate local couriers may be allowed with prior approval 
from the AbbVie Clinical Contact (or designee) identified in Section 7.0.  
If Marken is not utilized, the study site is responsible for ensuring the 
courier will transport the study drug under appropriate temperature-
controlled conditions and require a signature for delivery.
●
Shipments may also include other study supplies (e.g., drug dosing diaries).  
Subjects should provide dosing updates to site staff during remote phone or 
video conference visits and return diaries to the site at the time of the next 
onsite visit.
●
Prior to arranging shipment, the study site should contact the subject to 
confirm the subject will be available to accept delivery of the shipment.
●
Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature 
monitoring) within the labeled storage conditions.  Signature is required upon 
delivery; due to COVID-19 related social distancing, this may be provided by 
the courier after delivery.  Documentation of the shipment is to be retained by 
the clinical site.
●
The site should contact the patient to confirm delivery of the shipment and the 
date and time of the next dose, and document this in the source documents.
●
AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
The study site must keep records of all shipments within the subject source 
documentation.
 


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When DTP shipping is utilized, subjects are not to discard any study drug bottles.  The 
subject shall return the study drug bottles to the site at the time of the next onsite study 
visit unless the study site is directed otherwise by AbbVie.
5.5.2
Identity of Investigational Product
Information about the formulations to be used in this study is presented in Table 16.
Table 16.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Location
Venetoclax 
(ABT-199)
N/A
10 mg Tablet
Oral
AbbVie/Abbott
North 
Chicago, IL
Venetoclax 
(ABT-199)
N/A
50 mg Tablet
Oral
AbbVie/Abbott
North 
Chicago, IL
Venetoclax 
(ABT-199)
N/A
100 mg Tablet
Oral
AbbVie/Abbott
North 
Chicago, IL
Dexamethasone±
N/A
4 mg Tablet
Oral
N/A
N/A
±
Dexamethasone is considered Investigational Product during the VenDex combination and Phase 2 cohorts.
Table 17.
Identity of Non-Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Location
Dexamethasonea
N/A
Tablet
Oral
N/A
N/A
a.
Dexamethasone formulations may vary based on the source.  Dexamethasone is considered Non-Investigational 
Product during the dose escalation and safety expansion cohorts.
During the dose escalation and safety expansion cohorts, dexamethasone should be 
obtained commercially via the site pharmacy.  For operational or regulatory purposes, 
AbbVie may provide non investigational products depending on local requirements.
 


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5.5.2.1
Packaging and Labeling
The venetoclax tablets will be packaged in high density polyethylene (HDPE) plastic 
bottles to accommodate the study design.  Each bottle will be labeled per local regulatory 
requirements.
For the VenDex combination and Phase 2 cohorts, AbbVie will provide dexamethasone.  
It will be packaged in blistercards or bottles to accommodate study design.  Each 
blistercard or bottle will be labeled per local regulatory requirements.
5.5.2.2
Storage and Disposition of Study Drug
The venetoclax and dexamethasone study drug must be stored at 15° to 25°C (59° to 
77°F).  Dexamethasone should also be protected from moisture.  The investigational 
products (Table 16) are for investigational use only and are to be used only within the 
context of this study.  The study drug(s) supplied for this study must be maintained under 
adequate security and stored under the conditions specified on the label until dispensed for 
subject use or returned to AbbVie.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be assigned a unique subject number on the first day of screening via 
IRT.  Since this is an open-label study, subjects will maintain the same subject number 
regardless of the number of re-screens and through the duration of the study.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose for this study is discussed in Section 5.6.4.  The same dose will be 
administered to all subjects in each dose level within each portion.  Once the MTD is 
declared for dose escalation or safety expansion portion, subjects who remain on study 
and continue to tolerate the drug may escalate to the dose level determined to be the MTD 
or any dose level below the MTD, provided they have completed at least 2 cycles at their 
originally assigned dose level.  For Dose Escalation subjects, Cycle 2 Day 1 dosing will 
occur in the morning at the clinic (refer to Section 5.5.1) when subjects will receive 
 


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venetoclax within 30 minutes after the completion of a standard low-fat breakfast 
(Appendix D).  On all other dosing days, subjects will be instructed to take venetoclax 
tablets orally within 30 minutes after the completion of a low-fat breakfast once daily 
(QD).  All doses of venetoclax will be taken with approximately 240 mL of water.
5.5.5
Blinding
This is an open-label study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
To document compliance with the treatment regimen, subjects will be instructed to return 
all unused tablets and/or bottles, even if empty and any other study related items as 
necessary, to the study coordinator at scheduled study visits.  Compliance will be 
monitored and documented by the study coordinator on the appropriate form.  The 
investigator or designee will question the subject regarding adherence to the dosing 
regimen, record the number of tablets and/or bottles returned, the date returned, and
determine treatment compliance before dispensing new study drug to the subject.  
Compliance below 80% will require counseling of the subject by study site personnel.
5.5.7
Drug Accountability
The investigator or his/her designated representatives will administer study drug only to 
subjects enrolled in the study.  Documentation of the receipt of supplies will be supported 
by a signed and dated Proof of Receipt or similar document.  A current (running) and 
accurate inventory of study drug will be kept by the site and will include lot number, 
Proof of Receipt number(s), bottle numbers, and the date on which study drug is provided 
to the subject.
 


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An overall accountability of study drug will be performed and verified by AbbVie or the 
designated monitor(s) throughout the study and at the study site Closeout Visit.  Upon 
completion or termination of the study, all original containers (containing partially used or 
unused study drug) will be returned to AbbVie according to instructions from AbbVie or 
the designated monitor(s).  If prearranged between AbbVie and the site, destruction of 
used and unused study drug bottles will be performed at the site.  Empty containers will 
be destroyed at the site.  Labels must remain attached to the containers.
5.5.8
Safety Review Committee
A Safety Review Committee (SRC) will periodically review safety data across all studies 
with venetoclax in MM that do not have a study-specific independent monitoring 
committee.  This review committee will be responsible for periodic, regular reviews to 
assess the safety of the interventions during the trial.  A separate charter will be prepared 
outside of the protocol outlining the SRC member responsibilities, frequency of data 
reviews, and relevant data to be assessed.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
During the dose escalation portion of the study, dose cohorts (dose levels) will contain a 
minimum of 3 subjects each for evaluation and safety assessments which will be crucial 
for determining drug dose escalation as described in Section 5.1.  There are no control 
groups in this study.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.
5.6.3
Suitability of Subject Population
Subjects with relapsed or refractory MM will be selected to participate in this study.  
Subjects with MM must have relapsed following or be refractory to standard treatments 
 


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such as melphalan, bortezomib, and lenalidomide.  In addition, the subject should be 
unable to tolerate other available therapies or no other therapies are available.  Preclinical 
findings support the possibility of efficacy in this patient population.  Due to the expected 
mechanism-based lymphopenia, subjects will be monitored to assess risk for infection.  
As a preventative measure, prophylaxis for viral, fungal, bacterial or Pneumocystis 
infections will be implemented when appropriate.
Subjects who harbor t(11;14) assessed by the central laboratory will be eligible for the 
VenDex combination cohort and Phase 2 portion of this study.
5.6.4
Selection of Doses in the Study
The 800 mg QD RPTD of venetoclax in the VenDex combination cohort was selected 
based on the results from a Phase 1b study (Study M12-901) of venetoclax plus 
bortezomib and dexamethasone in relapsed or refractory MM subjects and the venetoclax 
monotherapy portions of this study (Study M13-367).  An exposure-response analysis of 
the efficacy (best response) and safety (grade ≥ 3 anemia, thrombocytopenia, and 
neutropenia) from Study M12-901 indicated that a venetoclax dosage regimen of 600 mg 
QD or higher in combination with bortezomib and dexamethasone would likely result in a 
substantial VGPR or better response rate with these response rates increasing through 
1200 mg QD.  No relationship was observed between venetoclax exposure and anemia or 
thrombocytopenia, but the neutropenia (grade ≥ 3) rates began to increase at doses above 
800 mg QD.  Similar exploratory exposure-response analyses from the venetoclax 
monotherapy portions of this study (Study M13-367) indicated a trend of increasing 
response rates through 1200 mg QD in the t(11;14) positive subjects.  However, with 
venetoclax monotherapy in MM, no relationship was observed between venetoclax 
exposure and anemia, thrombocytopenia, or neutropenia.  The 40 mg once weekly 
dexamethasone dose in the VenDex combination cohort was selected as it is a commonly 
used dexamethasone dose in MM combination therapy, such as with daratumumab and 
lenalidomide or bortezomib.
 


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Subsequent to completion of the VenDex combination cohort of the study, additional 
venetoclax exposure-response analyses were conducted using both the monotherapy and 
dexamethasone combination therapy portions of this study.  These analyses confirmed the 
benefit of the addition of dexamethasone to the venetoclax regimen, that response rates 
(ORR and VGPR+) were expected to increase with higher venetoclax doses in 
combination with dexamethasone in t(11;14) positive patients, and that no relationship 
was evident between venetoclax exposure and anemia, thrombocytopenia, or neutropenia.  
Based on these efficacy and safety results, and considering treatment compliance 
considerations, a venetoclax dose of 800 mg QD with 40 mg dexamethasone once weekly 
was selected to be used in the Phase 2 portion of the study.
The maximum dose of venetoclax for this protocol will not exceed 1200 mg/day.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.1.6).  For adverse events, please refer to Section 6.1
through 6.1.12.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an other cause of the event.  For adverse events to be considered 
 


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intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meet protocol specific criteria (see Section 6.1.8 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition 
and/or the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
 


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A treatment-emergent adverse event is defined as any adverse event with onset or 
worsening reported by a subject from the time that the first dose of study drug is 
administered until 30 days have elapsed following discontinuation of study drug 
administration.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event within 24 hours of the site being made aware of the serious adverse 
event:
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical 
intervention had not been taken.  This does not include 
an event that would have been fatal if it had occurred in 
a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for 
any length of time or prolongs the subject's hospital 
stay.  This does not include an emergency room visit or 
admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include 
experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
 


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Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency 
or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
Hospitalization for a subject with high disease burden as indicated by elevated white 
blood cells, bulky disease and/or hyperuricemia who require observation and management 
(e.g., for IV hydration) for the purpose of TLS prophylaxis will not be captured as a 
serious adverse event (SAE), unless there is an additional reason for hospitalization or an 
additional criterion for seriousness other than hospitalization.
Hospitalization of a subject within 30 days following discontinuation of study drug for 
subsequent line of therapy will not be recorded as serious adverse events.
Certain adverse events are anticipated to occur in the study population (MM) at some 
frequency independent of the study drug exposure.  Such events include known 
consequences of the underlying disease or condition under investigation (e.g., symptoms, 
disease progression) and events unlikely to be related to the underlying disease or 
condition under investigation but common in the study population independent of the 
study drug (e.g., cardiovascular events in an elderly population).
 


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Cytopenias (anemia, neutropenia, or thrombocytopenia) are part of the natural history of 
MM.  Persistent cytopenias at the same CTCAE grade as at baseline are not to be reported 
as adverse events, unless they fulfill a seriousness criteria, result in permanent 
discontinuation of a study drug, or the investigator had an identifiable cause other than the 
underlying disease.  However, all laboratory data should be entered regardless of whether 
an adverse event is reported.
These events are listed in Appendix H (Adverse Events Commonly Associated with MM 
Study Population or Progression of MM).
These adverse events may occur alone or in various combinations and are considered 
expected for reporting purposes for this protocol.
Although exempted from expedited reporting to Health Authorities and IRBs as 
individual cases, if an event commonly associated with MM or progression of MM meets 
seriousness criteria it must be reported to AbbVie within 24 hours of the site being made 
aware of the serious adverse event (Refer to Section 6.1.6).  For deaths related to disease 
progression (coded to malignant neoplasm progression), the date and cause of death will 
be recorded on the appropriate case report form, but the event will not be expedited as an 
individual case safety report to regulatory authorities.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.0).26  If a reported adverse event increases in severity, the initial adverse event 
should be given an outcome date and a new adverse event reported on a different onset 
date than the end date of the previous adverse event to reflect the change in severity.  For 
all reported serious adverse events that increase in severity, the supplemental eCRFs also 
need to be updated to reflect the change in severity.
 


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For adverse events not captured by the Common Terminology Criteria, the following 
should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe).
Grade 4
The adverse event is life-threatening requiring urgent intervention 
(severe).
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
Adverse Events Expected Due to Study Related Endpoints
6.1.3.1
Deaths
Deaths that occur during the protocol specified adverse event reporting period (see 
Section 6.1.5) that are more likely related to disease progression will therefore be an 
expected adverse event and will not be subject to expedited reporting.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported.  
The term "sudden death" should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within 1 hour of the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.
 


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6.1.3.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.
6.1.4
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the investigator for the serious 
adverse event.
6.1.5
Adverse Event Collection Period
All protocol-related serious adverse events must be collected from the signing of the study 
specific informed consent until study drug administration.
 


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Serious adverse events occurring after the study-specific informed consent is signed but 
prior to the initial dose of venetoclax will be collected only if they are considered by the 
investigator to be causally related to the study-required procedures.
In addition, all serious and non-serious adverse events reported from the time of study 
drug administration until 30 days or 5 half lives, whichever is longer, following 
discontinuation of study drug administration have elapsed will be collected, whether 
elicited or spontaneously reported by the subject.
Adverse event information will be collected as shown in Figure 6.
Figure 6.
Adverse Event Collection
Protocol-related
SAEs*
Serious and Non-Serious Adverse Events
Elicited and/or Spontaneously Reported
↓
↓
↓
↓
Consent 
Signed
Study Drug Start
Study Drug 
Stopped
30 Days 
After Study 
Drug Stopped
*
Only if considered by the investigator to be causally related to study-required procedures.
During the Phase 2 Portion, after the end of the adverse event reporting period 
(30 days after the final dose of study drug):
●
All deaths, including any relevant clinical information leading to death, 
regardless of cause, should be reported on the appropriate eCRF.
Adverse events will be monitored throughout the study to identify any of special interest 
that may indicate a trend or risk to subjects.
Adverse Events of Special Interest (AESI)
The following AESI (serious and non-serious) is to be entered into the EDC system 
immediately (i.e., no more than 24 hours after the site becoming aware of the event):
●
Tumor lysis syndrome
 




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In emergency situations involving study subjects when the primary TA MD is not 
available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline
where your call will be re-directed to a designated AbbVie TA MD.
Phone:
+1 (973) 784-6402
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reaction 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines, and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI) for the AbbVie IMP.  The RSI in effect at the start of 
a Drug Safety Update Report (DSUR) reporting period serves as the RSI during the 
reporting period.  For follow-up reports, the RSI in place at the time of occurrence of the 
"suspected" Serious Adverse Reaction will be used to assess expectedness.
For comparator products being used as non-AbbVie IMPs, the SmPC will serve as the 
Reference Safety Information (RSI) for those non-AbbVie products.
The following definitions will be used for Serious Adverse Reactions (SAR) and 
Suspected Unexpected Serious Adverse Reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an IMP related to any dose 
administered that result in death, are life-threatening, require inpatient 
hospitalization or prolongation of existing hospitalization, result in persistent or 
significant disability or incapacity, or are a congenital anomaly or birth defect.
SUSAR
A suspected SAR:  refers to individual SAE case reports from clinical trials where a 
causal relationship between the SAE and the IMP was suspected by either the 
sponsor or the investigator, is not listed is the applicable Reference Safety
Information, and meets one of the following serious criteria:  results in death, is 
life-threatening, requires hospitalization or prolongation of an existing 
hospitalization, results in persistent or significant disability or incapacity, or is a 
congenital anomaly or birth defect.  All individually reported SARs are considered 
suspected.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed (for both serious and non-serious events):
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
Subjects with a confirmed (viral test positive) or suspected COVID-19 infection must 
interrupt all study drugs until the COVID-19 viral clearance criteria in Section 6.1.8.5 are 
met.  There are no time limits for study drug interruption if no permanent study 
discontinuation criteria have been met.  The investigator should notify the AbbVie TA 
MD or designee listed above when reintroducing any study drugs in subjects with 
confirmed or suspected COVID-19 infection.
6.1.7
Pregnancy
Pregnancy in a study subject must be reported to an AbbVie representative (Section 6.1.6
or Section 7.0) within 1 working day of the site becoming aware of the pregnancy.  
Subjects who become pregnant during the study must be discontinued (Section 5.4.1).
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 30 days after discontinuing study drug.  Male subjects should be 
informed that contraceptive measures should be taken by their female partner.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information form the 
 


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partner must be obtained prior to the collection of any pregnancy-specific information and 
the pregnancy will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
Although no potential risks have been identified in nonclinical studies (please refer to 
Investigator Brochure Section 7.4) the effect of Bcl-2 inhibition on pregnancy has not 
been fully characterized.  Venetoclax resulted in increased postimplantation loss and 
decreased fetal body weights were observed in the mouse embryofetal development study 
at the highest dosage administered.  Venetoclax is not advised in pregnancy or lactation.
6.1.8
Toxicity Management
6.1.8.1
Definition – Dose Limiting Toxicity (DLT)
Dose limiting toxicities (DLTs) for dose-escalation purposes will be determined during 
the lead-in period (if applicable) plus the first cycle (21 days) of study drug administration 
at the designated cohort dose.  Adverse events occurring following Cycle 1 will also be 
evaluated by the investigator and the AbbVie TA MD and may be considered as dose 
limiting.  Any of the following events that are considered to have a "reasonable 
possibility" of relationship to the administration of venetoclax, which cannot be attributed 
by the investigator to a clearly identifiable cause such as disease progression, concurrent 
illness, or concomitant medication, will be considered a DLT:
●
Grade 4 neutropenia lasting more than 7 days
●
Grade 3 or Grade 4 neutropenia with fever
●
Grade 4 thrombocytopenia
●
Grade 2 or higher bleeding associated with Grade ≥3 thrombocytopenia
●
Unexpected Grade 2 or higher toxicity which requires dose modification or 
delay of ≥1 week, will be considered a DLT (e.g., peripheral neuropathy)
 


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●
Clinical TLS will be considered a DLT.  Laboratory TLS will be considered a 
DLT if the metabolic abnormalities are deemed clinically significant by the 
investigator.
●
All other Grades 3, 4, or 5 adverse events will be considered a DLT with the 
exception of the following:
○
Grade 3 thrombocytopenia that does not result in bleeding
○
Grades 3, 4 lymphopenia
○
Grades 3, 4 leukopenia
○
Grade 3 neutropenia
○
Grade 3 nausea, vomiting, and/or diarrhea that is responsive to treatment
○
Grade 3 or 4 hyperuricemia or hypocalcemia or Grade 3 hyperkalemia, if 
transient (i.e., lasting < 48 hours) and without manifestations of clinical 
TLS (e.g., creatinine ≥ 1.5 × ULN, cardiac arrhythmias, seizures, or sudden 
death)
If a DLT of TLS is observed during the lead-in period, it will be attributed to the lead-in 
period and a modification will be made to the lead-in period regimen for subsequent 
cohorts.  Any other DLTs observed during the lead-in and/or designated cohort dosing 
period will require a modification of the designated cohort dose (and/or lead-in period 
regimen, if appropriate) as directed per the Dose Escalation Guidelines (Section 5.1 and 
Table 2).
Any DLT will require an interruption and possible discontinuation of venetoclax.  
Venetoclax may be reintroduced, but only at a reduced dose, if the toxicity grade returns 
to ≤ Grade 1 or to baseline if Grade 2 at study entry.
Drug interruption for up to 72 hours following transient (i.e., lasting < 48 hours) chemical 
changes and laboratory TLS may be allowed and may not be considered a DLT or require 
a dose reduction.  If the TLS has not resolved within 72 hours then a dose reduction 
should be considered.  The subject may be allowed to re-escalate to the final dose based 
on a risk assessment (including tumor burden status).
 


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Any reduced dose level will be defined by AbbVie after discussion between the 
investigator and the AbbVie TA MD.  The dose may be increased thereafter as defined by 
AbbVie after discussion between the investigator and the AbbVie TA MD.  This dose is 
not to exceed the highest tolerated dose level.  All decisions regarding continued dosing 
for individual subjects will be medically managed by the investigator, in conjunction with 
the AbbVie TA MD, as appropriate.  These decisions will be driven by the definition of 
DLTs as described above.
6.1.8.2
Management of Infection and Lymphopenia
There is a potential for clinically significant infection and lymphopenia (B and 
T lymphocyte subtypes) in this study.
It is recommended that subjects should receive anti-infective prophylaxis 
(e.g., amoxicillin/clavulanic acid or levofloxacin or equivalent per institutional guidelines) 
at least during the first 90 days of study and upon disease progression for at least 30 days, 
unless contraindicated per investigator discretion.  Furthermore, it is recommended that 
subjects deemed at high risk of infection receive immunoglobulin replacement therapy 
(i.e., IVIG) per institutional guidelines or at the Investigator's discretion.
The use of antibiotics that are moderate or strong CYP3A inhibitors (See Section 5.2.4.3
and Appendix C) should be avoided or used with caution and with appropriate venetoclax 
dose modification (See Table 4) as per protocol.
All subjects with MM receiving venetoclax should be closely monitored for infections.  In 
the event of a Grade ≥ 3 infection or any serious infection, treatment with venetoclax 
should be interrupted.  Upon resolution, treatment can either be resumed at a reduced dose 
(see Table 18 or Table 19) or discontinued at the discretion of the Investigator.  Please 
refer to Table 20 for guidance on dose interruptions and/or reductions related to 
venetoclax toxicities.  All anti-infective measures should be appropriately recorded on the 
eCRF.  Potential for drug-drug interactions should be considered.  Please refer to 
Appendix C for a description of excluded and cautionary medications.
 


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6.1.8.3
Management of Neutropenia
There is a potential for clinically significant neutropenia in this study.  If clinically 
indicated, standard management practices for neutropenia should be implemented at the 
investigator's discretion.
Anti-infective prophylaxis and granulocyte-colony stimulating factor (G-CSF) for 
management of neutropenia should be considered per institutional guidelines and 
appropriately recorded on the eCRF.  It is recommended that subjects should receive anti-
infective prophylaxis (e.g., amoxicillin/clavulanic acid or levofloxacin or equivalent per 
institutional guidelines) when Grade 4 neutropenia develops (ANC < 500 cells/uL) and 
continued until the neutropenia improves to Grade 3 or better (ANC >500 cells/uL).
6.1.8.4
Management of Tumor Lysis Syndrome
There is a potential for TLS in subjects affected by hematologic malignancies.  Depending 
on the specific tumor type, risk factors may include one or more of the following:  bulky 
disease or high tumor burden, elevated pretreatment lactate dehydrogenase (LDH) levels, 
elevated leukocyte count, renal insufficiency, and dehydration.
Multiple myeloma patients with high tumor burden (e.g., high bone marrow plasma cell 
infiltration, plasma cell leukemia or bulky plasmacytoma), rapidly increasing M-protein 
or light chains or high proliferative activity, plasmablastic morphology, or compromised 
renal function (CrCl < 50 mL/minute) may be at higher risk of developing TLS.31  Also, 
subjects with t(11;14) and high bone marrow plasma cell infiltration or a significant 
number of circulating plasma cells appear to have an increased risk for TLS when treated 
with venetoclax.
Consider TLS prophylaxis with oral hydration (at least 1 – 2 liters, as tolerable, daily) in 
all subjects at least 72 hours prior to the first day of dosing with venetoclax.  Prophylaxis 
with uric acid reducing agents may be required for subjects with high uric acid levels.  
Monitor for clinical and laboratory evidence of TLS during treatment, and manage 
abnormalities in serum creatinine, uric acid and electrolytes promptly according to 
 


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institutional guidelines (Guidance also available in Appendix G Recommendations for 
Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome 
(TLS) in Multiple Myeloma Subjects).  
For subjects with t(11;14) and > 50% bone marrow plasma cell infiltration or CrCl 
< 50 mL/min, oral hydration as asforementioned is required and chemistry labs 
(phosphate, potassium, calcium, uric acid, creatinine, LDH, and AST at a minimum) 
should be done at approximately 6 hours after the first dose of venetoclax.  More intensive 
measures (e.g., intravenous hydration, frequent monitoring of labs, hospitalization, etc.) 
should be considered at the Investigator discretion or in accordance with institutional 
guidelines.  All TLS prophylaxis measures should be appropriately recorded in the eCRF.
In case of evidence of TLS, dosing with venetoclax should be interrupted.  Drug 
interruption for up to 72 hours following transient (i.e., lasting < 48 hours) chemical 
changes and laboratory TLS will not require a dose reduction.
If the TLS has not resolved within 72 hours, then a dose reduction should be considered.  
The subject may be allowed to re-escalate to the final dose based on a risk assessment 
(including tumor burden status).  If active correction of electrolytes was performed, the 
first dose of venetoclax should only be given when electrolytes have been stable without 
additional treatment for at least 24 hours.
If a subject meets criteria for clinically significant laboratory or clinical TLS, the subject 
must dose reduce (Refer to Table 19 as applicable).  The subject may be allowed to re-
escalate to the intended cohort dose based on a risk assessment (including tumor burden 
status) after discussion between the Investigator and the TA MD.
Additional TLS prophylaxis and monitoring (more frequent lab collection, IV hydration, 
dose ramp-up requirements, etc.) can be implemented as needed based upon review of 
safety data (e.g., if a higher than expected rate of laboratory TLS is observed or cases of 
clinical TLS are identified).
 


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6.1.8.5
Guidelines for Dose Modifications and Treatment
During the VenDex combination and Phase 2 cohorts, if the dose of dexamethasone is 
delayed outside of the protocol allowed window or interrupted for any reason
(i.e., – subject missed dose, dose held due to toxicity, etc.), the dose will be considered 
missed and the subject will continue on in the cycle (i.e., – if Cycle 2 Day 1 dose of 
dexamethasone is held and not completed within 48 hours, Cycle 2 Day 1 would be 
considered missed and subject would continue to be evaluated for dosing at Cycle 2 
Day 8).  If a dose is held, all assessments listed for that day would still be completed.
Interruption/Discontinuation of Study Drug Due to Confirmed or Suspected 
COVID-19 Infection
Subjects with a confirmed (SARS-Cov-2 test positive) or suspected COVID-19 infection 
must interrupt all study drugs until the following SARS-Cov-2 viral clearance criteria are 
met and Covid-19 related complications do not change the subject's risk/benefit ratio per 
Investigator assessment.
Confirmed COVID-19 infection:
●
Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 14 days have passed since recovery, defined as resolution of fever 
without use of antipyretics and improvement in respiratory symptoms (e.g., 
cough, shortness of breath)
●
Asymptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours 
apart after at least 14 days have passed since prior positive result (note:  
subjects who develop symptoms will follow guidance above for symptomatic 
subjects)
Suspected COVID-19 infection:
●
Subjects with suspected COVID-19 infection should interrupt treatment with 
study drugs while SARS-Cov-2 testing is pending.  Treatment may be 
 


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reinitiated upon confirmation of negative SARS-Cov-2 test result and 
notification to the AbbVie TA MD or designee.
The investigator should contact the AbbVie TA MD before reintroducing any study drugs 
in subjects with confirmed or suspected COVID-19 infection.
Interruptions in study drug dosing due to the above COVID-19 testing guidance for 
subjects must be discussed with the AbbVie TA MD, along with the possibility of 
premature discontinuation from the study drug dosing period.  There are no time limits for 
study drug interruption if no permanent study discontinuation criteria have been met.  
Follow protocol Section 5.3.1, Section 5.4.1, Section 5.4.2, Section 6.1.1, Section 6.1.5
and Appendix C for subjects who discontinue study drug.
Frequency or timing of COVID-19 testing and intervals between testing for the above 
viral clearance criteria may be adjusted to account for epidemiologic trends, updated 
information regarding infectivity, and local/institutional guidelines.
6.1.8.6
Dose Modifications or Delays for Venetoclax Toxicities
Dose modifications and treatment guidelines for venetoclax monotherapy, Table 18, 
venetoclax with dexamethasone, Table 19, and venetoclax-related toxicities, Table 20 are 
provided below.
Table 18.
Venetoclax Monotherapy Dose Levels
Designated Venetoclax Dose Level 
Dose Level –1
Dose Level –2
1200 mg QD
800 mg QD
400 mg QD
900 mg QD
600 mg QD
300 mg QD
600 mg QD
300 mg QD
100 mg QD
300 mg QD
200 mg QD
100 mg QD
If the dose of venetoclax at the lowest dose level is not tolerable, then no further 
reductions will be allowed and venetoclax should be discontinued.  Upon resolution of the 
AE leading to dose reduction, the dose of venetoclax can be increased following Table 18
 


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guidelines, based on the Investigator's clinical judgment.  If the AE recurs upon increasing 
the dose of venetoclax, then the subject should remain at the reduced and tolerated dose 
level.  Guidelines in Table 4 should also be followed for venetoclax-toxicity related dose 
reductions when moderate or strong CYP3A inhibitors are concomitantly administered.
Table 19.
Venetoclax Combined with Dexamethasone Dose Levels
Designated Venetoclax Dose 
Level
Dose Level –1
Dose Level –2
Dose Level –3
800mg QD
600 mg QD
400 mg QD
200 mg
 


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Table 20.
Hematological and Non-Hematological Toxicities Related to 
Venetoclax
Toxicities
Recommended Action
Grade 3 or Grade 4 neutropenia 
with infection or fever; or Grade 
4 hematologic toxicities (except 
for lymphopenia)

G-CSF or growth factors for neutropenia should be 
administered with venetoclax if clinically indicated.

For Grade 4 neutropenia (ANC < 500 cells/uL) without 
infection, anti-infective prophylaxis 
(e.g., amoxicillin/clavulanic acid or levofloxacin or equivalent 
per institutional guidelines) is recommended until the 
neutropenia improves to Grade 3 or better (ANC 
> 500 cells/uL) 

First episode:  Interrupt venetoclax and once the toxicity has 
resolved to Grade 1 or baseline level, venetoclax may be 
resumed at the same dose.

For subsequent episodes:  Interrupt venetoclax.  Consider using 
G-CSF as clinically indicated.  Follow dose reduction 
guidelines in Table 18 and Table 19, as applicable when 
resuming treatment with venetoclax after resolution.  A larger 
dose reduction may occur at the discretion of the physician and 
according to the dose reduction guidelines in Table 18 and 
Table 19, as applicable.
Grade ≥ 3 or Serious Infection

Interrupt venetoclax and upon resolution, treatment can either 
be resumed at a reduced dose (See Table 18 or Table 19, as 
applicable) or discontinued, at the discretion of the Investigator.  
Grade 3 or 4 non hematologic 
events

First episode:  Interrupt venetoclax.  Once toxicity has resolved 
to Grade ≤ 1 or baseline, venetoclax may be resumed at the 
same dose.  No dose modification is required.

For subsequent episodes:  Interrupt venetoclax.  Follow dose 
reduction guidelines in Table 18 and Table 17, as applicable
when resuming treatment with venetoclax after resolution.  A 
larger dose reduction may occur at the discretion of the 
physician and according to the dose reduction guidelines in 
Table 18 and Table 19, as applicable.
Blood chemistry changes or 
symptoms suggestive of TLS

Withhold the next day's dose.  If resolved within 24 – 48 hours 
of last dose, resume at the same dose.

For any blood chemistry changes requiring more than 48 hours 
to resolve, resume at a reduced dose (see Table 18 and 
Table 19, as applicable).

For any events of clinical TLS, resume at a reduced dose 
following resolution.
 


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6.1.9
Management of Decreased Spermatogenesis
Based on findings in a preclinical study, there is a potential for decreased 
spermatogenesis.  Male subjects should consider sperm banking before treatment with 
venetoclax if they are considering preservation of fertility.
6.1.10
Toxicities Related to Dexamethasone
All VenDex combination and Phase 2 cohort subjects should start dexamethasone at 
40 mg.  All subjects who are ≥ 75 years old may start at a 20 mg dose.  Dose reduction 
levels and treatment guidelines for dexamethasone-related toxicities are provided in 
Table 21 and Table 22.
Table 21.
Dose Reductions for Dexamethasone
Reduced Dexamethasone Doses
Dexamethasone
Dose –1
Dose –2
Dose –3
Dose –4
40 mg
20 mg
12 mg
8 mg
4 mg
 


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Table 22.
Treatment Guidelines for Toxicity Related to Dexamethasone
Body System
Symptom
Recommended Action
Gastrointestinal
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1 – 2 (requiring 
medical management)
Treat with H2 blockers, sucralfate, or 
omeprazole.  If symptoms persist despite above 
measures, decrease dexamethasone dose by 
1 dose level.
Gastrointestinal
> Grade 3 (requiring 
hospitalization or surgery)
Hold dexamethasone until symptoms adequately 
controlled.  Restart at 1 dose decrement along 
with concurrent therapy with H2 blockers, 
sucralfate, or omeprazole.  If symptoms persist 
despite above measures, discontinue 
dexamethasone permanently.
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone permanently.
Cardiovascular
Edema
≥ Grade 3 (limiting function 
and unresponsive to therapy 
or anasarca)
Diuretics as needed, and restart dexamethasone 
at 1 dose decrement; if edema persists despite 
above measures, decrease dose by another level.  
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction.
Neurology
Confusion or mood alteration 
> Grade 2 (interfering with 
function ± interfering with 
activities of daily living)
Hold dexamethasone until symptoms resolve.  
Restart at 1 dose decrement.  If symptoms persist 
despite above measures, discontinue 
dexamethasone permanently.
Musculoskeletal
Muscle weakness 
> Grade 2 (symptomatic and 
interfering with function 
± interfering with activities 
of daily living)
Decrease dexamethasone by 1 dose level.  If 
weakness persists, decrease dose by 1 more dose 
level.  Discontinue dexamethasone permanently 
if symptoms persist.
Metabolic
Hyperglycemia 
≥ Grade 3
Treatment with insulin or oral hypoglycemic 
agents as needed.  If uncontrolled despite above 
measures, decrease dose by 1 dose level until 
levels are satisfactory.
6.1.11
Determination of the MTD
Escalation of venetoclax to the next designated cohort dose level will proceed if all 
assigned subjects at a dose level complete the lead-in period (if applicable) plus one cycle 
(21 days) at the designated cohort dose without experiencing a DLT (refer to 
Section 6.1.8.1).  If one (1) subject within any dose level experiences a DLT, up to 
6 subjects will be enrolled at that dose level.  Additional subjects may be enrolled at the 
 


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current dose level at the discretion of the AbbVie TA MD.  If < 33% of the subjects 
enrolled at a dose level experience a DLT, then escalation of the designated cohort dose 
may continue.  If ≥33% of the subjects enrolled at a dose level experience a DLT, dose 
escalation will stop and the previous lead-in period and designated cohort dosing regimen 
will be considered the MTD.  Dose de-escalation of the designated cohort dose, and/or a 
modified lead-in period may be explored if MTD is not declared.
If dose de-escalation or modification of the lead-in period occur and < 33% of subjects 
enrolled experience a DLT at the reduced designated cohort dose and/or the modified 
lead-in period regimen, this dosing regimen will be declared the MTD.  If ≥ 33% of the 
subjects enrolled at the reduced designated cohort dose and/or the modified lead-in period 
regimen still experience a DLT, dose de-escalation of the designated cohort dose and/or 
modified lead-in period regimen will continue to be explored.
The MTD will be defined as the highest designated cohort dose level (and corresponding 
lead-in period regimen, if applicable) at which < 33% of the subjects enrolled experience 
a DLT.
6.1.12
Determination of the RPTD
If an MTD is reached, the RPTD will not be a dose higher than the MTD and will be 
selected based on the types of DLTs which occur and the MTD identified.  If an MTD is 
not reached, then the RPTD will be defined based on the safety and PK data.
6.2
Product Complaint 
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product, if present (see below).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
 


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discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
6.2.2
Reporting
Product Complaints concerning the investigational product and must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.).  In instances where a return is requested, every effort should 
be made by the investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  If a protocol deviation occurs (or is 
identified, including those that may be due to the COVID-19 pandemic) after a subject has 
been enrolled, the principal investigator is responsible for notifying Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) regulatory authorities (as applicable), 
and their assigned CRO clinical monitor or the following AbbVie clinical 
representative(s):
 




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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical Analysis Plans
8.1.1
Definition of Analysis Population
All analyses will be performed for all subjects who take at least one dose of study drug.
8.1.2
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics prior to the 
initiation of study drug.  Unless otherwise stated, baseline for a given variable will be 
defined as the last value for that variable obtained prior to the first dose of study drug.
Continuous baseline characteristics data (e.g., age, height, and weight) will be 
summarized with means, standard deviation, minimum, maximum, and range.  
Frequencies and percentages will be computed for categorical data (e.g., sex, race, prior 
therapies, cytogenetics).
8.1.3
Pharmacokinetics
8.1.3.1
Tabulations and Summary Statistics
Plasma concentrations and PK parameter values of venetoclax will be tabulated for each 
subject and each dose level, and summary statistics will be computed for each sampling 
time and each parameter.
8.1.3.2
Model and Tests
Dose Proportionality
Pharmacokinetic parameters of venetoclax from the dose escalation subjects assessed on 
Cycle 2 Day 1 will be analyzed as follows.  An analysis will be performed for Tmax, dose 
normalized Cmax, dose-normalized AUC24 and β provided that they can be adequately 
determined from the data.  The model used for the statistical analyses will include dose 
 


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level.  This may be done by classifying subjects by dose level or, if appropriate, using 
dose level as a continuous variable.  Covariates such as age, body weight, body surface 
area, gender, and perhaps others that might explain some of the variability in the 
population will be included in the model initially.  However, a covariate may be dropped 
from the model if the regression coefficient is not significant at alpha level 0.10.  The 
natural logarithmic transformation will be employed for Cmax and the AUC's unless the 
data clearly indicate that other transformation or the untransformed variable provides 
more nearly symmetric probability distributions and/or more nearly homogenous 
variances across dose levels.  Within the framework of the model, tests that have good 
power for a trend with dose will be performed on the effect of dose level.
Steady State Trough Hour 0 Concentrations
Exploratory analyses of trough (pre-dose) concentrations of venetoclax on Day 1 of 
Cycle 2, 3, 5, 7 and 9 for Phase 1 and Phase 2 portion subjects combined may be done to 
characterize the achievement of steady-state pharmacokinetics.  Cycle may be included in 
the model as a categorical variable (to generate pairwise comparisons of various time 
points), or it may be treated as a continuous variable in a regression analysis framework 
(where a slope of zero indicates steady-state pharmacokinetics).  The term for dose will 
also be included in the model, and the potential interaction between cycle and dose will be 
evaluated.
Additional analyses will be performed if useful and appropriate.
8.1.3.3
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue due to 
an adverse event will be addressed.  Normally values of PK variables (Cmax, AUC, etc.) 
will be determined without replacing missing individual concentration values, simply 
using the available data, and if necessary doing the analysis with some missing values for 
a PK variable.  However, missing concentration values for isolated individual blood 
samples may be replaced (imputed) if such might affect study conclusions or 
meaningfully affect point estimates.
 


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8.1.4
Efficacy Endpoints
8.1.4.1
Objective Response Rate and Very Good Partial Response 
or Better Rate
The ORR is defined as the proportion of subjects with documented PR or better (i.e., PR, 
VGPR, CR, or sCR) based on IMWG criteria in Section 5.3.3.1.  VGPR+ is defined as the 
proportion of subjects with documented VGPR or better (i.e., VGPR, CR, or sCR) based 
on IMWG criteria in Section 5.3.3.1.
8.1.4.2
Time to Disease Progression
For a given subject, TTP is defined as the number of days from the date of the first dose 
of study drug to the date of first documented PD or death due to MM, whichever occurs 
first.  If the subject does not have an event of PD and the subject has not died due to MM, 
the subject's data will be censored.  Detailed event and censoring information for TTP are 
provided in Table 23.
Table 23.
Event and Censoring Date Used in TTP
Situation
Option for End-Date
Outcome
No baseline assessment
Date of first dose of study drug
Censor
PD or death due to multiple 
myeloma at scheduled 
assessment date or before the 
next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple 
myeloma after exactly 
one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple 
myeloma after two or more 
missing assessments
If no adequate assessment is available prior 
to PD/death then date of first dose of study 
drug.  Otherwise, date of the last adequate 
assessment prior to PD/death
Censor
No PD and no death due to 
multiple myeloma
If no adequate assessment is available then 
date of first dose of study drug.  Otherwise, 
date of the last adequate assessment
Censor
 


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8.1.4.3
Duration of Response
For a given subject, DOR is defined as the number of days from the subject's date of 
first documented response (PR or better) to the date of first documented PD or death due 
to MM, whichever occurs first.  If the subject does not have an event of PD and the 
subject has not died due to MM, the subject's data will be censored.  Detailed event and 
censoring information for DOR are provided in Table 24.
For subjects who never achieve a documented response (PR or better), the subjects data 
will not be included in the analysis of DOR.
Table 24.
Event and Censoring Date Used in DOR
Situation
Option for End-Date
Outcome
No baseline assessment
Date of first dose of study drug
Censor
PD or death due to multiple myeloma 
at scheduled assessment date or 
before the next scheduled assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple myeloma 
after exactly one missing assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death due to multiple myeloma 
after two or more missing assessments
Date of the last adequate assessment prior 
to PD/death
Censor
No PD and no death due to multiple 
myeloma
Date of the last adequate assessment
Censor
8.1.4.4
Progression-Free Survival
For a given subject, PFS is defined as the number of days from the date of the first dose of 
study drug to the date of the first documented PD or death due to any cause, whichever 
occurs first.  All events of PD will be included, regardless of whether the event occurred 
while the subject was still taking study drug or had previously discontinued study drug.  
Events with an outcome of death will be included for subjects who had not experienced an 
event of PD.  If the subject does not have an event of PD and the subject has not died, the 
subject's data will be censored.  Detailed event and censoring information for PFS are 
provided in Table 25.
 


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Table 25.
Event and Censoring Date Used in PFS
Situation
Option for End-Date
Outcome
No baseline assessment
Date of first dose of study drug
Censor
PD or death at scheduled assessment 
date or before the next scheduled 
assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death after exactly one missing 
assessment
If there is documented PD then date of PD.  
Otherwise date of death
Event
PD or death after two or more missing 
assessments
Date of the last adequate assessment prior 
to PD/death
Censor
No PD and no death
Date of the last adequate assessment
Censor
8.1.4.5
Overall Survival
For a given subject, OS is defined as the number of days from the date of the first dose of 
study drug to the date of the subject's death due to any cause.  All events of death will be 
included, regardless of whether the event occurred while the subject was still taking study 
drug or after the subject discontinued study drug.  If a subject has not dies, the data will be 
censored at the date they were last known to be alive.
8.1.4.6
Time to Response
For a given subject, TTR is defined as the number of days from the date of the first dose 
of study drug until the date of their first favorable response (i.e., PR, VGPR, CR, or sCR).  
If a subject does not experience a favorable response, they will be censored at the date of 
last adequate assessment.
8.1.5
Statistical Analysis of Efficacy
For the Phase 2 portion, confirmatory testing will be performed for ORR and VGPR+ 
rate, i.e.,:
1.
H0a:  ORR ≤ 30% vs H1a:  ORR > 30%
2.
H0b:  VGPR+ ≤ 12% vs H1b:  VGPR+ > 12%
 


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Because two tests are being performed, multiplicity control must be implemented.  The 
Hochberg procedure will be used, as follows:
●
Calculate the p-value for each test, i.e., pORR and pVGPR+
○
If pORR and pVGPR+ are both less than 0.025, reject both H0a and H0b, and 
declare efficacy.
○
Else, if min(pORR, pVGPR+) is less than 0.0125, reject either H0a or H0b (as 
appropriate), and declare efficacy, where min() denotes the minimum.
○
Otherwise, do not declare efficacy.
This procedure controls the family-wise error rate at 0.025 and is uniformly more 
powerful than the Bonferroni correction.
In addition, point estimates and 95% exact confidence intervals of ORR and VGPR+ rate 
will be determined for different dose groups and treatments (venetoclax and venetoclax in 
combination with dexamethasone).  The distribution of PFS, OS, TTR, TTP and DOR 
will be estimated for all subjects using Kaplan-Meier product-limit methodology.  If 
reached, median time to event and a corresponding 95% confidence interval will be 
estimated.
DOR will be analyzed only based on data from responders (PR or better).
For PROs, change in score from baseline will be evaluated for the following domains:  
Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30), Fatigue (PROMIS-
Fatigue), and Global Health Status/QoL (EORTC QLQ-C30).
Descriptive statistics will be used to summarize patient-reported outcomes based on the 
remaining subscales of BPI-SF, EORTC QLQ-C30, EORTC QLC-MY20, and 
EQ-5D-5L.
Additional analysis may be performed if deemed necessary and helpful in understanding 
the drug effect.
 


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8.1.5.1
Phase 2 Efficacy Subgroup Analysis
The Phase 2 portion of this study may explore potential differences in efficacy for various 
subgroups.  Subjects may be compared by:  age (< 65 years vs ≥ 65 years), ISS stage (I vs 
II/III), cytogenetic factors, the nature of subjects' previous therapies, and high versus low 
BCL-2:BCL-XL ratio.
In particular, the presentation of IMWG response rates (including ORR and VGPR+ rates) 
and time-to-event endpoints (PFS, OS, and DOR) may be broken down by subgroup 
membership.
8.1.6
Statistical Analysis of Safety
The safety of venetoclax monotherapy and venetoclax plus dexamethasone (combination 
and Phase 2) will be assessed by evaluating study drug exposure, adverse events, serious 
adverse events, deaths, and changes in laboratory values and vital sign parameters.
8.1.6.1
Duration of Study Drug Exposure
A summary of the number of days and/or cycles subjects were exposed to study drug will 
be provided.
8.1.6.2
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of the study drug.  Analyses will not 
include those that have an onset greater than 30 days after the last dose of the study drug.
Treatment-emergent adverse events will be coded and summarized by system organ class 
and preferred term according to the Medical Dictionary for Regulatory Activities 
(MedDRA)27 adverse event coding dictionary.  The percentage of subjects experiencing 
an adverse event will be provided by relationship to study drug and by NCI CTCAE 
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8.1.6.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described above in Section 8.1.6.2.
8.1.6.4
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study drug in this study, 2) for deaths occurring off treatment 
within 30 days after the last dose of study drug and 3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.
8.1.6.5
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be summarized for each scheduled post-baseline visit and for 
the Final Visit blood chemistry, hematology, urinalysis, and vital sign parameters, where 
applicable.  If more than one measurement exists for a subject on a particular day, an 
arithmetic average will be calculated.  This average will be considered to be that subject's 
measurement for that day.  Post-baseline measurements more than 30 days after the last 
dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post baseline measurements will not be included.
8.1.6.6
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, laboratory values will be categorized according to the NCI CTCAE 
version 4.03)26 grades, and shifts from baseline grade to maximum and final post-baseline 
grades will be assessed.  The baseline and final grades will be defined respectively as the 
grade of the last measurement collected prior to the first dose of study drug, and as the 
grade of the last post-baseline measurement collected no more than 30 days after the last 
dose of study drug.  If multiple values are available for a post baseline measurement, then 
the value with the highest NCI CTCAE grade will be used in the assessment of shift.  The 
percentage of subjects experiencing a shift from baseline grades of 0 to 2 to maximum 
post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 to final post-baseline 
grades of 3 to 4 will be summarized.
 


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Detailed listings of data for subjects experiencing NCI CTCAE grades 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
8.1.6.7
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Detailed listings of data for subjects experiencing potentially clinically significant vital 
sign values according to the AbbVie-defined criteria for vital sign values will be provided.  
All measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
8.1.7
Biomarkers and Exploratory Research Variables 
If biomarkers and/or exploratory end point data are determined from the collected 
samples, any statistical analyses of these data are outside the scope of this protocol and 
may be reported separately from the final clinical study report.
8.2
Determination of Sample Size
The Phase 1 portion is a dose escalation study.  The number of subjects required will 
depend upon the toxicities observed as the trial progresses.  Once MTD is reached and 
RPTD is determined, approximately 36 additional subjects will be enrolled at the MTD 
(or RPTD) of venetoclax into the safety expansion portion.
The safety expansion portion will evaluate the MTD (or RPTD) defined during the dose 
escalation portion of the study to provide increased precision in the estimation of safety 
parameters for different Bcl-2 family expression profiles.  Each of these Bcl-2 expression 
family profiles will include approximately 12 additional subjects, as the probablilty of 
observing at least one dose-limiting adverse event in 12 subjects is 99% if the true but 
unknown dose limiting adverse event rate is 33%.
 


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The VenDex combination portion will explore the safety and efficacy of venetoclax in 
combination with dexamethasone in subjects with t(11;14)-positive MM.  Approximately 
18 additional subjects will be enrolled as the probability to observe at least one occurrence 
of an adverse event is ≥ 85%, if the true incidence of the respective adverse event rate is 
≥10%.
The primary objective of the Phase 2 portion of the study is to test (a) H0a:  ORR ≤ 30% 
against H1a:  ORR > 30% and (b) H0b:  VGPR+ rate ≤ 12% against H1b:  VGPR+ rate 
> 12%.  These hypotheses will be tested using a family-wise one-sided type-I error rate of 
0.025.  The Hochberg procedure will be used to control for multiplicity.  This part of the 
study is powered for a true ORR of 50% and a true VGPR+ rate of 30%.  Under the 
considerations above, if at least 80 subjects are enrolled in the Phase 2 portion of the 
study, there will be over 95% power to reject H0a, 96% power to reject H0b, 92% power to 
reject both H0a and H0b, and 99% power to declare efficacy (due to high ORR, high 
VGPR+ rate, or high values of both).
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval and approval by 
Regulatory Authority (ies), if required by local regulations, prior to implementation of any 
changes made to the study design.  The investigator will be required to submit, maintain 
 


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and archive study essential documents according to ICH GCP and all other applicable 
regulatory requirements.
Serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible Ethics Committees and Regulatory Agencies as 
required by local regulations.  During the conduct of the study, the investigator should 
promptly provide written reports (e.g., ICH Expedited Reports or any additional reports 
required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing 
clinical study conduct and ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat) occurs leading to difficulties in performing protocol-specified 
procedures, AbbVie may engage with study site personnel in efforts to ensure the safety 
of subjects, maintain protocol compliance, and minimize risks to the integrity of the study 
while trying to best manage subject continuity of care.  This may include alternative 
methods for assessments (e.g., phone contacts or virtual site visits), alternative locations 
for data collection (e.g., use of a local lab instead of a central lab), and shipping 
investigational product and/or supplies direct to subjects to ensure continuity of treatment 
where allowed.  COVID-19 pandemic-related acceptable protocol modifications are 
detailed throughout the protocol.  In all cases, these alternative measures must be allowed 
by local regulations and permitted by IRB/IEC.
 


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9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject and answer all questions regarding this study.  Prior to any study-related screening 
procedure being performed on the subject the informed consent statement will be 
reviewed, signed and dated by the subject, the person who administered the informed 
consent, and any other signatories according to local requirements.  A copy of the 
informed consent form will be given to the subject and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
Pharmacogenetic analysis will only be performed if the subject has voluntarily signed and 
dated a pharmacogenetic informed consent, approved by an IRB/IEC, after the nature of
the testing has been explained and the subject has had an opportunity to ask questions.  
The pharmacogenetic informed consent must be signed before the pharmacogenetic 
testing is performed.  If the subject does not consent to the pharmacogenetic testing, it will 
not impact the subject's participation in the study.
In the event a subject withdraws consent to participate from the study, stored biomarker 
and exploratory research samples will continue to be used for research and analysis.  In 
the event that a subject would like to withdraw consent for research using these samples, 
the subject may request that their samples be withdrawn.  Once AbbVie receives the 
request, remaining biomarker and exploroatory research samples will be destroyed.  If the 
subject changes his/her consent, and the samples have already been tested, those results 
will still remain as part of the overall research data.
 


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An informed consent, approved by an IEC/IRB, must be voluntarily signed and dated 
before samples are collected for optional exploratory research.  The nature of the testing 
should be explained and the subject given an opportunity to ask questions.  The informed 
consent must be signed before the samples are collected and any testing is performed.  If 
the subject does not consent to provide samples for the optional exploratory research, it 
will not impact their participation in the study.
If a subject specifically requests to withdraw consentfrom survival follow up, study sites 
may enter confirmation of death using source documentation from available public 
records such as death registries or funeral notices, as appropriate per local regulations.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data, and records.  These may 
include hospital records, clinical and office charts, laboratory data/information, subject 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded to the appropriate 
source document.  The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.  All source documents should 
be attributable, legible, contemporaneous, original, accurate, and complete to ensure 
accurate interpretation of data.  Clinical site monitoring is conducted to ensure that the 
rights and well-being of human subjects are protected, that the reported trial data are 
accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local 
regulatory requirement(s).  The Investigator Awareness Date (SAE CRF) may serve as the 
source for this data point.  This adverse event data point required for eCRF completion 
can be entered directly in the eCRF.
 


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The investigator/institution will permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s), providing direct access to source data documents.
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10.2
Case Report Forms
Case report forms (CRFs) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
 


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Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Patient-reported data have been completed for Phase 2 subjects.  These data have been 
collected with an Electronic Patient Reported Outcome (ePRO) system called Trialmax, 
provided by the technology vendor CRF Health of Plymouth Meeting, PA, USA.  The 
ePRO system is in compliance with Title 21 CFR Part 11.  The documentation related to 
the system validation of the ePRO system is available through the vendor, CRF Health, 
while the user acceptance testing of the study specific PRO design will be conducted and 
maintained at AbbVie.
The subjects have been entering the data on an electronic device; the data has been 
uploaded to a server.  The data on the server will be considered source, and maintained 
and managed by CRF Health.
Internet access to the ePRO data has been provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
The ePRO data has been collected electronically via a tablet device into which the patient 
has directly enter the required pieces of information.  The electronic device has been 
programmed to allow data entry for only the visits specified in the protocol and did not 
allow for patients to complete more than one of the same assessments at any one visit.  All 
data entered on the device has been immediately stored to the device itself and 
 


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automatically uploaded to a central server administrated by CRF Health.  The Investigator 
and delegated staff will be able to access all uploaded patient entered data via a password 
protected website, up until the generation, receipt and confirmation of the study archive.
11.0
Data Quality Assurance
AbbVie will ensure that the clinical trial is conducted with a quality management system 
that will define quality tolerance limits in order to ensure human subject protection and 
reliability of study results.  Data will be generated, documented, and reported in 
compliance with the protocol, ICH GCP, and applicable regulatory requirements.
Prior to enrolling any subject in the study, an initiation meeting will be held with AbbVie 
personnel, the investigator(s), and the study coordinators/project manager(s).  This 
meeting will include a detailed discussion and review of the protocol and essential 
documents, performance of study procedures, case report form completion and specimen 
collection methods.
The AbbVie monitor will monitor the study site throughout the study.  Source document 
review will be made against entries on the case report forms and a quality assurance check 
will be performed to ensure that the investigator is complying with the protocol and 
regulations.  In addition, after the case report forms are retrieved, a review of the data will 
be conducted by a physician or representative at AbbVie.
All data hand-entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the hard-copy case report form and corrected on-line.  After 
completion of the entry process, computer logic and manual checks will be created to 
identify such items as inconsistent study dates.  Any necessary corrections will be made to 
the database via the appropriate change form/electronic CRF.
Routine hematology, serum chemistry and serology, and urinalysis tests will be conducted 
using a certified clinical laboratory.  Laboratory reference ranges will be obtained prior to 
the initiation of the study.  A review of all laboratory results will be conducted by the 
AbbVie monitor, the investigator and other appropriate personnel from AbbVie.
 


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During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
12.0
Use of Information
All information concerning venetoclax and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
venetoclax.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or subject management.  Hence, the subject will not be informed of 
 


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individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to investigators used in scientific publications or presented at medical 
conventions.  Optional exploratory research information will be published or presented 
only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the time frame specified in the contract between the investigator and 
AbbVie.  Continuation of this study beyond this date must be mutually agreed upon in 
writing by both the investigator and AbbVie.  The investigator will provide a final report 
to the IEC/IRB following conclusion of the study, and will forward a copy of this report 
to AbbVie or their representative.
The investigator must submit, maintain and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory coordinating investigator from the investigators who 
participate in each multicenter study.  Selection criteria for this signatory investigator will 
be based on level of participation, and significant knowledge of the clinical research, 
investigational drug, and study protocol.  The signatory investigator for the study will 
review and sign the final study report in accordance with the European Agency for the 
Evaluation of Medicinal Products (EMEA) Guidance on Investigator's Signature for Study 
Reports.
The end of study is defined as the date of the last subject's last visit, including Safety 
Follow Up.
 


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for venetoclax and 
product labeling for dexamethasone.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Phase 1/2 Study Evaluating the Safety and Pharmacokinetics of 
ABT-199 in Subjects with Relapsed or Refractory Multiple 
Myeloma
Protocol Date:
17 February 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
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Kyle RA, Rajkumar SV.  Multiple myeloma.  Blood.  2008;111(6):2962-72.
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Myeloma Trialists' Collaborative Group.  Combination chemotherapy versus 
melphalan plus prednisone as treatment for multiple myeloma:  an overview of 
6,633 patients from 27 randomized trials.  J Clin Oncol.  1998;16(12):3832-42.
3.
Kumar SK, Rajkumar SV, Dispenzieri A, et al.  Improved survival in multiple 
myeloma and the impact of novel therapies.  Blood.  2008;111(5):2516-20.
4.
Brenner H, Gondos A, Pulte D.  Recent major improvement in long-term survival 
of younger patients with multiple myeloma.  Blood.  2008;111:2521-6.
5.
Siegel DS, Martin T, Wang M, et al.  Results of PX-171-003-A1, an open-label, 
single-arm, Phase 2 (Ph 2) study of Carfilzomib (CFZ) in patients (pts) with 
relapsed and refractory multiple myeloma (MM) [ASH 2010 poster #985].  
53rd ASH Annual Meeting and Exposition; 2010 Dec 07; San Diego, CA.
6.
Lacy M, Mandrekar S, Gertz MA, et al.  Pomalidomide plus low-dose 
dexamethasone in myeloma refractory to both bortezomib and lenalidomide:  
comparison of two dosing strategies in dual-refractory disease [ASH 2010 
abstract #863].  53rd ASH Annual Meeting and Exposition; 2010 Dec 06; San 
Diego, CA.
7.
Palumbo A, Bringhen S, Caravita T, et al.  Oral melphalan and prednisone 
chemotherapy plus thalidomide compared with melphalan and prednisone alone in 
elderly patients with multiple myeloma:  randomised controlled trial.  Lancet.  
2006;367(9513):825-31.
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Touzeau C, Dousset C, Le Gouill S, et al.  The Bcl-2 specific BH3 mimetic 
ABT-199:  a promising targeted therapy for t(11;14) multiple myeloma.  Leukemia.  
2014;28(1):210-2.
9.
Del Gaizo Moore V, Schlis KD, Sallan SE, et al.  BCL-2 dependence and ABT-737 
sensitivity in acute lymphoblastic leukemia.  Blood.  2008;111(4):2300-9.
 


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10.
Yan W, Huang J-X, Lax A-S, et al.  Overexpression of Bcl-w in the testis disrupts 
spermatogenesis:  revelation of a role of BCL-W in male germ cell cycle control.  
Mol Endocrinol.  2003;17(9):1868-79.
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Sugiyama N, Obinata M, Matsui Y.  Bcl-2 inhibits apoptosis of spermatogonia and 
growth of spermatogonial stem cells in a cell-intrinsic manner.  Mol Reprod Dev.  
2001;58(1):30-8.
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Oldereid NB, Angelis PD, Wiger R, et al.  Expression of Bcl-2 family proteins and 
spontaneous apoptosis in normal human testis.  Mol Hum Reprod.  
2001;7(5):403-8.
13.
Yamamura K, Kamada S, Ito S, et al.  Accelerated disappearance of melanocytes in 
bcl-2-deficient mice.  Cancer Res.  1996;56(15):3546-50.
14.
Wilson H, O'Connor A, Czuczman S, et al.  Phase 1/2a study of navitoclax 
(ABT-263) in relapsed or refractory lymphoid malignancies [abstract 0292].  
Haematologica.  2010;95(S2):116-7.
15.
AbbVie.  ABT-199 Investigator's Brochure Edition 5.  21 April 2014.
16.
AbbVie.  ABT-199 Investigator's Brochure Edition 5, Addendum 1.  August 2014.
17.
AbbVie.  ABT-199 Investigator's Brochure Edition 6.  07 April 2015.
18.
Matulis SM, Gupta VA, Nooka AK, et al.  Dexamethasone treatment promotes 
Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax.  
Leukemia.  2015 Dec 28.  doi:  10.1038/leu.2015.350.
19.
Coiffier B, Altman A, Pui C-H, et al.  Guidelines for the management of pediatric 
and adult tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26(16):2767-78.
20.
Rajkumar SV, Richardson P, San Miguel JF.  Guidelines for determination of the 
number of prior lines of therapy in multiple myeloma.  Blood.  2015;126(7):921-2.
21.
Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 update of recommendations 
for the use of white blood cell growth factors:  an evidence-based clinical practice 
guideline.  J Clin Oncol.  2006;24(19):3187-205.
 


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22.
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649-55.
23.
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria 
for multiple myeloma.  Leukemia.  2006;20(9):1467-73.
24.
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria 
for multiple myeloma.  Leukemia.  2006;20(9):1467-73.  Erratum in:  Leukemia.  
2007;21(5):1134.
25.
Rajkumar SV, Harousseau JL, Durie BG, et al.  Consensus recommendations for 
the uniform reporting of clinical trials:  report of the International Myeloma 
Workshop Consensus Panel 1.  Blood.  2011;117(18):4691-5.
26.
National Cancer Institute.  Common Terminology Criteria for Adverse Events 
(CTCAE), v4.0.  28 May 2009 (v4.03:  14 June 2010).  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
27.
AbbVie.  Coding Guidelines for MedDRA Term Selection Edition 16.1.
28.
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.
29.
AbbVie.  Venetoclax Investigator's Brochure Edition 10.  22 February 2019.
30.
Kumar, S, Paiva B, Anderson KC, et al.  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma.  Lancet Oncol.  2016;17(8):e328-46.
31.
Fassas AB, Desikan KR, Siegel D, et al.  Tumour lysis syndrome complicating 
high-dose treatment in patients with multiple myeloma.  Br J Haematol.  
1999;105(4):938-41.
32.
Cleeland CS:  Pain assessment in cancer.  In Effect of Cancer on Quality of Life.  
Edited by Osaba D.  Boca Raton:  CRC Press; 1991:21.
33.
Atkinson TM, Mendoza TR, Sit L, et al.  The Brief Pain Inventory and its "pain at 
its worst in the past 24 hours" item:  clinical trial endpoint considerations.  Pain 
Med.  2010;11:337-46.
 


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34.
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
in international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
35.
Cocks K, Cohen D, Wisloff F, et al.  An international field study of the reliability 
and validity of a disease-specific questionnaire module (the QLQ-MY20) in 
assessing the quality of life of patients with multiple myeloma.  Eur J Cancer.  
2007;43:1670-8.
36.
Cella D, Yount S, Rothrock N, et al.  The patient-reported outcomes measurement 
information system (PROMIS):  progress of an NIH roadmap cooperative group 
during its first 2 years.  Med Care.  2007;45 (5 Suppl 1):S3-S11.
37.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
information system initiative.  J Clin Oncol.  2007;25(32):5106-12.
38.
Cella D, Riley W, Stone A, et al.  The patient-reported outcomes measurement 
information system (PROMIS) developed and tested its first wave of adult sel 
reported health outcome item banks:  2005-2008.  J Clin Epidemiol.  
2010;63(11):1179-94.
39.
EQ-5D-5L and EQ-5D-VA.  Available from:  http://www.euroqol.org.
40.
Smith TJ, Bohlke K, Lyman GH, et al.  Recommendations for the Use of WBC 
Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol. 2015;33(28):3199-212.
 


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
Good Clinical Practices (GCP) and local regulations and guidelines governing the study at 
the site location.  In signing the Investigator's Agreement in Section 14.0 of this protocol, 
the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory 
requirements and current protocol, and making changes to a protocol only after 
notifying AbbVie and the appropriate Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC), except when necessary to protect the subject 
from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees' [e.g., independent ethics committee (IEC) or 
institutional review board (IRB)] review and approval of the protocol and its 
amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
 


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8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Providing direct access to source data documents for study-related monitoring, 
audits, IEC/IRB review, and regulatory inspection(s).
 


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Study Project Manager I 
Clinical
 
Director
Statistics
Medical Director
Clinical
Executive Medical Director, 
Hematology
Clinical
Director
Clinical Pharmacology and 
Pharmacometrics
Senior Principal Research Scientist
Precision Medicine, Oncology
 




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1
Moderate CYP3A inhibitor per venetoclax FDA USPI.
2
Closely monitor the international normalized ratio (INR).
Note that this is not an exhaustive list.  For an updated list, see the following link:  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm.
In addition to the medications listed in this table, subjects receiving venetoclax should not 
consume grapefruit, grapefruit products, Seville oranges (including marmalade containing 
Seville oranges) or starfruits.
 


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Appendix D.
Sample Meal Description
Standard American Heart Association Healthy (Low-Fat) Breakfast
1 box cereal (30 – 40 g)
Skim milk (240 mL)
1 boiled egg
1 slice toast (15 g)
Margarine (10 g)
Total calories, approximately 520 Kcal; 30% of the total caloric content of the meal is 
from fat; total grams of fat, approximately 17 grams.
 


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Appendix E.
IMWG Response Criteria for Multiple Myeloma
IMWG 201123-25 Response Criteria
Response Subcategory 
Response Criteriaa
Stringent complete 
response (sCR)*

Negative immunofixation on the serum and urine (regardless of 
whether disease at baseline was measurable on serum, urine, both, 
or neither) and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrowb and

Normal FLC (free light chain) ratio** and

Absence of clonal plasma cells in bone marrowb by 
immunohistochemistry or immunofluorescencec or 2 to 4 color 
flow cytometry
Complete response 
(CR)*

Negative immunofixation on the serum and urine (regardless of 
whether disease at baseline was measurable on serum, urine, both, 
or neither) and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrowb and

For subjects in whom the only measurable disease is by serum FLC 
levels, a normal FLC ratio** is also required
Very good partial 
response (VGPR)*

Serum and urine M-component detectable by immunofixation but 
not on electrophoresis or

≥ 90% reduction in serum M-component plus urine M-component 
< 100 mg per 24 hr
For subjects in whom the only measurable disease is by serum FLC levels, 
VGPR is defined as:

≥ 90% decrease in the difference between involved and uninvolved 
FLC levels
Partial response (PR)

≥ 50% reduction of serum M-protein and

≥ 90% reduction in 24-hr urinary M-protein or to < 200 mg per 
24 hr
o
If the serum and urine M-protein are unmeasurabled, a ≥50% 
decrease in the difference between involved and uninvolved 
FLC levels is required in place of the M-protein criteria

≥50% reduction in the size of soft tissue plasmacytomas, if present 
at baseline
Minimal response (MR)

25% – 49% reduction of serum M-protein, and

50% – 89% reduction in 24-hour urinary M-protein, and

25% – 49% reduction in size of soft tissue plasmacytomas, if 
present at baseline, and

No increase in size or number of lytic bone lesions (development of 
compression fracture dose not exclude response)
Stable disease (SD)e
Not meeting criteria for sCR, CR, VGPR, PR, MR or progressive disease 
(PD)
 


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a.
All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed.  Radiographic studies are not required to satisfy these response requirements.
b.
Confirmation with repeat bone marrow biopsy not needed.
c.
Presence/absence of clonal cells is based upon the k/λ ratio.  An abnormal k/λ ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting 
presence of an abnormal clone is k/λ of > 4:1 or < 1:2.
d.
Measurable disease is defined as meeting at least one of the following four measurements:  serum M-protein 
≥1 g/dL (≥ 10 g/L) or urine M-protein ≥ 200 mg/24 hr or serum FLC assay with an involved FLC level 
≥10 mg/dL (≥ 100 mg/L) provided serum FLC ration is abnormal or bone marrow plasma cells ≥ 30%.
e.
Not recommended for use as an indicator of response; stability of disease is best described by providing the time to 
progression estimates.
*
Serum and urine M-protein testing is required to fulfill requirements of VGPR and CR categories regardless of 
whether disease at baseline was measurable on serum, urine, both, or neither.
**
Clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by 
serum FLC levels:  CR in such patients is defined as a normal FLC ratio of 0.26 – 1.65 in addition to CR criteria 
listed above.  VGPR in such patients is defined as a > 90% decrease in the difference between involved and 
uninvolved free light chain FLC levels.
Relapse Subcategory
Relapse Criteria
Progressive disease (PD)*
Requires any one or more of the following:

Increase of ≥ 25% from lowest response level in any of the 
following:
o
Serum M-proteina absolute increase ≥ 0.5 g/dL, and/or 
o
Urine M-protein absolute increase ≥200 mg/24 hr, and/or
o
In subjects without measurable serum and urine M-protein 
levels, the difference between involved and uninvolved FLC 
levels (the absolute increase must be > 10 mg/dL), and/or

Definite development of new bone lesions or soft tissue 
plasmacytomas, and/or

Definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas, and/or

Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder
 


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Clinical Relapse
Requires any one or more of the following direct indicators of increasing 
disease and/or end organ dysfunction (CRAB features).

Development of new soft tissue plasmacytomas or bone lesions 
on skeletal survey, MRI or other imaging, and/or

Definite increase in size of existing plasmacytomas or bone 
lesions.  A definite increase is defined as a 50% (and at least 
1 cm) increase as measured serially by the sum of the products of 
the cross-diameters of the measurable lesion, and/or

Hypercalcemia > 11.5 mg/dL (>2.875 mmol/L), and/or

Decrease in hemoglobin of ≥ 2 g/dL (≥ 1.25 mmol/L) or 
< 10 g/dL, and/or

Rise in serum creatinine by > 2 mg/dL (≥ 177 mmol/L), and/or

Hyperviscosity
a.
For progressive disease, serum M-component increases of ≥ 1 g/dL are sufficient to define relapse if starting 
M-component is ≥ 5 g/dL.
*
The "25% increase" refers to M-protein, FLC, and bone marrow results and does not refer to bone lesions, soft 
tissue plasmacytomas, or hypercalcemia.  The "lowest response value" does not need to be a confirmed value.
Standard IMWG 201630 Response Criteria
Note: MRD IMWG30 criteria will be evaluated as an exploratory endpoint.
Response Subcategory
Response Criteriaa
Stringent complete 
response*

Negative immunofixation on the serum and urine (regardless of whether 
disease at baseline was measurable in serum, urine, both, or neither) and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrowb and

Normal FLC ratio** and

Absence of clonal cells in bone marrowb by immunohistochemistry
(κ/λ ratio ≤ 4:1 or ≥ 1:2 for κ and λ patients, respectively, after counting 
≥ 100 plasma cells)c
Complete response*,c

Negative immunofixation on the serum and urine (regardless of whether 
disease at baseline was measurable on serum, urine, both, or neither) 
and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrowb and

For subjects in whom the only measurable disease is by serum FLC 
levels, a normal FLC ratio** is also required
 


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Response Subcategory
Response Criteriaa
Very good partial 
response*

Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or

≥ 90% reduction in serum M-protein plus urine M-protein < 100 mg per 
24 hours

For subjects in whom the only measurable disease is by serum FLC 
levels, VGPR is defined as:
o
≥ 90% decrease in the difference between involved and uninvolved 
FLC levels
Partial response

≥ 50% reduction of serum M-protein and

Reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 
24 hours
o
If the serum and urine M-protein are unmeasurable,d a ≥50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria
o
If the serum and urine M-protein are unmeasurable,d and serum-free 
light assay is also unmeasurable, a ≥ 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma-cell percentage was ≥ 30%

≥ 50% reduction in the size of soft tissue plasmacytomas is also 
required, if present at baseline
Minimal response

25% – 49% reduction of serum M-protein and

50% – 89% reduction in 24-hour urinary M-protein and

≥ 50% reduction in the size (SPD)f of soft tissue plasmacytomas if 
present at baseline
Stable diseasee

Not meeting criteria for CR, VGPR, PR, MR or progressive disease
 


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Response Subcategory
Response Criteriaa
Progressive disease

Any one or more of the following criteria:
o
Increase of 25% from lowest confirmed response value in one or 
more of the following criteria: 

Serum M-protein (absolute increase must be ≥ 0.5 g/dL); 

Serum M-protein increase ≥ 1 g/dL, if the lowest M component 
was ≥ 5 g/dL;

Urine M-protein (absolute increase must be ≥ 200 mg/24 h); 
o
In patients without measurable serum and urine M-protein levels, 
the difference between involved and uninvolved FLC levels 
(absolute increase must be > 10 mg/dL); 
o
In patients without measurable serum and urine M-protein levels 
and without measurable involved FLC levels, bone marrow plasma-
cell percentage irrespective of baseline status (absolute increase 
must be ≥ 10%);
o
Appearance of a new lesion(s), ≥ 50% increase from nadir in SPDf
of > 1 lesion, or ≥ 50% increase in the longest diameter of a 
previous lesion > 1 cm in short axis; 
o
≥ 50% increase in circulating plasma cells (minimum of 200 cells 
per μL) if this is the only measure of disease
Clinical Relapse

Clinical relapse requires one or more of the following criteria: 
o
Direct indicators of increasing disease and/or end organ dysfunction 
(CRAB features) related to the underlying clonal plasma-cell 
proliferative disorder. It is not used in calculation of time to 
progression or progression-free survival but is listed as something 
that can be reported optionally or for use in clinical practice; 
o
Development of new soft tissue plasmacytomas or bone lesions 
(osteoporotic fractures do not constitute progression); 
o
Definite increase in the size of existing plasmacytomas or bone 
lesions. A definite increase is defined as a 50% (and ≥ 1 cm) 
increase as measured serially by the SPDf of the measurable lesion; 
o
Hypercalcemia (>11 mg/dL); 
o
Decrease in hemoglobin of ≥ 2 g/dL not related to therapy or other 
non-myeloma-related conditions; 
o
Rise in serum creatinine by 2 mg/dL or more from the start of the 
therapy and attributable to myeloma; 

Hyperviscosity related to serum paraprotein
CR = complete response; FLC = free light chain; IMWG = International Myeloma Working Group; 
M-protein = myeloma protein; MR = minimal response; PR = partial response; sCR = stringent complete response; 
SPD = sum of the products of the maximal perpendicular diameters of measured lesions; VGPR = very good partial 
response
 


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Notes:
*
Clarification to IMWG criteria for coding CR and VGPR in subjects whom the only measurable disease is by 
serum FLC levels.  In these subjects, CR is defined as a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria 
listed above, and VGPR is defined as a ≥ 90% decrease in the difference between involved and uninvolved FLC 
levels.
**
Serum and urine M-protein testing is required to fulfill requirements of VGPR and CR categories regardless of 
whether disease at baseline was measurable in serum, urine, both, or neither.
a.
All response categories require 2 consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions or extramedullary 
plasmacytomas if radiographic studies were performed.  Radiographic studies are not required to satisfy these 
response requirements.
b.
Confirmation with repeat bone marrow biopsy not needed.
c.
Presence/absence of clonal cells on immunohistochemistry is based upon the k/λ ratio.  An abnormal k/λ ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting presence 
of an abnormal clone is k/λ of > 4:1 or < 1:2.
d.
Measurable disease is defined as meeting at least one of the following 3 measurements:  serum M-protein ≥1 g/dL 
(≥10 g/L) or urine M-protein ≥ 200 mg/24 hours or serum FLC assay with an involved FLC level ≥10 mg/dL 
(≥100 mg/L) provided serum FLC ration is abnormal.
e.
Not recommended for use as an indicator of response; stability of disease is best described by providing the time to 
progression estimates.
f.
Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT 
scans where applicable.  For patients with only skin involvement, skin lesions should be measured with a ruler.  
Measurement of tumor size will be determined by the SPD.
 


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Appendix F.
Howard Definition of Tumor Lysis Syndrome
Table 1.
Tumor Lysis Syndrome Classification
Metabolic Abnormality
Criteria for Classification of Laboratory Tumor Lysis 
Syndrome*
Criteria for Classification of Clinical Tumor 
Lysis Syndrome**
Hyperuricemia
Uric acid > 8 mg/dL (475.8 μmol/liter)
N/A
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/liter)
N/A
Hyperkalemia
Potassium > 6 mmol/liter
Cardiac dysrhythmia or sudden death probably or 
definitely caused by hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL
(1.75 mmol/liter) or ionized calcium < 1.12 mg/dL (0.3 
mmol/liter)#
Cardiac dysrhythmia, sudden death, seizure, 
neuromuscular irritability (tetany, paresthesias, 
muscle twitching, carpopedal spasm, Trousseau's 
sign, Chvostek's sign, laryngospasm, or 
bronchospasm), hypotension, or heart failure 
probably or definitely caused by hypocalcemia
Acute Kidney Injury!
N/A
Increase in the serum creatinine level of 0.3 mg/dL
(26.5 μmol/liter) or the presence of oliguria 
(average urine output of < 0.5 mL/kg/hr over a 6-
hour period)
*
Laboratory TLS requires two or more metabolic abnormalities must be present during the same 24-hour period within 3 days before the start of therapy or up to 7 days 
afterward.
**
Clinical TLS requires the presence of Laboratory TLS plus one or more findings from the Clinical TLS column.
#
Corrected calcium = measured calcium level in mg/dL + 0.8 × (4 – albumin in gm/dL).
!
Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS are not satisfied.
*
Not directly or probably attributable to therapeutic agent.
Note:
Laboratory tumor lysis syndrome and at least one clinical complication.
Source:  Howard 201128
 


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Appendix G.
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS) in 
Multiple Myeloma Subjects
Section 1:  First Dose of Venetoclax or Dose Escalation
●
Within the first 24 hours after either the first dose or dose escalation, if any
laboratory criteria below are met, the subject should be hospitalized for
monitoring and the Investigator notified.  No additional venetoclax doses 
should be administered until resolution.  A rapidly rising serum potassium is a 
medical emergency.
●
Nephrology (or acute dialysis service or other) should be contacted/consulted 
on admission (per institutional standards to ensure emergency dialysis is 
available) for any subject who is high risk for TLS being hospitalized in 
response to laboratory changes or per Investigator discretion.
●
IV fluids (e.g., D5 1/2 normal saline) initiated at a rate of at least 1 mL/kg/hr 
rounded to the nearest 10 mL (target 150 to 200 mL/hr; not < 50 mL/hr).  
Modification of fluid rate should also be considered for individuals with 
specific medical needs.
●
Monitor for symptoms or signs of TLS (e.g., fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, 
paresthesias, mental status changes, confusion, seizures). If any clinical 
features are observed, recheck potassium, phosphorus, uric acid, calcium and 
creatinine within 1 hour immediately.
●
Vital signs should be taken at time of all blood draws or any Intervention.
●
The management recommendations below focus on the minimum initial 
responses required.  If a diagnosis of TLS is established, ongoing intensive 
monitoring and multi-disciplinary management will be per institutional 
protocols.  
 








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Section 2:  Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals > 24 hours after either the 
first dose or dose escalation (e.g., 48 or 72 hours) is as below.
Note:  If the patient is hospitalized, no additional venetoclax doses should be administered 
until resolution.
●
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or 
any level > upper limit of normal.
○
Refer to the management guidelines for electrolyte changes observed 
within the first 24 hours after either the first dose or dose escalation 
(see prior table).
●
If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 24 hours and confirm no evidence of tumor lysis prior to further 
venetoclax dosing.
●
For uric acid, calcium, phosphorus and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after 
either the first dose or dose escalation (see prior table).
 


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Appendix H.
Adverse Events Commonly Associated with MM Study Population 
or Progression of MM
Disease-Related Events
Renal Insufficiency
Bone Complications (pathologic fractures, spinal cord compressions, hypercalcemia, bone pain)
Neurologic complications (spinal cord and nerve root compression, intracranial plasmacytomas, 
leptomeningeal involvement [increased intracranial pressure, cranial nerve palsies, confusion])
Peripheral neuropathy
Paraesthesia
Cytopenia (neutropenia, anaemia, thrombocytopenia)
Febrile neutropenia
Infections (bacterial, viral, and fungal)
Second primary cancers, all types
Fatigue
Unexplained weight loss
Intermittent fever
Bruising 
Minor hemorrhages
Pain, all types
Malignant neoplasm progression, including death
 


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Population-Related Comorbidities
Hypertension
Rheumatoid arthritis/osteoarthritis
Hyperlipidemia
Peptic ulcer
Inflammatory bowel disease
Coronary artery disease
Peripheral vascular disease
Cardiomyopathy 
Valvular disease
Atrial fibrillation
Diabetes mellitus
Chronic obstructive pulmonary disease
Cerebrovascular accident
Transient ischemia attack
 


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Appendix I.
Corticosteroid Conversion Table
Corticosteroid Conversion Table
Glucocorticoid
Approximate Equivalent Dose (mg)
Short-Acting
Cortisone
25
Hydrocortisone
20
Intermediate-Acting
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Triamcinolone
4
Long-Acting
Betamethasone
0.6-0.75
Dexamethasone
0.75
Reference: 
Dixon JS.  Second-line Agents in the Treatment of Rheumatic Diseases.  Informa Health Care.  1991;456.
Meikle AW, Tyler FH.  Potency and duration of action of glucocorticoids.  Am J of Med.  1977;63:200.
Webb R, Singer M.  Oxford Handbook of Critical Care.  Oxford; New York:  Oxford University Press, 2005.
 

SAP_001.pdf: 
Venetoclax
M13-367 – Statistical Analysis Plan 
Version 1.1 (Portion 2) – 11 January 2022
1
Statistical Analysis Plan for Study M13-367 
(Portion 2)
A Phase 1/2 Study Evaluating the Safety and 
Pharmacokinetics of ABT-199 in Subjects with 
Relapsed or Refractory Multiple Myeloma
Date:  11 January 2022
Version 1.1
 
NCT01794520


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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives and Hypotheses..................................................................... 5
2.2
Study Design Overview.......................................................................... 6
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Sample Size Determination .................................................................... 7
3.0
Endpoints...............................................................................7
3.1
Primary Endpoint(s) ............................................................................... 8
3.2
Secondary Endpoint(s) ........................................................................... 8
3.2.1
Secondary Efficacy Endpoints................................................................ 8
3.2.2
Secondary Patient Reported Outcomes ................................................. 12
3.3
Other Efficacy Endpoint(s)................................................................... 13
3.4
Safety Endpoint(s)................................................................................ 15
4.0
Analysis Populations ...........................................................15
5.0
Subject Disposition..............................................................16
6.0
Study Treatment Duration and Compliance .....................16
6.1
Exposure to Study Treatment................................................................ 16
6.2
Compliance .......................................................................................... 19
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................19
7.1
Demographics and Baseline Characteristics.......................................... 19
7.2
Medical History.................................................................................... 20
7.3
Prior and Concomitant Medications...................................................... 20
8.0
Efficacy Analyses.................................................................21
8.1
General Considerations......................................................................... 21
8.2
Primary Efficacy Endpoint(s) and Analyses.......................................... 22
8.2.1
Primary Efficacy Endpoint(s) ............................................................... 22
8.2.2
Primary Efficacy Analysis.................................................................... 22
8.3
Secondary Efficacy Analyses ............................................................... 22
8.4
Additional Efficacy Analyses ............................................................... 22
8.5
Efficacy Subgroup Analyses................................................................. 23
 


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9.0
Safety Analyses....................................................................23
9.1
General Considerations......................................................................... 23
9.2
Adverse Events..................................................................................... 23
9.2.1
Treatment-Emergent Adverse Events.................................................... 23
9.2.2
Adverse Event Overview...................................................................... 24
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 25
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Treatment Discontinuation, Dose Reduction, or Dose Interruption........ 26
9.2.5
Deaths .................................................................................................. 26
9.2.6
Listing of Adverse Events..................................................................... 26
9.2.7
Adverse Events of Special Interest........................................................ 27
9.3
Analysis of Laboratory Data................................................................. 27
9.4
Analysis of Vital Signs......................................................................... 29
10.0
Interim Analyses..................................................................30
10.1
Data Monitoring Committee................................................................. 30
11.0
Version History ...................................................................30
12.0
References............................................................................31
List of Tables
Table 1.
Event and Censoring Rules for PFS........................................................ 9
Table 2.
Event and Censoring Rules for DOR .................................................... 10
Table 3.
Event and Censoring Rules for TTR..................................................... 10
Table 4.
Event and Censoring Rules for TTP...................................................... 11
Table 5.
Laboratory Criteria for TLS.................................................................. 29
Table 6.
SAP Version History Summary ............................................................ 30
List of Figures
Figure 1.
Study Schematic..................................................................................... 6
 


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List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 33
Appendix B.
Definition of Adverse Events of Special Interest Selected Adverse 
Events .................................................................................................. 34
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 35
Appendix D.
PRO assessments.................................................................................. 36
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Venetoclax 
(ABT-199) Phase 2 Portion of Study M13-367 A Phase 1/2 Study Evaluating the Safety 
and Pharmacokinetics of ABT-199 in Subjects with Relapsed or Refractory Multiple 
Myeloma.  A separate SAP is available in eDocs for Phase 1 Portion of the 
Study M13-367.
Study M13-367 examines the efficacy and safety of venetoclax in subjects with Relapsed 
or Refractory Multiple Myeloma.  The SAP will not be updated in case of administrative 
changes or amendments to the protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
Changes from the SAP version 1.0 are summarized in Section 11.0. 
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
Primary Objective:
The primary objective of the Phase 2 Portion is to further evaluate the overall response 
(ORR) and very good partial response or better rate (VGPR+) in subjects with 
t(11;14)-positive multiple myeloma.
Secondary Objectives:
The secondary objectives are to monitor safety, progression free survival (PFS), duration 
of response (DOR), time to response (TTR), time to disease progression (TTP), and 
overall survival (OS) and to evaluate Patient Reported Outcomes (PRO) including Worst 
Pain (Brief Pain Inventory – Short Form [BPI-SF]), Physical Functioning and Global 
Health Status/Quality of Life (GHS/QoL) (European Organization for Research and 
 


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Treatment of Cancer Quality of Life Questionnaire Core [EORTC QLQ-C30]), and 
Fatigue (Patient Reported Outcomes Measurement Information System [PROMIS] Cancer 
Fatigue Short Form [SF]).
Tertiary objectives:
The Tertiary objectives are to assess other PRO endpoints (remaining subscales/items 
from BPI-SF, EORTC QLQ-C30, European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Multiple Myeloma Module [EORTC QLQ-MY20], 
and EuroQol-5 Dimensions-5 Level (EQ-5D-5L).
2.2
Study Design Overview
The Phase 2 Portion of the study is an expansion of the combination cohort which further 
evaluate ORR and VGPR+ of venetoclax and dexamethasone in approximately 80 –
100 relapsed or refractory subjects with t(11;14)-positive MM.  Disease assessment for 
each post-baseline IMWG assessment will be performed by the investigator.  Subjects in 
Phase 2 Portion will receive venetoclax daily (Day 1 – 21) with dexamethasone orally 
Day 1, 8, and 15 per the prescribing information.  Subjects will receive study treatment 
for up to 2 years following the first dose of the last subject enrolled on study provided 
they continue to tolerate venetoclax, have no evidence of disease progression, and do not 
meet any criteria for subject discontinuation.  The schematic of the Study M13-367 is 
shown in Figure 1.
Figure 1.
Study Schematic
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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2.3
Treatment Assignment and Blinding
The Phase 2 Portion of the Study M13-367 is not randomized.  Eligible subjects will be 
enrolled into a single arm. 
2.4
Sample Size Determination
The primary objective of the Phase 2 portion of the study is to test 
a.
H0a:  ORR ≤ 30% against H1a:  ORR > 30% and 
b. H0b:  VGPR+ rate ≤ 12% against H1b:  VGPR+ rate > 12%.  
These hypotheses will be tested using a family-wise one-sided type-I error rate of 0.025.  
The Hochberg procedure will be used to control for multiplicity.  The Phase 2 Portion of 
the study is powered for a true ORR of 50% and a true VGPR+ rate of 30%.  Under the 
considerations above, if at least 80 subjects are enrolled in the Phase 2 portion of the 
study, there will be over 95% power to reject H0a, 96% power to reject H0b, 92% power to 
reject both H0a and H0b, and 99% power to declare efficacy (due to high ORR, high 
VGPR+ rate, or high values of both).
3.0
Endpoints
Best overall response (BOR) will be derived for each patient based on timepoint-wise 
disease assessment performed by the investigator and ordered as:  stringent complete 
response (sCR) > complete response (CR) > very good partial response (VGPR) > partial 
response (PR) > minimal response (MR) > stable disease (SD) > progressive disease (PD).  
BOR for a patient will be sCR if there are two consecutive disease assessments with sCR 
assessed, otherwise will be CR if there are two consecutive disease assessments CR (or 
better) assessed, otherwise will be VGPR if there are two consecutive disease assessments 
with VGPR (or better) assessed, otherwise will be PR if there are two consecutive disease 
assessments with PR (or better) assessed, otherwise will be MR if there are two 
consecutive disease assessments with MR (or better) assessed, otherwise will be PD if the 
best timepoint-wise disease assessment is PD (confirmation is needed if the initial PD is 
 


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based on lab – serum M-protein, urine M-protein, or serum FLC), otherwise will be NE if 
the best timepoint-wise disease assessment is unconfirmed lab-based PD, otherwise will 
be SD.
3.1
Primary Endpoint(s)
Overall Response Rate (ORR):  defined as the proportion of subjects with BOR of sCR, 
CR, VGPR or PR based on IMWG criteria.
Very Good Partial Response or Better Rate (≥ VGPR Rate):  defined as the proportion of 
subjects with BOR of sCR, CR, or VGPR based on IMWG criteria.
3.2
Secondary Endpoint(s)
MM-related death is based on investigator opinion and is collected in Death eCRF page. 
3.2.1
Secondary Efficacy Endpoints
Progression-free Survival (PFS)
The PFS is defined as the number of days from the date of the first dose of study 
treatment to the date of first documented PD or death due to any cause, whichever occurs 
first. 
PFS (days) = Date of first documented PD or death due to any cause –
Date of the first dose of study treatment + 1
Details on event and censoring rules for PFS are provided in Table 1.
 


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Table 1.
Event and Censoring Rules for PFS
Situation
Date of Censor or Event
Outcome
PD/death due to any cause occurred not 
more than 12 weeks after the last 
adequate disease assessment
Date of PD/death
Event
PD/death due to any cause occurred 
more than 12 weeks after the last 
adequate disease assessment
Date of the last adequate disease 
assessment prior to PD/death due to any 
cause
Censored
No post-baseline assessment
Date of the first dose of study treatment
Censored
No PD/ no death due to any cause
Date of the last adequate disease 
assessment
Censored
Start of new anti-MM therapy prior to 
PD/death
Date of the last adequate disease 
assessment prior to start of new anti-MM 
therapy
Censored
Duration of Response (DOR)
DOR is defined as the number of days from the date of the first confirmed response of PR 
or better until date of first documented PD or death due to MM, whichever occurs first, 
i.e.,:
DOR (day) = Date of first documented PD or MM-related death – Date of the first 
confirmed response (PR or better) + 1
Only subjects who achieved a BOR of PR or better will be included in this analysis.  
Details on event and censoring rules for DOR are provided in Table 2.
 


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Table 2.
Event and Censoring Rules for DOR
Situation
Date of Censor or Event
Outcome
PD/death due to MM occurred not more 
than 12 weeks after the last adequate 
disease assessment
Date of PD/death
Event
PD/death due to MM occurred more than 
12 weeks after the last adequate disease 
assessment
Date of the last adequate disease 
assessment prior to PD/death due to MM
Censored
No PD/no death due to MM
Date of the last adequate assessment
Censored
Start of new anti-MM therapy prior to 
PD/death
Date of the last adequate disease 
assessment prior to start of new anti-MM 
therapy
Censored
Time to Response (TTR)
TTR is defined as the number of days from the date of the first dose of study treatment 
until the date of the first confirmed response of PR or better, i.e.:
TTR (days) = Date of the first confirmed response – Date of the first dose of study 
treatment + 1
Details on event and censoring rules for TTR are provided in Table 3.
Table 3.
Event and Censoring Rules for TTR
Situation
Date of Censor or Event
Outcome
Confirmed response of PR or better
Date of first confirmed response of PR or 
better
Event
No post-baseline assessment
Date of the first dose of study treatment
Censored
No confirmed response of PR or better
Date of the last adequate disease 
assessment
Censored
Start of new anti-MM therapy prior to
first confirmed response of PR or better
Date of the last adequate disease 
assessment prior to start of new anti-MM 
therapy
Censored
 


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Time to Progression (TTP)
TTP is defined as the number of days from the date of the first dose of study treatment 
until the date of first documented PD or death due to MM, whichever occurs first, i.e.,:
TTP (days) = Date of first documented PD or MM-related death – Date of the first dose of 
study treatment + 1
Details on event and censoring rules for TTP are provided in Table 4.
Table 4.
Event and Censoring Rules for TTP
Situation
Date of Censor or Event
Outcome
PD/death due to MM occurred not more 
than 12 weeks after the last adequate 
disease assessment
Date of PD/death
Event
No post-baseline disease assessment
Date of the first dose of study treatment
Censored
PD/death due to MM occurred more than 
12 weeks after last adequate disease 
assessment
Date of the last adequate disease 
assessment prior to PD/death due to MM
Censored
No PD/no death due to MM
Date of the last adequate disease 
assessment
Censored
Start of new anti-MM therapy prior to 
PD/death
Date of the last adequate disease 
assessment prior to start of new anti-MM 
therapy
Censored
Overall Survival (OS):
For a given subject, OS is defined as the number of days from the date of the first dose of 
study treatment to the date of death due to any cause.  
OS (days) = Date of death due to any cause – Date of the first dose of study treatment + 1
If a subject is not known to be died, OS will be censored at the date of last known alive 
date. 
 


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All events of death will be included, regardless the event occurred while the subject was 
still taking study treatment or after the subject discontinued study treatment.
3.2.2
Secondary Patient Reported Outcomes
Mean changes from baseline to each appliable post-baseline visit will be summarized for 
the secondary Patient Reported Outcomes as follows:  
Worst Pain (Brief Pain Inventory – Short Form [BPI-SF])):
For Worst Pain, scores will be computed according to procedures outlined in BPI-SF 
scoring manual, available at https://www.mdanderson.org/documents/Departments-and-
Divisions/Symptom-Research/BPI_UserGuide.pdf.  The patient-reported outcome 
instruments are described in detail in Appendix D.  
Physical Functioning (EORTC QLQ-C30):
For Physical Functioning scale, scores will be computed according to procedures outlined 
in the EORTC QLQ-C30 scoring manual, available at http://groups.eortc.be/qol/manuals.  
The patient-reported outcome instruments are described in detail in Appendix D.  Time to 
deterioration in physical functioning as measured by the physical functioning domain of 
the EORTC QLQ-C30.  Median time to deterioration will be defined as ≥ 10-point 
deterioration in physical functioning score from baseline.
GHS/QoL (EORTC QLQ-C30):
The GHS/QoL scale specific scores will be calculated from the 22 items in EORTC QLQ-
C30 for each subject based on the QLQ-C30 instruction.  Higher scores are indicative of 
better HRQOL.  The QLQ-C30 is described in detail in Appendix D.  Time to 
deterioration in GHS/QoL score as measured by the GHS/QoL domain of the EORTC 
QLQ-C30.  Median time to deterioration will be defined as ≥ 10-point deterioration in 
GHS/QoL score from baseline.
 


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Fatigue (PROMIS Cancer Fatigue SF):
For PROMIS Cancer Fatigue SF 7a, scores will be computed according to the procedures 
outlined in the PROMIS Fatigue scoring manual, available at 
https://www.assessmentcenter.net/Manuals.aspx.  Higher scores are indicative of worse 
levels of fatigue.  The Cancer Fatigue SF is described in detail in Appendix D.  
3.3
Other Efficacy Endpoint(s)
Mean changes from baseline to each appliable post-baseline visit will be summarized for 
the Patient Reported Outcomes as follows
EORTC QLQ-MY20:
For EORTC QLQ-MY20, the endpoints are scores change from baseline.  Scores will be 
summarized for four scales:
●
Future perspective
●
Body image
●
Disease symptoms– overall domain and individual domain items listed below 
○
Bone aches or pain
○
Back pain 
○
Hip pain 
○
Arm or shoulder pain
○
Chest pain
○
Pain increasing with activity
●
Side effects of treatment
Scores for each scale will be computed according to procedures outlined in EORTC QLQ-
MY20 scoring manual, available at 
http://www.eortc.be/qol/files/ScoringInstructions/MY20_summary.pdf and Appendix D.
 


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EQ-5D-5L:
For EQ-5D-5L, the endpoints are scores change from baseline.  Scores will be 
summarized for six scales:
●
Mobility
●
Self-care
●
Usual activities
●
Pain/Discomfort
●
Anxiety/Depression
●
EQ VAS score
Scores for each scale will be computed according to procedures outlined in EQ-5D-5L 
scoring manual, available at https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf. 
Remaining Subscales of BPI-SF and EORTC QLQ-C30
Remaining subscales of BPI-SF are Pain Severity and Pain Interference.  Scores for each 
subscale will be computed according to BPI-SF scoring manual, respectively.  The 
endpoints are score change from baseline.
Remaining subscales of EORTC QLQ-C30 are
●
Role Function
●
Emotional Functioning
●
Cognitive Functioning
●
Social Functioning
●
Fatigue
●
Nausea and Vomiting
●
Pain
●
Dyspnea
 


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●
Insomnia
●
Appetite Loss
●
Constipation
●
Diarrhea
●
Financial Difficulties
Scores for each subscale will be computed according to EORTC QLQ-C30 scoring 
manual, respectively.  
3.4
Safety Endpoint(s)
The following are safety endpoints.
●
Adverse Events (AEs)
●
Serious Adverse Events (SAEs)
●
Deaths
●
Electrocardiography (ECG)
●
Vital signs
●
Laboratory results
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Intent-to-Treat (ITT) population includes all enrolled subjects who received at least 
1 dose of study treatment.  The ITT population will be used for all efficacy and baseline 
analyses.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study 
treatment.  The Safety Analysis Set will be used for all safety analyses.
 


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5.0
Subject Disposition
The total number of subjects who were screened, enrolled, and treated will be 
summarized.  Reasons for exclusion, including screen failure, will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized:
●
Treated subjects
●
Discontinued study treatment
●
Discontinued venetoclax 
●
Discontinued dexamethasone
●
Discontinued from study
●
Ongoing (Treatment, Follow Up)
Number and percentage of subjects who discontinued study treatment (primary and all 
reasons separately for venetoclax and dexamethasone, respectively) and study will be 
summarized. 
6.0
Study Treatment Duration and Compliance
Analyses of study treatment exposure and compliance listed below will be performed for 
study treatment components (venetoclax and dexamethasone) separately on the safety 
analysis set. 
6.1
Exposure to Study Treatment
Duration of study treatment exposure
Duration of study treatment exposure will be calculated as the number of days between 
the start date and end date of study treatment.
Duration of study treatment exposure (days) = date of last dose of study treatment – date 
of first dose of study treatment + 1
 


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For Risk Management Plan:  Patient-years of exposure
Patient-years of exposure is computed as:
Patient-years of exposure (pt-yrs) = Sum of duration of study treatment for all subjects 
(day)/365.25
Duration of study treatment component exposure
Duration of study treatment component exposure will be calculated as the number of days 
between the start date and end dates for each study treatment component 
Duration of study treatment component exposure (days) =
Date of last dose study treatment component – Date of the first dose of study treatment 
component + 1
Cumulative dose
The cumulative dose is defined as the total dose given during the study treatment 
exposure and will be summarized by study treatment component and treatment group.  
For patients who did not take any drug, the cumulative dose is 0.
Dose intensity (DI) and relative dose intensity (RDI)
The following DI or planned DI (PDI) (per protocol) calculations apply for both IV and 
oral dosing.  In the case of IV dosing, the dose was given based on BSA calculation of DI 
or PDI involves BSA in the division.  The RDI will be summarized separately for each 
study treatment component.  
venetoclax and dexamethasone
DI(mg/day) =
Cumulative dose [mg]
∑
Actual duation of cycle c [day]

 !"
where k = total number of cycles.
 


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PDI is defined as follows:
1.
The last cycle length is not shorter than planned cycle length
PDI(mg/day) =
Cumulative planned dose [mg]
∑
Planned duration of cycle c [day]

 !"
2.
The last cycles length is shorter than planned cycle length
PDI(mg/day)
=
Total planned dose for first k −1 cycles [mg]
+ total planned dose for actual duration of the last cycle k
∑
Planned duration of cycle c + Actual duration of the last cycle [day]
,"
 !"
k is the actual total number of cycles.
RDI is defined as 
RDI[%] = DI [mg/day]
PDI [mg/day] × 100
The RDI will be summarized based on data collected on the drug administration eCRF 
pages.  Descriptive statistics, including the mean, standard deviation, median, minimum, 
and maximum will be presented for duration of exposure and RDI.  Number and 
percentage of subjects who have dose reductions or interruptions, as well as their reasons, 
will be provided.  Number of cycles of study treatment received will be provided.  In 
addition, summary statistics of cumulative dose and frequencies for RDI (%) will be 
provided by treatment group for the following categories:
●
0 to < 50%
●
50% to < 70%
●
70% to < 90%
●
90% to < 110%
●
≥ 110%
 


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6.2
Compliance
To assess compliance, a listing of protocol deviations will be given.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT population.  Categorical 
variables will be summarized with the number and percentage of subjects; percentages 
will be calculated based on the number of non-missing observations.  Continuous 
variables will be summarized with descriptive statistics (number of non-missing 
observations, mean and standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic and baseline variables include age, body weight, body height, 
time since diagnosis and number of lines of prior therapy.
Categorical demographic and baseline variables include
●
Sex (Female, Male);
●
Race (White, Black, Asian, American Indian/Alaska Native, Native Hawaiian 
or Other Pacific Islander, Other, Multi Race);
●
Ethnicity (Hispanic or Latino, No Ethnicity);
●
Age (< 40, 40 – < 60, ≥ 60);
●
Type of myeloma (IgG, non-IgG, free light chain);
●
ISS status (I, II, III);
●
t(11;14) status (negative, positive);
●
17P status (deleted, not deleted, undetermined);
●
13Q status (deleted, not deleted, undetermined);
●
Type of myeloma (IgG, non-IgG, free light chain);
●
Prior exposure to proteasome inhibitors (PI) (naive, sensitive, or refractory);
 


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Prior exposure to an immunomodulatory drug (IMiD) (naive, sensitive, or 
refractory);
●
Prior exposure to an anti-CD38 monoclonal antibody (naive, sensitive, or
refractory);
●
Prior allogenic stem cell transplant (yes, no);
●
Prior autologous stem cell transplant (yes, no);
●
Prior bortezomib (yes, no);
●
Bortezomib refractory status (yes, no);
●
Prior lenalidomide (yes, no);
●
Lenalidomide refractory status (yes, no);
●
Lines of prior therapy (< 1, 1 – 3, 4 – 6, 7 – 9, > 9);
●
ECOG Performance Status (grade 0, grade 1, grade 2, grade 3, grade 4).
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized.  The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
treatment.  A concomitant medication is defined as medications (other than study 
treatment) taken after the first dose of any component of study treatment and within 
30 days of the last dose of any component of study treatment.  For summaries of 
concomitant medications, if an incomplete start date was collected for a medication, the 
 


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medication will be assumed to be a concomitant medication unless there is evidence that 
confirms that the medication was not a concomitant medication (e.g., the medication end 
date was prior to the first dose of study treatment).
The number and percentage of subjects taking medications will be summarized by generic 
drug name based on the World Health Organization (WHO) Drug Dictionary for both 
prior and concomitant medications.  The prior MM medications taken by the treatment 
experienced subjects will be summarized separately from other prior medications.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted in the ITT Population.
For time-to-event endpoints, survivorship functions will be estimated by using Kaplan-
Meier product-limit methodology.  Estimated survival curves will be presented.  If 
reached, median time to event and its two-sided 95% confidence interval will be 
presented.
Study Drug and Study Treatment
Study drug:  venetoclax 
Study treatment:  venetoclax + dexamethasone
Study treatment components:
●
venetoclax
●
dexamethasone
Baseline
"Baseline" refers to the last non-missing observation before the first administration of 
study treatment.
 


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Last Adequate Disease Assessment
"Last adequate Disease Assessment" refers to the last evaluable disease response per 
investigator assessment that is not more than 12 weeks after the previous evaluable 
disease response per investigator assessment or prior to the start of new anti-MM therapy. 
8.2
Primary Efficacy Endpoint(s) and Analyses
8.2.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoints are ORR (the proportion of subjects with BOR of sCR, 
CR, VGPR or PR) and ≥ VGPR Rate (the proportion of subjects with BOR of sCR, CR, 
or VGPR) based on IMWG criteria.1
8.2.2
Primary Efficacy Analysis
Point estimates of ORR and VGPR+ rates and 95% confidence intervals using exact 
method will be provided. 
8.3
Secondary Efficacy Analyses
The distribution of PFS, OS, TTR, TTP and DOR will be estimated for all subjects using 
Kaplan-Meier product-limit methodology on the ITT population.  If reached, median time 
to event and a corresponding 95% confidence interval will be estimated.
For PROs, change in score from baseline will be evaluated for the following domains:  
Worst Pain (BPI-SF), Physical Functioning (EORTC QLQ-C30), Fatigue (PROMIS-
Fatigue), and Global Health Status/QoL (EORTC QLQ-C30).
In addition, reason for censoring will be provided for PFS and OS.
8.4
Additional Efficacy Analyses
For PROs, descriptive statistics will be used to summarize change from baseline for 
remaining subscales of BPI-SF, EORTC QLQ-C30, European Organization for Research 
 


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and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 
[EORTC QLQ-MY20], and EQ-5D-5L.
8.5
Efficacy Subgroup Analyses
Subgroup analyses will be performed for the following efficacy endpoints:  ORR and 
VGPR+ rates, PFS, OS, and DOR if there are at least 5 subjects within the subgroup level.
The following subgroups will be analyzed:
●
age (< 65 years or ≥ 65 years);
●
ISS stage (I or II/III);
●
Lines of prior therapy (< 1, 1 – 3, 4 – 6, 7 – 9, > 9) 
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
9.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose 
of study treatment and no more than 30 days after the last dose of study treatment.  Events 
 


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where the onset date is the same as the study treatment start date are assumed to be 
treatment-emergent.  All treatment-emergent AEs will be summarized overall, as well as 
by primary MedDRA SOC and Preferred Term.  The SOCs will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
9.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
venetoclax; 
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
dexamethasone; 
●
Treatment-emergent AEs with NCI-CTCAE toxicity grade 3 or 4;
●
Serious treatment-emergent AEs;
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to venetoclax; 
●
Serious treatment-emergent AEs with a "reasonable possibility" of being 
related to dexamethasone; 
●
Treatment-emergent AEs leading to death;
●
Treatment-emergent AEs leading to venetoclax discontinuation;
●
Treatment-emergent AEs leading to dexamethasone discontinuation;
●
Treatment-emergent AEs leading to venetoclax dose reduction;
●
Treatment-emergent AEs leading to dexamethasone dose reduction;
●
Treatment-emergent AEs leading to venetoclax interruption;
●
Treatment-emergent AEs leading to dexamethasone interruption;
●
All deaths
 


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○
Deaths occurring ≤ 30 days after last dose of study treatment
○
Deaths occurring > 30 days after last dose of study treatment.
9.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Adverse Events by SOC and PT
The following summaries of AEs by SOC and PT will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
venetoclax;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
dexamethasone;
●
Treatment-emergent AEs with NCI-CTCAE toxicity grade 3 or 4.
Adverse Events by SOC/PT and by NCI-CTCAE Toxicity Grade
AEs will also be summarized by SOC/PT and by maximum NCI-CTCAE toxicity grade.  
If a subject has an adverse event with an unknown NCI-CTCAE toxicity grade, then the 
subject will be counted in the category of "unknown," even if the subject has another 
occurrence of the same adverse event with a grade present.  The only exception is if the 
subject has another occurrence of the same AE with the highest grade level (Grade 5).  In 
this case, the subject will be counted under the "Grade 5" category.
Specific adverse events will be counted once for each subject for calculating percentages, 
unless stated otherwise.  In addition, if the same adverse event occurs multiple times 
within a subject, the highest severity and level of relationship to investigational product 
will be reported.
 


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Adverse Events by PT
The following summaries of treatment-emergent AEs tabulated according to PT and 
sorted by decreasing frequency will be generated:
●
Treatment-emergent AEs;
●
Treatment-emergent AEs with a "reasonable possibility" of being related to 
venetoclax; 
●
Treatment-emergent AEs with NCI-CTCAE toxicity grade 3 or 4;
●
Treatment-emergent AEs of Grade 3 or higher with a "reasonable possibility" 
of being related to venetoclax.
9.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Treatment Discontinuation, Dose Reduction, or Dose 
Interruption
The number and percentage of subjects experiencing SAEs (including deaths), SAE with a 
"reasonable possibility" of being related to venetoclax, SAE with "reasonable possibility" 
of being related to dexamethasone and AEs leading to venetoclax discontinuation, dose 
reduction, or dose interruption will be summarized by SOC and PT.
9.2.5
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study treatment in this study, 2) for deaths occurring off 
treatment within 30 days after the last dose of study treatment and 3) for all deaths in this 
study regardless of the number of days after the last dose of study treatment.
9.2.6
Listing of Adverse Events
The following additional summaries of adverse events will be prepared:
●
All serious AEs;
●
Treatment-emergent SAEs;
 


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●
Treatment-emergent AEs with NCI-CTCAE toxicity grade 3 or 4;
●
Treatment-emergent AEs leading to death;
●
Subject deaths occurring ≤ 30 days after last dose of study treatment;
●
Subject deaths occurring > 30 days after last dose of study treatment.
9.2.7
Adverse Events of Special Interest
Adverse events of special interest will be summarized by PT and will be based on 
standardized or company MedDRA queries (SMQs or CMQs).  Detailed information 
about the search criteria are provided in Appendix B.
Listings of AEs of special interest meeting the search criteria will be provided.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study treatment will be excluded.  
The hematology and chemistry laboratory tests defined in the protocol Section 5.3.1.1 
Table 13 will be summarized.
The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study treatment.  Values on Day 1 must also be 
before the time of the first dose of study treatment if time is available.  The same baseline 
value will be used for analyses of the baseline and post-baseline period.
Shift Tables
Changes in laboratory parameters will be tabulated using shift tables.  For hematology and 
chemistry laboratory parameters with NCI CTCAE 4.03 toxicity grade exist, baseline and 
post-baseline values will be assigned a toxicity grade of 0, 1, 2, 3, or 4.  For laboratory 
values either within the normal range or outside the normal range but in the direction 
opposite the test will be classified as grade 0 values. 
 


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The baseline value for clinical laboratory tests will be the last non-missing measurement 
on or before the day of the first dose of study treatment.  The maximum post-baseline NCI 
toxicity grade value is the value with highest NCI toxicity grade collected after the 
first dose of study treatment and within 30 days following the last dose of study treatment.  
If multiple values are collected on the same day, the maximum grade value will be used as 
the value for that day.
For each variable, cross tables will be generated for the number of subjects with baseline 
values of Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, or missing grade, versus 
maximum post-baseline observations of Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, 
missing grade.  All subjects in the safety analysis set will be included in the cross 
tabulation regardless whether baseline or post-baseline measurements are collected.
Assessment of Drug-Induced Liver Injury
The number and percentage of subjects in each treatment group who have at least 
one observed post-baseline value meeting the following criteria will be tabulated
●
Alanine Amino Transferase (ALT) > 3 × Upper Limit Normal (ULN)
●
AST > 3 × ULN
●
AST or ALT > 3 × ULN
●
Total bilirubin value > 2 × ULN
●
ALT or AST > 3 × ULN AND Total bilirubin > 2 × ULN within 72 hours.
A listing of all observed ALT, AST, and total bilirubin values will be generated for 
subjects with an observed value meeting any of these criteria.
Laboratory Assessments for Tumor Lysis Syndrome
To determine if a subject's laboratory values qualify for Tumor Lysis Syndrome (TLS), 
the Howard criteria2 will be assessed.  The Howard definition for laboratory TLS requires 
 


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≥ 2 of the metabolic abnormalities specified in Table 5 post-baseline and within 24 hours 
of each other.
Table 5.
Laboratory Criteria for TLS
Element
Value
Uric Acid
> 476 μmol/L
Potassium
> 6.0 mmol/L
Inorganic Phosphorus
> 1.5 mmol/L
Corrected Calcium
< 1.75 mmol/L
The following summaries of laboratory criteria will be provided:
●
Number and percentage of subjects meeting the definition of laboratory TLS 
(at least two values meeting the criteria in Table 5, occurring within 24 hours 
of each other).
●
Listing of all values for these four analyses for each subject meeting the 
definition of laboratory TLS at least once during treatment.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and body 
temperature will be summarized.
The baseline value for vital signs will be the last measurement on or before the day of the 
first dose of study treatment.  The same baseline value will be used analyses of the 
baseline and post-baseline period.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C).  For each vital sign PCI criterion, the number and percentage of 
subjects who have an on-treatment vital sign value meeting the criteria will be 
summarized.  A post-baseline value must be more extreme than the baseline value to be 
considered a PCS finding.  Listings will be provided to summarize subject-level vital sign 
data for subjects meeting PCI criteria.
 


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10.0
Interim Analyses
There will be no interim analysis.  Final analysis will occur after all enrolled subjects have 
completed the study.  Data will be locked after performing appropriate data cleaning.
10.1
Data Monitoring Committee
This study does not require a separate data monitoring committee (DMC) to review either 
safety or efficacy data. A Safety Review Committee (SRC) will periodically review 
safety data across all studies with venetoclax in MM that do not have a study-specific 
independent monitoring committee. This review committee will be responsible for
periodic, regular reviews to assess the safety of the interventions during the trial. A 
separate charter will be prepared outside of the protocol outlining the SRC member 
responsibilities, frequency of data reviews, and relevant data to be assessed.
11.0
Version History
Table 6.
SAP Version History Summary
Version
Date
Summary
1.0
06 April 2020
Original version
1.1
11 January 2022
Changes from SAP version 1.0

Clarify the description of event and censoring rules of 
PFS in Table 1

Clarify the description of event and censoring rules of 
DOR in Table 2

Specify the analysis TTR to be conducted in the ITT 
population.  Add the description of event and censoring 
rules of TTR in Table 3

Renumber Table 3 to Table 4. Clarify the description of 
event and censoring rules of PFS in Table 4

Define last adequate disease assessment in Section 8.1

Correct minor typos
 


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12.0
References
1.
Kumar, S, Paiva B, Anderson KC, et al.  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma.  Lancet Oncol.  2016;17(8):e328-46.
2.
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.
3.
Cleeland CS.  Pain assessment in cancer.  In Effect of Cancer on Quality of Life.  
Osaba D, editor.  Boca Raton:  CRC Press; 1991:21.
4.
Atkinson TM, Mendoza TR, Sit L, et al.  The brief pain inventory and its "pain at 
its worst in the past 24 hours" item:  clinical trial endpoint considerations.  Pain 
Med.  2010;11(3):337-46.
5.
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
in international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
6.
Cocks K, Cohen D, Wisloff F, et al.  An international field study of the reliability 
and validity of a disease-specific questionnaire module (the QLQ-MY20) in 
assessing the quality of life of patients with multiple myeloma.  Eur J Cancer.  
2007;43(11):1670-8.
7.
Cella D, Yount S, Rothrock N, et al.  The patient-reported outcomes measurement 
information system (PROMIS):  progress of an NIH roadmap cooperative group 
during its first two years.  Med Care.  2007;45 (5 Suppl 1):S3-S11.
8.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
information system initiative.  J Clin Oncol.  2007;25(32):5106-12.
9.
Cella D, Riley W, Stone A, et al.  The patient-reported outcomes measurement 
information system (PROMIS) developed and tested its first wave of adult self-
reported health outcome item banks:  2005-2008.  J Clin Epidemiol.  
2010;63(11):1179-94.
 


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10.
EQ-5D-5L and EQ-5D-VA.  Available from:  http://www.euroqol.org.
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
Definition of Adverse Events of Special Interest Selected Adverse 
Events
Adverse Events of Special Interest (AESI) and Selected Adverse Events will be identified 
using the following search criteria.
Risk
Search Criteria
Tumor Lysis Syndrome (5 searches) -AESI
1)
SMQ 20000219 – "Tumour lysis syndrome" 
(Narrow-scope)
2)
PT terms of "Hyperkalaemia" and "Blood potassium 
increased"
3)
PT terms of "Hyperphosphataemia" and "Blood 
phosphorus increased" 
4)
PT terms of "Hypocalaemia" and "Blood calcium 
decreased"
5)
PT terms of "Hyperuricaemia" and "Blood uric acid 
increased"
Neutropenia – expanded search
Neutropenia CMQ 80000171
Neutropenia
PT terms – "Neutropenia" and "Neutrophil count 
decreased"
Serious Infection
SAEs in the SOC of "Infections and Infestations"
Opportunistic infection
BCL-2 CMQ
Second Primary Malignancy 
SMQ 20000194 – "Malignant tumours" (Narrow) and 
SMQ 20000217 - "Myelodysplastic syndromes" (Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count 
decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count 
decreased"
 


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Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) vital sign findings are described in
Table C.
Table C.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic Blood Pressure
High
Value ≥ 160 mmHg
Diastolic Blood Pressure
High
Value ≥ 100 mmHg
Pulse
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature 
Low
Value < 36°C
High
Value ≥ 38.5°C
 


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Appendix D.
PRO assessments
PRO assessments include:  BPI-SF, EORTC QLQ-C30, EORTC QLC MY20, PROMIS 
Cancer Fatigue SF, and EQ-5D-5L.
BPI-SF
The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or 
intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in 
patients with cancer pain.3  The four pain severity items assess pain at its "worst," "least," 
"average," and "now" (current pain).  For these items, patients are asked to rate their pain 
on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you 
can imagine).  The BPI "worst" pain severity item has been shown to be reliable and valid 
for use as a single item.4  The BPI-SF also includes questions to measure the interference 
of pain in the patient's daily life, including general activity, mood, ability to walk, normal 
work (both outside the home and housework), relationships with other people, sleep, and 
enjoyment of life.  For these items, patients are asked to describe the extent to which pain 
has interfered on an 11-point numeric rating scale with anchors of 0 (does not interfere) to 
10 (completely interferes).
 


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Table D-1.
BPI-SF Scales
Scales
Items
Pain Severity*
BPI2-Pain Right Now
BPI2-Pain at its Least in Last 24 Hours
BPI2-Pain on the Average
BPI2-Pain at its Worst in Last 24 Hours
Pain Interference**
BPI2-Pain Interfered Enjoyment of Life
BPI2-Pain Interfered General Activity
BPI2-Pain Interfered Walking Ability
BPI2-Pain Interfered with Mood
BPI2-Pain Interfered with Normal Work
BPI2-Pain Interfered with Relations
BPI2-Pain Interfered with Sleep
*
Calculated as sum of scores of all 4 items and then dividing by 4.  This gives the Pain Severity score out of 10.
**
Calculated as sum of scores of all 7 items and then dividing by 7.  This gives the Pain Interference score out of 10.
EORTC QLQ-C30
HRQoL, functioning, and symptoms will be assessed with the EORTC-QLQ-C30 
version 3.5  The QLQ-C30 is a 30-item subject self-report questionnaire composed of both 
multi-item and single scales, including five functional scales (physical, role, emotional, 
social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a 
global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial difficulties).  The subjects rate items on a 
four point scale, with 1 as "not at all" and 4 as "very much."  The QLQ-C30 was 
developed and validated for use in a cancer patient population, and its reliability and 
validity is highly consistent across different language cultural groups.  The items and 
scales of the QLQ-C30 are as in Table D-2:
 


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Table D-2.
EORTC QLQ-C30 Scales
Scale
Number of 
Items
Item 
Range
Item 
Numbers
Global Health Status/Quality of Life
Global Health Status/Quality of Life
QL2
2
6
29, 30
Functional Scales
Physical Functioning*
PF2
5
3
1 – 5
Role Function*
RF2
2
3
6 – 7
Emotional Functioning*
EF
4
3
21 – 24
Cognitive Functioning*
CF
2
3
20, 25
Social Functioning*
SF
2
3
26 – 27
Symptom Scales
Fatigue
FA
3
3
10, 12, 18
Nausea and Vomiting
NV
2
3
14, 15
Pain
PA
2
3
9, 19
Dyspnoea
DY
1
3
8
Insomnia
SL
1
3
11
Appetite Loss
AP
1
3
13
Constipation
CO
1
3
10
Diarrhoea
DI
1
3
17
Financial Difficulties
FI
1
3
28
*
Function Scales.
Note:
Item range is the difference between the possible maximum and the minimum response to individual items.
Scoring algorithms for scales are as follows:
For all Scales, the Raw Score (RS) is the mean of the component items (I):
If items I1, I2..., In are included in a scale, the procedures are as follows:
Raw Score (RS) = (I1 + I2 + ... + In)/(number of non-missing items),
Then the Functional Scales:
Score = (1 - (RS - 1)/range) × 100
 


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where range is provided in Table 13.
For example, to calculate Emotional Functioning (EF),
RSEF = (I21 + I22 + I23 + I24)/4
ScoreEF = (1 - (RSEF - 1)/3) × 100
If a subject completed more than 50% of the items in a scale, then the raw score of that 
subject will contribute to the summary statistics of that scale.  If a subject completed less 
than 50% of the items in a scale, then the raw score of that subject will be dropped from 
the calculation of the summary statistics of that scale.
EORTC QLQ-MY20
The EORTC QLQ-MY20 was developed as an additional module for the QLQ-C30 and is 
composed of 20 items specific to multiple myeloma.6 The QLQ-MY20 includes scales 
for disease symptoms, side effects of treatment, future perspective, and body image.  
Values for each scale range from 0 to 100.  The subjects rate items on a four-point scale, 
with 1 as "not at all" and 4 as "very much."  The QLQ-MY20 is a reliable and valid 
instrument for measuring quality of life in myeloma patients.
Table D-3.
QLQ-MY20 scales
Scale
Number 
of Items
Item 
Range
QLQ-MY20 Item 
Numbers
Functional Scales/items
Future perspective
MYFP
3
3
18 - 20
Body image
MYBI
1
3
17
Symptom Scales
Disease symptoms
MYDS
6
3
1 - 6
Side effects of treatment
MYSE
10
3
7 - 16
 


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PROMIS Cancer Fatigue SF
The PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.7  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Cancer Fatigue SF that has been developed 
for use in oncology populations.8,9  PROMIS Cancer Fatigue SF is a seven item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days.  All 
questions employ the following five response options:  1 = Not at all, 2 = A little bit, 
3 = Somewhat, 4 = Quite a bit, and 5 = Very much.  The score is calculated as below:
Score = Sum of score from all questions × 7/Total number of answered questions
If 4 or more questions were not being answered, then the score is considered as missing.  
The details of scoring method can be found in the scoring manual 
https://www.assessmentcenter.net/documents/PROMIS%20Fatigue%20Scoring%20Manu
al.pdf.
EQ-5D-5L
The EQ-5D-5L is a generic preference instrument that has been validated in numerous 
populations.10  The EQ-5D-5L has five dimensions:  mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression.  These dimensions are measured on a five level 
scale:  no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.  Detailed EQ-5D-5L scoring method can be found at 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf.
 


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1.0
Title Page
Statistical Analysis Plan — Phase 1 Subjects
Study M13-367
A Phase 1/2 Study Evaluating the Safety and 
Pharmacokinetics of ABT-199 in Subjects with 
Relapsed or Refractory Multiple Myeloma
Date:  20 Sep 2018
Version 1.0
 


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Background.................................................................5
4.1
Objectives .............................................................................................. 5
4.1.1
Primary Objectives................................................................................. 5
4.1.2
Secondary Objectives ............................................................................. 5
4.1.3
Exploratory Objectives........................................................................... 6
4.2
Study Design.......................................................................................... 6
4.3
Endpoints ............................................................................................... 7
4.3.1
Safety Endpoints .................................................................................... 7
4.3.2
Efficacy Endpoints ................................................................................. 7
4.3.2.1
Disease Progression Definition and Confirmation................................... 7
4.3.2.2
Response Rates....................................................................................... 7
4.3.2.2.1
Overall Response Rate (ORR)................................................................ 8
4.3.2.2.2
Very Good Partial Response or Better Rate (≥ VGPR Rate) ................... 8
4.3.2.3
Time to Event Endpoints ........................................................................ 8
4.3.2.3.1
Time to Progression (TTP) ..................................................................... 8
4.3.2.3.2
Time to Response (TTR) ........................................................................ 9
4.3.2.3.3
Duration of Response (DOR).................................................................. 9
4.3.2.4
Exploratory Efficacy Endpoint:  Minimal Residual Disease 
(MRD) Negativity Rate .......................................................................... 9
5.0
Analysis Population and Subgroup Reporting ..................10
5.1
Analysis Population.............................................................................. 10
5.2
Subgroup Reporting ............................................................................. 10
6.0
Analysis Conventions ..........................................................12
6.1
Definition of Study Drug...................................................................... 12
6.2
Definition of Baseline........................................................................... 12
6.3
Definition of Final Observation ............................................................ 12
6.3.1
Definition of Date of Last Contact........................................................ 13
 


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6.4
Definition of Study Rx Days (Days Relative to the First Dose of 
Study Treatment).................................................................................. 13
6.5
Definition of Analysis Windows........................................................... 14
7.0
Subject Disposition..............................................................14
8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............15
8.1
Demographic and Baseline Characteristics ........................................... 15
8.1.1
Categorical Demographic Characteristics ............................................. 15
8.1.2
Continuous Demographic Characteristics ............................................. 16
8.2
Study Drug Exposure ........................................................................... 16
8.3
Medical History.................................................................................... 17
8.4
Prior/Concomitant Medications and Prior Multiple Myeloma 
Therapies.............................................................................................. 17
8.4.1
Concomitant Medications..................................................................... 17
8.4.2
Prior medication................................................................................... 18
8.5
Compliance .......................................................................................... 18
9.0
Safety Analysis.....................................................................18
9.1
General Considerations......................................................................... 18
9.2
Analysis of Adverse Events.................................................................. 19
9.2.1
Treatment-Emergent Adverse Events (TEAEs)..................................... 19
9.2.2
Serious Adverse Events........................................................................ 21
9.2.3
Deaths .................................................................................................. 22
9.2.4
Non-Treatment-Emergent Adverse Events............................................ 22
9.3
Analysis of Laboratory and Vital Signs ................................................ 22
9.3.1
Longitudinal Analyses of Laboratory and Vital Signs Data................... 22
9.3.2
Analyses of Laboratory Data Using NCI CTCAE................................. 23
9.3.3
Laboratory Search Strategy for TLS ..................................................... 24
9.3.4
Assessment of Drug-Induced Liver Injury ............................................ 24
9.4
Analysis of Vital Signs......................................................................... 24
9.4.1
Potentially Clinically Significant Values............................................... 24
9.4.2
Mean Change from Baseline................................................................. 24
9.5
Analysis of ECG Parameters ................................................................ 25
10.0
Efficacy Analysis .................................................................25
 


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10.1
Response Rates..................................................................................... 25
10.2
Time to Event Endpoints ...................................................................... 26
11.0
Pharmacokinetic Analysis...................................................26
11.1
Tabulations and Summary Statistics ..................................................... 26
11.2
Model and Test..................................................................................... 27
11.3
Missing Values and Model Violations .................................................. 28
12.0
References............................................................................28
13.0
Appendix..............................................................................29
13.1
IMWG 20111-3 Response Criteria ......................................................... 29
List of Tables
Table 1.
Event and Censoring Rules for TTP........................................................ 8
Table 2.
Event and Censoring Rules for DOR ...................................................... 9
Table 3.
Search Criteria for Selected Adverse Events......................................... 21
Table 4.
Time Windows for Analysis of Laboratory and Vital Signs 
Parameters – Phase 1 Monotherapy Subjects ........................................ 32
Table 5.
Time Windows for Analysis of Laboratory and Vital Signs 
Parameters – Phase 1 VenDex Combination Subjects ........................... 33
Table 6.
Clinical Laboratory Tests – Phase 1 Portion ......................................... 34
Table 7.
Definitions of Laboratory Tumor Lysis Syndrome (TLS) ..................... 34
Table 8.
Criteria for Potentially Clinically Significant Vital Signs 
Parameters............................................................................................ 35
List of Figures
Figure 1.
Overall Study Design ............................................................................. 6
 


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3.0
Introduction
This statistical analysis plan (SAP) provides details on the planning, analysis, and 
reporting of demographics, efficacy, and safety in venetoclax (ABT-199) Study M13-367.
Unless noted otherwise, all analyses will be performed using SAS version 9.4 or later 
(SAS Institute Inc., Cary, NC 27513) under the Unix operating system.
This SAP only pertains to the Phase 1 portion of Study M13-367, which includes the dose 
escalation, safety expansion, and venetoclax + dexamethasone (VenDex) combination 
cohorts.  The analyses for the Phase 2 portion of Study M13-367 will be documented in a 
separate SAP.
4.0
Study Background
4.1
Objectives
4.1.1
Primary Objectives
The primary objectives are to assess the safety profile, characterize pharmacokinetics 
(PK), determine the dosing schedule, the maximum tolerated dose (MTD), and the 
recommended Phase 2 dose (RPTD) of venetoclax monotherapy when administered in 
subjects with relapsed or refractory multiple myeloma (MM).  This study will also assess 
the safety profile and PK of VenDex in subjects with t(11;14)-positive MM.
4.1.2
Secondary Objectives
The secondary objectives are to evaluate the preliminary efficacy data regarding the effect 
of venetoclax monotherapy or combined with dexamethasone in regard to overall 
response rate (ORR), time to response (TTR), time to disease progression (TTP), and 
duration of response (DOR).
 


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4.1.3
Exploratory Objectives
The exploratory objectives are to evaluate pharmacodynamic and predictive biomarkers 
for associations with PK, safety, and efficacy.  Additionally, minimal residual disease 
(MRD) will be assessed in the bone marrow by next generation sequencing (NGS).
4.2
Study Design
This is a Phase 1/2, open-label, multicenter dose escalation and expansion study. 
Phase 1 includes the following cohorts utilizing a 3 + 3 design:
●
Dose escalation (venetoclax monotherapy, 30 subjects)
○
300 mg (6 subjects)
○
600 mg (9 subjects)
○
900 mg (6 subjects)
○
1200 mg (9 subjects)
●
Safety expansion (venetoclax monotherapy, 36 subjects at designated cohort 
dose of 1200 mg)
●
VenDex combination (800 mg venetoclax + 40 or 20 mg dexamethasone, 
20 subjects, positive for t(11;14))
Figure 1.
Overall Study Design
See protocol for information on dosing schedules.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Disease assessments will be based on the International Uniform Response Criteria for 
Multiple Myeloma (IMWG, 2011), per investigator assessment.  See Appendix 13.1 for 
complete details.
4.3
Endpoints
4.3.1
Safety Endpoints
Safety endpoints include:
●
Adverse events (AE)
●
Serious adverse events (SAE)
●
Deaths
●
Electrocardiography (ECG, MUGA)
●
Vital sign parameters
●
Laboratory assessments
4.3.2
Efficacy Endpoints
4.3.2.1
Disease Progression Definition and Confirmation
Disease progression (PD) is defined as satisfying at least one of the following:
●
PD due to imaging (new lesion, increase in lesion size, etc.)
●
Clinical PD
●
Per IMWG PD (non-imaging) that is confirmed by a consecutive assessment
4.3.2.2
Response Rates
We will report the best overall response a subject experienced before discontinuation due 
to any reason (PD, death, etc.).  All responses must be confirmed by a subsequent visit, 
with the exception of SD, which is confirmed by the baseline assessment.  Responses 
occurring after the start of a new line of anti-MM therapy will not be considered.
 


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4.3.2.2.1
Overall Response Rate (ORR)
ORR is defined as the proportion of subjects who experienced a response of PR or better.  
In particular, this includes subjects with a best overall response of PR, VGPR, CR, or 
sCR.
4.3.2.2.2
Very Good Partial Response or Better Rate (≥ VGPR Rate)
≥ VGPR rate is defined as the proportion of subjects who experienced a response of 
VGPR or better.  In particular, this includes subjects with a response of VGPR, CR, or 
sCR.
4.3.2.3
Time to Event Endpoints
4.3.2.3.1
Time to Progression (TTP)
TTP is defined as the number of days from the date of first dose until the date of PD or 
death due to MM, whichever occurs first, i.e.,:
TTP (days) = PD or MM-related death date – date of first dose + 1
Table 1.
Event and Censoring Rules for TTP
Situation
Date of Censor or Event
Outcome
PD/death due to MM
PD/death date
Event
No adequate baseline and/or 
post-baseline disease assessment
Date of first dose
Censored
PD/death due to MM more than 
12 weeks after last adequate 
disease assessment
Last adequate disease assessment date
Censored
No PD/no death due to MM
Last adequate disease assessment date
Censored
Start of new anti-MM therapy 
prior to PD/death
Last adequate disease assessment date prior 
to start of new anti-MM therapy
Censored
 


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4.3.2.3.2
Time to Response (TTR)
TTR is defined as the number of days from the date of first dose until the date of 
first response of PR or better, i.e.,:
TTR (days) = date of first response – date of first dose + 1
Only subjects who achieved a response (PR or better) will be included in this analysis.
4.3.2.3.3
Duration of Response (DOR)
DOR is defined as the number of days from the date of first response of PR or better until 
date of PD or death due to MM, whichever occurs first, i.e.,:
DOR (day) = PD or MM-related death date – date of first response (PR or better) + 1
Only subjects who achieved a response of PR or better will be included in this analysis.
Table 2.
Event and Censoring Rules for DOR
Situation
Date of Censor or Event
Outcome
PD/death due to MM
PD/death date
Event
PD/death due to MM more than 
12 weeks after last adequate 
disease assessment
Last adequate disease assessment date
Censored
No PD/no death due to MM
Last adequate disease assessment date
Censored
Start of new anti-MM therapy 
prior to PD/death
Last adequate disease assessment date 
prior to start of new anti-MM therapy
Censored
4.3.2.4
Exploratory Efficacy Endpoint:  Minimal Residual Disease 
(MRD) Negativity Rate
MRD negativity rate is defined as the proportion of subjects who have negative MRD by 
bone marrow aspirate at any time point after receiving their first dose of study drug.  
MRD negativity will be defined at the 10–4, 10–5, and 10–6 thresholds (less than 
one residual myeloma cell per 104, 105, and 106 total nucleated cells, respectively) as 
 


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measured by centralized testing of bone marrow aspirate by next generation sequencing 
(NGS).  Subjects who were dosed but have missing or indeterminate MRD status per 
given threshold will be considered as positive for the calculation of MRD negativity 
status.
5.0
Analysis Population and Subgroup Reporting
5.1
Analysis Population
Unless otherwise specified, all analyses will be performed using all subjects who received 
at least one dose of study drug.
One notable exception is that any reporting of dexamethasone related information (i.e., 
AEs related to dexamethasone, subject dexamethasone discontinuation, etc.) will be 
inherently relevant to only the VenDex treated subjects.
5.2
Subgroup Reporting
●
Response rates (including ORR and ≥ VGPR rate) will be summarized for the 
following groups, where sufficient data is available:
○
All monotherapy subjects
○
300 mg venetoclax monotherapy cohort
○
600 mg venetoclax monotherapy cohort
○
900 mg venetoclax monotherapy cohort
○
1200 mg venetoclax monotherapy and safety expansion cohorts
○
Venetoclax monotherapy subjects with t(11;14)
○
Venetoclax monotherapy subjects that are non-t(11;14) 
○
VenDex combination subjects
○
All subjects
○
t(11;14) subjects, by dosing cohort:
a.
300 mg venetoclax monotherapy t(11;14) subjects
b. 600 mg venetoclax monotherapy t(11;14) subjects
 


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c.
900 mg venetoclax monotherapy t(11;14) subjects
d. 1200 mg venetoclax monotherapy and safety expansion t(11;14) 
subjects
e.
All t(11;14) subjects
○
t(11;14) subjects, by therapy and BCL-2 status:
a.
BCL2 high subjects with t(11;14) on monotherapy
b. BCL2 low subjects with t(11;14) on monotherapy
c.
BCL2:BCL2L1 ratio high subjects with t(11;14) on monotherapy
d. BCL2:BCL2L1 ratio low subjects with t(11;14) on monotherapy
e.
BCL2 high subjects in the VenDex combination cohort
f.
BCL2 low subjects in the VenDex combination cohort
g. BCL2:BCL2L1 ratio high subjects in VenDex combination cohort
h. BCL2:BCL2L1 ratio low subjects in VenDex combination cohort
●
Time to event endpoints (TTP, TTR, and DOR) will be summarized for the 
following groups:
○
All monotherapy subjects
○
Venetoclax monotherapy subjects with t(11;14)
○
Venetoclax monotherapy subjects that are non-t(11;14)
○
VenDex combination subjects
○
All subjects
●
MRD negativity rate will be reported for the following groups:
1.
All subjects
2.
Subjects who achieved a response of CR or better.
●
All other reporting (demographics, safety, listings, etc.,) will be broken down 
into the following groups:
○
300 mg venetoclax monotherapy
○
600 mg venetoclax monotherapy
○
900 mg venetoclax monotherapy
 


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○
1200 mg venetoclax monotherapy
○
Safety expansion subjects (venetoclax monotherapy)
○
Dose escalation subjects (venetoclax 1200 mg monotherapy)
○
All subjects on venetoclax monotherapy
○
VenDex combination subjects
○
All subjects
6.0
Analysis Conventions
6.1
Definition of Study Drug
Subjects who took at least one dose of study drug will be included all analyses.
For the monotherapy cohort subjects, study drug is defined as venetoclax whereas for the 
combination VEN + DEX subjects, study drug is defined as either venetoclax or 
dexamethasone. 
Study drug discontinuation is defined as the last dose of study drug.
6.2
Definition of Baseline
For all analyses where baseline values are used, baseline refers to the last non-missing 
observation collected on or prior to the date of first dose of study drug.  If there was a 
measurement collected on the day of the first dose of study drug, if there was no time 
collected, it is assumed this measurement was collected before the first dose of study 
drug.
6.3
Definition of Final Observation
The final observation will be defined as the last non-missing observation collected after 
baseline and less than or equal to 30 days after the last dose of study drug.
 


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6.3.1
Definition of Date of Last Contact
The date of last contact will be derived from the following list of data panels:
●
Vital signs
●
Physical exam
●
Lab variables, including SAE lab reports
●
ECOG performance status
●
Study drug administration
●
IMWG assessments
●
Transfusions
●
Electrocardiogram 
●
Adverse event
●
Concomitant Medication
●
Laboratory sample collection (e.g., PK, biomarker) 
●
Clinical disease progression assessments
The data panels with the last recorded date will be considered the date of last contact.
6.4
Definition of Study Rx Days (Days Relative to the First Dose 
of Study Treatment)
Rx Days will be calculated for each time point relative to the first dose of study drug.  
They will be defined as the number of days between the day of the first dose of study drug 
and the specific time point.  Different distinctions of Rx days are displayed below.
●
Rx days will be negative values when the time point of interest is prior to the 
first study drug dose day.  
●
Rx days will be positive values when the time point of interest is on or after 
the first study drug dose day.  
●
The day of the first dose of study drug is defined as Rx Day 1, while the day 
prior to the first study drug dose is defined as Rx Day –1 (there is no Rx 
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6.5
Definition of Analysis Windows
Analysis time windows are given in Table 4 and Table 5 and will be constructed using the 
following algorithm:
●
Determine the nominal Study Rx Day for each scheduled visit
●
Determine the window around the specific nominal Study Rx Day as in
Table 4 and Table 5
●
If more than one assessment is included in a time window, the assessment 
closest to the nominal day will be used.  If there are two observations of equal 
distance to the nominal day, the latest one will be used
●
If more than one post-baseline measurement exists for a subject on a particular 
day, an arithmetic average is calculated and used as the subject's measurement 
for that day.  For laboratory shift tables, the CTC grade will be assigned based 
on all observed laboratory values and no averages will be taken
●
One cycle is defined as 21 days
7.0
Subject Disposition
A listing will be provided for the subjects who:
●
Screen failed
●
Enrolled, but were not treated
A summary will be provided for the number and percentage of subjects who:
●
Discontinued venetoclax for any by and primary reason
●
Discontinued dexamethasone for any by and primary reason
●
Discontinued the study for any and by primary reason (for subjects in the 
monotherapy portion of the trial, subjects who discontinue venetoclax also 
discontinue the study)
●
Are active/ongoing
 


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8.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
8.1
Demographic and Baseline Characteristics
8.1.1
Categorical Demographic Characteristics
Categorical demographic characteristics will be summarized by the frequency and 
percentage (calculated using non-missing values) of subjects.  The following categorical 
demographic characteristics will be reported:
●
Sex (Female, Male)
●
Race (White, Black, Asian, American Indian/Alaska Native, Native Hawaiian 
or Other Pacific Islander, Other, Multi Race)
●
Ethnicity (Hispanic or Latino, No Ethnicity)
●
Age (< 40, 40 – < 60, ≥ 60)
●
Type of myeloma (IgG, non-IgG, free light chain)
●
ISS status (I, II, III)
●
t(11;14) status (negative, positive)
●
t(4;14) status (negative, positive)
●
t(14;16) status (negative, positive)
●
17P status (deleted, not deleted, undetermined)
●
13Q status (deleted, not deleted, undetermined)
●
Chromosomal Abnormality (CA) risk by FISH (High/Standard)
○
High risk subjects include those that are t(4;14) positive OR t(14;16) 
positive OR 17p13 deleted
○
Standard risk subjects include those that are t(4;14) negative AND t(14;16) 
negative AND 17p13 not deleted 
○
Subjects with missing or indeterminate t(4;14), t(14;16), or 17p13 status 
are unable to be categorized by CA risk, and are considered missing
●
Prior allogenic stem cell transplant (yes, no)
●
Prior autologous stem cell transplant (yes, no)
 


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●
Prior bortezomib (yes, no)
●
Bortezomib refractory status (yes, no)
●
Prior lenalidomide (yes, no)
●
Lenalidomide refractory status (yes, no)
●
Lines of prior therapy (< 1, 1 – 3, 4 – 6, 7 – 9, > 9)
●
ECOG Performance Status (GRADE 0, GRADE 1, GRADE 2, GRADE 3, 
GRADE 4)
8.1.2
Continuous Demographic Characteristics
Continuous demographic characteristics will be summarized by sample size, mean, 
standard deviation, median, minimum, and maximum values, which will be calculated 
using only the non-missing observations.  The following continuous demographic 
characteristics will be reported:
●
Age
●
Weight
●
Weight – female
●
Weight – male
●
Height
8.2
Study Drug Exposure
Duration of exposure to study drug will be defined for each subject as (last study drug 
dose date – first study drug dose date) + 1 and will be summarized by sample size, mean, 
standard deviation, median, minimum and maximum.  The number and percentage of 
subjects exposed to study drug will be summarized for the following durations:  0 to 
1 cycle, > 1 cycle to 2 cycles, > 2 cycles to 3 cycles, > 3 cycles to 4 cycles, > 4 cycles to 
5 cycles, > 5 cycles to 6 cycles, and > 6 cycles. 
 


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8.3
Medical History
Medical history and ongoing conditions, including MM-related conditions and symptoms 
will be summarized and listed.  Separate summaries will be presented for ongoing and 
historical medical conditions.  The summaries will be presented by primary system organ 
class and preferred term.  Medical history/current medical conditions are coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
The body systems will be presented in alphabetical order and the conditions/diagnoses 
will be presented in alphabetical order within each body system.  Subjects reporting more 
than one condition/diagnosis within a body system will be counted only once for that 
body system.
8.4
Prior/Concomitant Medications and Prior Multiple Myeloma 
Therapies
8.4.1
Concomitant Medications
●
Definition:  Concomitant medications are defined as medications (other than 
study treatment) taken after the first dose of study drug and within 30 days of 
the last dose of study drug that (1) was started prior to the first dose of study 
drug and continued to be taken after the first dose of study drug or (2) was 
started after the first dose of study drug, but was not started 30 days after the 
last dose of study drug.  Concomitant medications will be reported by generic 
name assigned by the World Health Organization (WHO) dictionary.
●
Analysis:  The number and percentage of subjects who take at least 
one concomitant medication will be summarized.  For each specific 
concomitant medication, the number and percentage of subjects who take at 
least one dose of this medication will also be summarized.  For summaries of 
concomitant medications, if an incomplete start date was collected for a 
medication, the medication will be assumed to be a concomitant medication 
unless there is evidence that confirms that the medication was not a 
concomitant medication (i.e., if the medication end date was prior to the 
first dose of study drug).
 


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8.4.2
Prior medication
●
Definition:  A prior medication (also identified as prior therapy) will be 
defined as any medication taken with an end date prior to the first dose of 
study drug.  
●
Analysis:  The number and percentage of subjects who take at least one prior 
medication will be summarized.  For each specific prior medication, the 
number and percentage of subjects who take at least one dose of this 
medication will also be summarized.  The frequency and percentage of 
subjects who have prior multiple myeloma therapies will be summarized by 
regimen names.  In addition, the best response to any therapies prior to 
first dose of study drug will be summarized.
8.5
Compliance
To assess compliance, a listing of protocol deviations will be given.
9.0
Safety Analysis
9.1
General Considerations
For basophils, eosinophils, lymphocytes, monocytes, neutrophils and reticulocytes, 
reporting in tables will be done only for absolute values.  If sites have provided only a % 
and no absolute value, conversion from % to absolute will be performed according to the 
following formulas:
●
Basophils [absolute value] = basophils [%] • leukocytes [absolute value], same 
for eosinophils, lymphocytes, monocytes, and neutrophils
●
Reticulocytes [absolute value] = reticulocytes • erythrocytes [absolute value]
Reference intervals for absolute values will be used (i.e., reference intervals will not be 
converted).
 


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For urea, reporting in tables will be done only as blood urea nitrogen (BUN).  In case sites 
have provided only a urea value and no BUN value, conversion from Urea to BUN will be 
performed according to the following formula:
●
BUN [mmol/L] = urea [mmol/l]/2.14
9.2
Analysis of Adverse Events
Adverse event intensity and laboratory evaluation changes will be assessed using National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0.
9.2.1
Treatment-Emergent Adverse Events (TEAEs)
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug or increases severity after 
the first dose of study drug.  Analyses will not include those that have an onset greater 
than 30 days after last dose of study drug.  Events where the onset date was the same as 
the study drug start date will be assumed to be treatment-emergent, unless the study drug 
start time and the AE start time are collected and the AE start time is prior to the study 
drug start time.  If an incomplete onset date is collected for an AE, the AE will be 
assumed to be treatment-emergent unless there is evidence that confirms that the AE was 
not treatment-emergent (e.g., the AE end date is prior to the date of the first dose of study 
drug). 
Treatment-emergent adverse events will be summarized by preferred term (PT) within a 
system organ class (SOC) according to the MedDRA dictionary.  Subjects reporting more 
than one AE within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one AE for a PT will be counted only once for that PT.  For summaries of 
TEAEs by the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) grade, at each level of summation (overall, SOC, and PT) each 
subject is counted only once at the maximum grade level.  The possible grade levels are 
1 – 5, and unknown.  If a subject had an AE with unknown grade, then the subject will be 
 


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counted in the grade category of "unknown," even if the subject had another occurrence of 
the same event with a grade present.  The only exception is if the subject had another 
occurrence of the same AE with a grade of 3, 4 or 5.  In this case, the subject will be 
counted under the grade 3, 4 or 5 category based on the maximum grade level reported.
The number and percentage of subjects experiencing at least one TEAE will be further 
summarized by assigned venetoclax dose and overall as follows:
●
Any TEAE
●
Any TEAE occurring in at least 5% of subjects in any venetoclax dose level
●
Any TEAE with NCI CTCAE toxicity grade 3, 4 or 5
●
Any TEAE with NCI CTCAE toxicity grade 3 or 4
●
Any TEAE broken down by maximum NCI CTCAE toxicity grade (severity)
●
Any TEAE with reasonable possibility of related to venetoclax by the 
investigator
●
Any TEAE with reasonable possibility of related to dexamethasone by the 
investigator
●
Any TEAE with NCI CTCAE toxicity grade 3, 4, or 5 and reasonable 
possibility of related to venetoclax by the investigator
●
Any TEAE with NCI CTCAE toxicity grade 3, 4, or 5 and reasonable 
possibility of related to dexamethasone by the investigator
●
Any TEAE leading to discontinuation of venetoclax
●
Any TEAE leading to discontinuation of dexamethasone
●
Any TEAE leading to discontinuation of venetoclax not related to progression
●
Any TEAE leading to discontinuation of dexamethasone not related to 
progression
●
Any TEAE leading to Venetoclax dose interruption
●
Any TEAE leading to dexamethasone dose interruption
●
Any TEAE leading to Venetoclax dose reduction
●
Any TEAE leading to dexamethasone dose reduction
●
Any TEAE leading to Dose limiting toxicities
 


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Except for the discontinuation, interruption, reduction, and DLT AE summaries, the above 
tables will also be summarized by SOC and PT in descending order.
Table 3.
Search Criteria for Selected Adverse Events
Risk
Search Criteria
Tumor Lysis Syndrome 
SMQ – "Tumour lysis syndrome" (Narrow-scope)
Neutropenia
PT terms – "Neutropenia," "Neutrophil count decreased," "Febrile 
neutropenia," "Agranulocytosis," "Neutropenic infection," and 
"Neutropenic sepsis"
Serious Infection
SAEs in the SOC of "Infections and Infestations"
Second Primary Malignancy 
SMQ – "Malignant tumours" (Narrow) and "Myelodysplastic 
syndromes" (Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count decreased"
Drug Induced Liver Injury (DILI)
SMQ – "Drug related hepatic disorders – comprehensive search"
Peripheral Neuropathy
Peripheral Neuropathy SMQ – "narrow"
Sepsis 
PTs including the word 'sepsis' + PT 'septic shock'
Serious Opportunistic infections
SAEs in the Opportunistic infection CMQ (BCL-2 inhibitor 
product specific)
An AE overview and a summary by PT will be provided for each selected AE search in 
the table above by assigned venetoclax dose and overall.  In addition, a listing of events in 
each AE search will be provided.
9.2.2
Serious Adverse Events
Serious adverse events will be summarized by PT within an SOC according to the 
MedDRA dictionary.  The number and percentage of subjects experiencing at least one 
TEAE will be further summarized by assigned Venetoclax dose and overall as follows:
●
Any treatment-emergent serious adverse event (SAE).
●
Any SAE with reasonable possibility of related to venetoclax by the 
investigator.
 


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●
Any SAE with reasonable possibility of related to dexamethasone by the 
investigator.
9.2.3
Deaths
The number and percentage of subject deaths will be summarized (1) for all deaths in this 
study regardless of the number of days after the last dose of study drug, and (2) for deaths 
occurring within 30 days of the last dose of study drug.  Listings of subject deaths will be 
provided (1) for deaths occurring within 30 days of the last dose of study drug, and (2) for 
deaths occurring more than 30 days after the last dose of last study drug.
9.2.4
Non-Treatment-Emergent Adverse Events
The serious and non-serious adverse events occurring after the study-specific informed 
consent is signed but prior to the first dose of the investigational product considered to be 
causally related to study required procedures will be summarized for all dosed Phase 1 
subjects.
9.3
Analysis of Laboratory and Vital Signs
9.3.1
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and time 
point as well as for the final visit for blood chemistry and hematology parameters 
specified in Table 6.  If more than one measurement exists for a subject on a particular 
day and time point, then an arithmetic average will be calculated.  This average will be 
considered to be that subject's measurement for that day and time point.  Post-baseline 
measurements more than 30 days after last study drug will not be included.  Subjects that 
do not have a baseline measurement or do not have any post-baseline measurements will 
not be included.
If there are lab duplicates identified (same subject, visit, date, and time of collection) 
between the central (Covance) and the local lab (EDC-RAVE), we will utilize the central 
lab over the local lab (EDC-RAVE data) as opposed to taking the average.
 


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Mean changes from baseline at each scheduled post-baseline visit and time point as well 
as at Final Visit will be summarized with the baseline mean, visit mean, change from 
baseline mean, standard deviation, and median.
Laboratory tests to be summarized are included in Table 6.
9.3.2
Analyses of Laboratory Data Using NCI CTCAE
The maximum NCI CTCAE toxicity grade value will be the value with the highest NCI 
CTCAE toxicity grade collected after the first dose of study drug and within 30 days 
following last dose of study drug.  In cases where multiple values are collected on the 
same day, the maximum grade value will be selected as the value for that day.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after last dose of study drug will be included in these 
listings.
For shifts related to National Cancer Institute Common Toxicity Criteria (NCI CTC), 
baseline and post-baseline laboratory observations will be categorized as grade 0, grade 1, 
grade 2, grade 3, or grade 4, or given no grade according to NCI CTC grade version 4.0.  
For each parameter, shift tables will be generated that cross tabulate the number of subject 
with baseline values of no grade, grade 1, grade 2, grade 3, or grade 4 versus final 
observations of no grade, grade 1, grade 2, grade 3, or grade 4.  Additionally, for each 
parameter, the number and percentage of subjects that have a baseline observation with no 
grade or a baseline observation that is categorized as a grade 0, grade 1, grade 2, and that 
also have a grade 3 or 4 final observation will be presented.  For a laboratory parameter 
for which grading is performed separately for low and high values, a separate summary 
will be presented for each grading scale.  In addition to final observation, a similar set of 
summaries will be produced for the minimum or maximum post-baseline laboratory 
observations, as appropriate for the grading scale. 
 


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9.3.3
Laboratory Search Strategy for TLS
To determine if a subject's laboratory values qualify for TLS, the Howard criteria will be 
assessed.  The Howard criteria for TLS comprises ≥ 2 of the electrolyte abnormalities 
within 24 hours of each other and are specified in Table 7.  The number and percentage of 
subject having laboratory values qualify for TLS will be summarized.  A listing of such 
subjects will be generated.
9.3.4
Assessment of Drug-Induced Liver Injury
The number and percentage of subjects who have at least one observed post-baseline 
value meeting the following criteria will be tabulated by dose and overall:  ALT > 
3 × ULN, AST > 3 × ULN, AST or ALT > 3 × ULN, total bilirubin value > 2 × ULN, 
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN within 24 hours.  A listing of all 
observed ALT, AST, and total bilirubin values will be generated for subjects with an 
observed value meeting any of these criteria.
9.4
Analysis of Vital Signs
9.4.1
Potentially Clinically Significant Values
For selected vital signs variables (systolic blood pressure, diastolic blood pressure, heart 
rate, and temperature), a listing of all observations collected will be generated for subjects 
that had at least one post-baseline observation meeting pre-defined criteria for potentially 
clinically significant values.  The number and percentage of subjects who have at least 
one post-baseline observation meeting the pre-defined criteria for potentially clinically 
significant values will be provided for each variable by dose and overall.
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 8.
9.4.2
Mean Change from Baseline 
Changes from baseline will be analyzed for each scheduled post-baseline visit as well as 
for the final visit for vital signs variables (systolic blood pressure, diastolic blood 
 


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pressure, and heart rate).  If more than one measurement exists for a subject on a 
particular day, then an arithmetic average will be calculated.  This average will be 
considered to be that subject's measurement for that day.  Post-baseline measurements 
more than 30 days after last study drug will not be included.  Subjects that do not have a 
baseline measurement or do not have any post-baseline measurements will not be 
included.
Mean changes from baseline at each scheduled post-baseline visit as well as at Final Visit 
will be summarized with the baseline mean, visit mean, change from baseline mean, 
standard deviation, and median.
9.5
Analysis of ECG Parameters
A listing will be prepared that will include details about all abnormal ECG findings.
10.0
Efficacy Analysis
10.1
Response Rates
The distribution of best overall IMWG response (per investigator assessment) will be 
reported as the number and percentage of subjects who achieved each response as their 
"best" response.  In other words, each subject will only be counted in one of the following 
categories:
●
Stringent complete response (sCR)
●
Complete response (CR)
●
Very good partial response (VGPR)
●
Partial Response (PR)
●
Minimal response (MR)
●
Stable disease (SD)
●
Disease Progression (PD)
●
Missing
 


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All responses must be confirmed by a consecutive assessment in which that subject 
achieved as good or better of a response, with the exception of SD, which is confirmed by 
the baseline.  Section 4.3.2.1 details how PD is confirmed.
In addition to the aforementioned distributional breakdown of best overall response, the 
number, percentage, and 95% confidence interval (exact binomial distribution; Clopper-
Pearson methodology) will be reported for the following:
●
ORR (PR or better:  PR + VGPR + CR + sCR)
●
≥ VGPR rate (VGPR or better:  VGPR + CR + sCR)
10.2
Time to Event Endpoints
Analysis of the time to event endpoints (TTP and DOR) will include the following:
●
Number and % of subjects experiencing an event
●
Number and % of censored subjects
●
Point estimates and 95% confidence intervals (log-log; the SAS default) for 
survival time (months) for the 25th, 50th (median), and 75th percentiles, and for 
the survival estimates at months 6, 12, and 24 (% survivors remaining)
●
Kaplan-Meier plot w/curves and risk table
Analysis of TTR (PR or better) will include the mean and 95% CI, standard deviation, 
median, and range (i.e., minimum and maximum). 
11.0
Pharmacokinetic Analysis
11.1
Tabulations and Summary Statistics
Plasma concentrations and PK parameter values of venetoclax will be tabulated for each 
subject and each dose level, and summary statistics will be computed for each sampling 
time and parameter.  Significant pharmacokinetic sample time deviations will be 
identified and listed.
 


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11.2
Model and Test
Dose Proportionality and Covariate Selection of Venetoclax on Cycle 2 Day 1
Pharmacokinetic parameters of venetoclax from the dose escalation subjects assessed on 
Cycle 2 Day 1 will be analyzed as follows.  An analysis will be performed for Tmax, dose 
normalized Cmax, dose-normalized AUC24, and β, provided that they can be adequately 
determined from the data.  The model used for the statistical analyses will include dose 
level of venetoclax as a fixed effect.  This may be done by classifying subjects by dose 
level or, if appropriate, using dose level as a continuous variable.  Baseline covariates 
such as age, body weight, body surface area, calculated creatinine clearance, and gender 
will be included in the model initially.  A covariate will be dropped from the model if the 
regression coefficient is not significant at alpha level 0.10.  The natural logarithmic 
transformation will be employed for Cmax and the AUCs unless the data clearly indicate 
that another transformation or the untransformed variable provides more nearly symmetric 
probability distributions and/or more nearly homogenous variances across dose levels.  
Within the framework of the model, tests that have good power for a trend with dose will 
be performed on the effect of dose level.
Formula for calculated creatinine clearance is defined as follows:
eCCr = (140 – baseline Age) ●baseline weight (kg) ●[1.23 if Male, 1.04 if Female]
baseline Serum Creatinine (μmol/L)
Steady State Trough Hour 0 Concentrations
Exploratory analyses of trough (pre-dose) concentrations of venetoclax on Day 1 of 
Cycle 2, 3, 5, 7 and 9 for Phase 1 portion subjects will be done to characterize the 
achievement of steady-state pharmacokinetics.  Cycle will be included in the model as a 
categorical variable (to generate pairwise comparisons of various time points).  The term 
for dose will also be included in the model, and the potential interaction between cycle 
and dose will be evaluated.
 


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11.3
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue due to 
an adverse event will be addressed.  Normally values of PK variables (Cmax, AUC, etc.) 
will be determined without replacing missing individual concentration values, simply 
using the available data, and if necessary doing the analysis with some missing values for 
a PK variable.  However, missing concentration values for isolated individual blood 
samples may be replaced (imputed) if such might affect study conclusions or 
meaningfully affect point estimates.
12.0
References
1.
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria 
for multiple myeloma.  Leukemia.  2006;20(9):1467-73.
2.
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria
for multiple myeloma.  Leukemia.  2006;20(9):1467-73.  Erratum in:  Leukemia.  
2007;21(5):1134.
3.
Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials:  report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117(18):4691-5.
 


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13.0
Appendix
13.1
IMWG 20111-3 Response Criteria
Response Subcategory
Response Criteriaa
Stringent complete 
response (sCR)*

Negative immunofixation on the serum and urine (regardless of 
whether disease at baseline was measurable on serum, urine, both, 
or neither) and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrowb and

Normal FLC (free light chain) ratio** and

Absence of clonal plasma cells in bone marrowb by 
immunohistochemistry or immunofluorescencec or 2 to 4 color flow 
cytometry
Complete response 
(CR)*

Negative immunofixation on the serum and urine (regardless of 
whether disease at baseline was measurable on serum, urine, both, 
or neither) and

Disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrowb and

For subjects in whom the only measurable disease is by serum FLC 
levels, a normal FLC ratio** is also required
Very good partial 
response (VGPR)*

Serum and urine M-component detectable by immunofixation but 
not on electrophoresis or

≥ 90% reduction in serum M-component plus urine M-component 
< 100 mg per 24 hr
For subjects in whom the only measurable disease is by serum FLC levels, 
VGPR is defined as:

≥ 90% decrease in the difference between involved and uninvolved 
FLC levels
Partial response (PR)

≥ 50% reduction of serum M-protein and

≥ 90% reduction in 24-hr urinary M-protein or to < 200 mg per 
24 hr
o
If the serum and urine M-protein are unmeasurabled, a ≥ 50% 
decrease in the difference between involved and uninvolved 
FLC levels is required in place of the M-protein criteria

≥ 50% reduction in the size of soft tissue plasmacytomas, if present 
at baseline
 


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Response Subcategory
Response Criteriaa
Minimal response (MR)

25% – 49% reduction of serum M-protein, and

50% – 89% reduction in 24-hour urinary M-protein, and

25% – 49% reduction in size of soft tissue plasmacytomas, if 
present at baseline, and

No increase in size or number of lytic bone lesions (development of 
compression fracture dose not exclude response)
Stable disease (SD)e
Not meeting criteria for sCR, CR, VGPR, PR, MR or progressive disease 
(PD)
a.
All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed.  Radiographic studies are not required to satisfy these response requirements.
b.
Confirmation with repeat bone marrow biopsy not needed.
c.
Presence/absence of clonal cells is based upon the k/λ ratio.  An abnormal k/λ ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting 
presence of an abnormal clone is k/λ of > 4:1 or < 1:2.
d.
Measurable disease is defined as meeting at least one of the following four measurements:  serum M-protein 
≥1 g/dL (≥ 10 g/L) or urine M-protein ≥ 200 mg/24 hr or serum FLC assay with an involved FLC level 
≥10 mg/dL (≥ 100 mg/L) provided serum FLC ration is abnormal or bone marrow plasma cells ≥ 30%.
e.
Not recommended for use as an indicator of response; stability of disease is best described by providing the time to 
progression estimates.
*
Serum and urine M-protein testing is required to fulfill requirements of VGPR and CR categories regardless of 
whether disease at baseline was measurable on serum, urine, both, or neither.
**
Clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by 
serum FLC levels:  CR in such patients is defined as a normal FLC ratio of 0.26 – 1.65 in addition to CR criteria 
listed above.  VGPR in such patients is defined as a > 90% decrease in the difference between involved and 
uninvolved free light chain FLC levels.
 


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Relapse Subcategory
Relapse Criteria
Progressive disease (PD)*
Requires any one or more of the following:

Increase of ≥ 25% from lowest response level in any of the 
following:
o
Serum M-proteina absolute increase ≥ 0.5 g/dL, and/or 
o
Urine M-protein absolute increase ≥ 200 mg/24 hr, and/or
o
In subjects without measurable serum and urine M-protein 
levels, the difference between involved and uninvolved FLC 
levels (the absolute increase must be > 10 mg/dL), and/or

Definite development of new bone lesions or soft tissue 
plasmacytomas, and/or

Definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas, and/or

Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder
Clinical Relapse
Requires any one or more of the following direct indicators of increasing 
disease and/or end organ dysfunction (CRAB features).

Development of new soft tissue plasmacytomas or bone lesions on 
skeletal survey, MRI or other imaging, and/or

Definite increase in size of existing plasmacytomas or bone 
lesions.  A definite increase is defined as a 50% (and at least 1 cm) 
increase as measured serially by the sum of the products of the 
cross-diameters of the measurable lesion, and/or

Hypercalcemia > 11.5 mg/dL (> 2.875 mmol/L), and/or

Decrease in hemoglobin of ≥ 2 g/dL (≥ 1.25 mmol/L) or 
< 10 g/dL, and/or

Rise in serum creatinine by > 2 mg/dL (≥ 177 mmol/L), and/or

Hyperviscosity
a.
For progressive disease, serum M-component increases of ≥ 1 g/dL are sufficient to define relapse if starting 
M-component is ≥ 5 g/dL.
*
The "25% increase" refers to M-protein, FLC, and bone marrow results and does not refer to bone lesions, soft 
tissue plasmacytomas, or hypercalcemia.  The "lowest response value" does not need to be a confirmed value.
 


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Table 4.
Time Windows for Analysis of Laboratory and Vital Signs 
Parameters – Phase 1 Monotherapy Subjects
Scheduled Visit
Nominal Day
Time Window (Study Rx Day Range)
Screening
Screening
Screening Visit
Baseline
≤ 1
See the baseline definition (Section 6.2)
Lead-in Day 1
1
[1]
Lead-in Day 2
2
[2, 4]
Lead-in Day 8
8
[5, 11]
Cycle 1 Day 1
15
[12, 15]
Cycle 1 Day 2 
16
[16]
Cycle 1 Day 3
17
[17, 19]
Cycle 1 Day 8 
22
[20, 25]
Cycle 1 Day 15 
29
[26, 32]
Cycle 2 Day 1
36
[33, 36]
Cycle 2 Day 2
37
[37, 39]
Cycle 2 Day 8
43
[40, 46]
Cycle 2 Day 15
50
[47, 53]
Cycle 3 Day 1
57
[54, 60]
Cycle 4 Day 1
78
[61, 95]
Cycle 5 Day 1
99
[96, 130]
Cycle 7 Day 1
141
[131, 174]
Cycle 9 Day 1
183
[175, 224]
Cycle 13 Day 1
267
[225, 309]
Cycle 17 Day 1
351
[310, 394]
Every 4th Cycle thereafter
Rx day of Cycle X Day 1
[Rx day of Cycle (X) Day 1 – 42 to Rx 
day of Cycle (X) Day 1 + 42]
Final Observation
Last value within 30 days of study drug 
discontinuation
 


Venetoclax
M13-367 – Statistical Analysis Plan – Phase 1 Subjects
Version 1.0 – 20 Sep 2018
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Table 5.
Time Windows for Analysis of Laboratory and Vital Signs 
Parameters – Phase 1 VenDex Combination Subjects
Scheduled Visit
Nominal Day
Time Window (Study Rx Day Range)
Screening
Screening
Screening Visit
Baseline
≤ 1
See the baseline definition (Section 6.1)
Cycle 1 Day 1
1
[1]
Cycle 1 Day 2
2
[2]
Cycle 1 Day 3
3
[3]
Cycle 1 Day 8
8
[4, 11]
Cycle 1 Day 15 
15
[12, 18]
Cycle 2 Day 1
22
[19, 22]
Cycle 2 Day 2
23
[23, 26]
Cycle 2 Day 8
29
[27, 31]
Cycle 2 Day 15
36
[32, 40]
Cycle 3 Day 1
43
[41, 53]
Cycle 4 Day 1
64
[54, 75]
Cycle 5 Day 1
85
[76, 97]
Cycle 7 Day 1
127
[98, 140]
Cycle 9 Day 1
169
[141, 183]
Cycle 13 Day 1
211
[184, 226]
Cycle 17 Day 1
253
[227, 269]
Every 4th cycle 
thereafter
Rx day of Cycle X Day 1
[Rx day of Cycle (X) Day 1 – 42 to Rx day of 
Cycle (X) Day 1 + 42]
Final Observation
Last value within 30 days of study drug 
discontinuation
 


Venetoclax
M13-367 – Statistical Analysis Plan – Phase 1 Subjects
Version 1.0 – 20 Sep 2018
34
Table 6.
Clinical Laboratory Tests – Phase 1 Portion
Hematology
Clinical Chemistry
Hemoglobin
White Blood Cell (WBC) count
Platelet count 
Neutrophils
Creatinine
Total bilirubin
Serum glutamic-oxaloacetic transaminase 
(SGOT/AST)
Serum glutamic-pyruvic transaminase 
(SGPT/ALT)
Potassium
Calcium
Inorganic phosphate
Uric acid
a.
Chemistry tests should be obtained under fasting conditions, if possible.
Table 7.
Definitions of Laboratory Tumor Lysis Syndrome (TLS)
Metabolic Abnormality
Howard Criteria for Classification of Laboratory Tumor Lysis 
Syndrome (TLS)
Hyperruricemia
Uric acid > 8.0 mg/dL (475.8 μmol/L)
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/L)
Hyperkalemia
Potassium > 6.0 mmol/lL
Hypocalcemia
Corrected calcium < 7.0 mg/dL (1.75 mmol/L) or ionized calcium 
< 1.12 mg/dL (0.3 mmol/L)a
a.
The corrected calcium level in mg/dL = measured calcium level in mg/dL + 0.8 × (4-albumin in g/dL).
Note:
In laboratory tumor lysis syndrome, 2 or more metabolic abnormalities must be present during the same 
24-hour period within 3 days before the start of therapy or up to 7 afterward.  Clinical tumor lysis syndrome 
requires the presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac 
dysrhythmia, or death.
Source:
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54.
 


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Version 1.0 – 20 Sep 2018
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Table 8.
Criteria for Potentially Clinically Significant Vital Signs 
Parameters
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic Blood Pressure
High
Value ≥ 160 mmHg
Diastolic Blood Pressure
High
Value ≥ 100 mmHg
Heart Rate
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature 
Low
Value < 36°C
High
Value ≥ 38.5°C