Clinical trial NCT00481091
Conditions: Chronic Lymphocytic Leukemia
Keywords: Chronic Lymphocytic Leukemia (CLL) Navitoclax ABT-263 Cancer
Sponsor: AbbVie
Start date: 2007-07-25; Completion date: 2022-05-12
Enrollment: 60 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The Phase 1 portion of the study will evaluate the pharmacokinetic profile and safety of ABT-263 under two different dosing schedules with the objective of defining the dose limiting toxicity and maximum tolerated dose. The Phase 2a portion of the study will evaluate ABT-263 at the defined recommended Phase 2 dose to obtain additional safety information and a preliminary assessment of efficacy. The Extension Study portion will allow active subjects to continue to receive ABT-263 for up to 11 years after the last subject transitions with less frequent study evaluations.

Detailed description:

Arms: arm 1: Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. arm 2: Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. arm 3: Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. arm 4: Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. arm 5: Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle. arm 6: Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle. arm 7: Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle. arm 8: Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle. arm 9: Navitoclax 100 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s). arm 10: Navitoclax 250 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s).
Interventions: intervention 1: ABT-263
Intervention descriptions: intervention 1: Tablet; Oral

Protocol documents:
Prot_000.pdf: 
ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
1
1.0
Title Page
Clinical Study Protocol M06-873
A Phase 1/2a Study Evaluating the Safety, 
Pharmacokinetics, and Efficacy of ABT-263 in 
Subjects with Relapsed or Refractory Chronic 
Lymphocytic Leukemia
Incorporating Administrative Changes 1, 2, 3, 4, 5, 
and 6 and Amendments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 13, and 14
AbbVie Number/
  Investigational Product:
ABT-263 (navitoclax)
Date:
03 September 2020
Development Phase:
1/2a
Study Design:
This is an open-label study designed to determine the 
maximum tolerated dose (MTD), safety, pharmacokinetics 
and preliminary efficacy profile of ABT-263 in subjects 
with relapsed or refractory chronic lymphocytic leukemia.
Investigator:
Investigator information on file at AbbVie.
Sponsor:
AbbVie Inc. (AbbVie) and AbbVie GmbH & Co. KG
Sponsor/Emergency
  Contact:
 
Executive Medical Director 
1 North Waukegan Rd
North Chicago, IL 60064
Phone:
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.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
 
NCT00481091


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol
Date 
Original
03 January 2007
Amendment 1
18 September 2007
Amendment 2
31 March 2008
Amendment 3 
25 November 2008
Amendment 4
17 December 2008
Administrative Change 1
03 March 2009
Administrative Change 2
30 June 2009
Amendment 5
08 October 2009
Amendment 6
21 May 2010
Amendment 7
01 December 2010
Administrative Change 3
09 December 2010
Amendment 8
11 May 2011
Amendment 9
19 October 2011
Administrative Change 4
22 October 2012
Amendment 10
18 September 2014
Administrative Change 5
16 November 2015
Amendment 11
08 August 2016
Administrative Change 6
02 March 2018
Amendment 12
26 July 2018
Amendment 13
16 January 2020
The primary purpose of this amendment is to incorporate necessary protocol 
modifications due to the COVID-19 (Coronavirus 2019) pandemic as follows:
●
Section 3.0 – Included information on the re-evaluation of the benefit and risk 
to subjects participating in the study.
●
Section 5.4.1 – Added that the investigator should contact the sponsor medical 
contact before discontinuing a subject from the study for a reason other than 
"planned per protocol."
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
3
●
Section 5.5.1 – Added delays in study drug dosing due to the above 
COVID-19 testing guidance.
●
Section 5.5.4 – Included instructions that in the event the subject cannot pick 
up study drug onsite, DTP (Direct To Patient) shipment can be made, as 
permitted by local regulations.
●
Section 7.0 – clarified that protocol deviations may include modifications due 
to COVID-19.
●
Section 9.1 – Added that AbbVie will modify the study protocol as necessary 
due to the pandemic. Investigators must also notify AbbVie if any urgent 
safety measures are taken.
●
Section 10.1 – Added that remote monitoring may be employed as needed.
●
Appendix A – Addition of COVID-19 and DTP to list of abbreviations.
●
In addition, sponsor contact information updates have been made.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix H.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
4
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
2.0
Table of Contents.....................................................................4
3.0
Introduction .............................................................................9
4.0
Study Objectives....................................................................15
5.0
Investigational Plan...............................................................16
5.1
Overall Study Design and Plan:  Description ..........................................16
5.2
Selection of Study Population..................................................................27
5.2.1
Phase 1 Inclusion Criteria ........................................................................28
5.2.2
Phase 1 Exclusion Criteria.......................................................................29
5.2.3
Phase 2a Inclusion Criteria ......................................................................31
5.2.4
Phase 2a Exclusion Criteria .....................................................................33
5.2.5
Extension Study Inclusion Criteria ..........................................................35
5.2.6
Prior and Concomitant Therapy...............................................................36
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables...........................................................38
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................38
5.3.1.1
Study Procedures .....................................................................................50
5.3.1.2
Meals and Dietary Requirements.............................................................70
5.3.1.3
Blood Samples for Pharmacogenetic Analyses .......................................71
5.3.1.4
Specimens for Pharmacodynamic Analyses ............................................72
5.3.1.5
Disposition of Samples for Pharmacogenetic/Pharmacodynamic 
Analyses...................................................................................................77
5.3.2
Drug Concentration Measurements .........................................................78
5.3.2.1
Collection of Samples for Analysis .........................................................78
5.3.2.2
Handling/Processing of Samples .............................................................80
5.3.2.3
Disposition of Samples for ABT-263 Assay ...........................................80
5.3.2.4
Measurement Methods.............................................................................81
5.3.3
Efficacy Variables....................................................................................81
5.3.3.1
NCI-WG Criteria for Tumor Response....................................................81
5.3.3.1.1
NCI-WG Criteria - 1996 ..........................................................................82
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
5
5.3.3.1.2
IWCLL Updated NCI-WG Criteria – 2008 .............................................87
5.3.3.1.3
Definition of Clinical Disease Progression (Phase 2a)............................91
5.3.4
Safety Variables.......................................................................................92
5.3.5
Pharmacokinetic Variables ......................................................................92
5.3.6
Pharmacogenetic Variables......................................................................92
5.3.7
Pharmacodynamic Variables....................................................................93
5.4
Removal of Subjects from Therapy or Assessment.................................94
5.4.1
Discontinuation of Individual Subjects....................................................94
5.4.2
Discontinuation of Entire Study...............................................................96
5.5
Treatments................................................................................................96
5.5.1
Treatments Administered.........................................................................96
5.5.2
Identity of Investigational Product...........................................................97
5.5.2.1
Packaging and Labeling...........................................................................99
5.5.2.2
Storage and Disposition of Study Drug ...................................................99
5.5.2.3
Preparation/Reconstitution of Dosage Form..........................................100
5.5.3
Method of Assigning Subjects to Treatment Groups.............................100
5.5.4
Selection and Timing of Dose for Each Subject....................................101
5.5.5
Blinding..................................................................................................101
5.5.6
Treatment Compliance...........................................................................102
5.5.7
Drug Accountability...............................................................................102
5.6
Discussion and Justification of Study Design........................................103
5.6.1
Discussion of Study Design and Choice of Control Groups..................103
5.6.2
Appropriateness of Measurements.........................................................104
5.6.3
Suitability of Subject Population ...........................................................104
5.6.4
Selection of Doses in the Study .............................................................104
6.0
Adverse Events.....................................................................106
6.1
Definitions..............................................................................................107
6.1.1
Adverse Event........................................................................................107
6.1.2
Serious Adverse Events .........................................................................108
6.2
Adverse Event Severity..........................................................................109
6.3
Relationship to Study Drug....................................................................110
6.4
Adverse Event Collection Period...........................................................111
6.5
Adverse Event Reporting.......................................................................111
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
6
6.6
Pregnancy...............................................................................................113
6.7
Toxicity Management ............................................................................113
6.7.1
Definition - Dose Limiting Toxicity......................................................113
6.7.2
Management of Thrombocytopenia.......................................................115
6.7.3
Management of Lymphopenia ...............................................................116
6.7.4
Management of Tumor Lysis Syndrome ...............................................116
6.7.5
Determination of the MTD ....................................................................117
7.0
Protocol Deviations..............................................................117
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................119
8.1
Statistical and Analytical Plans..............................................................119
8.1.1
Demographics and Treatment Allocation ..............................................119
8.1.2
Pharmacokinetics ...................................................................................120
8.1.2.1
Tabulations and Summary Statistics......................................................120
8.1.2.2
Model and Tests.....................................................................................120
8.1.2.3
Missing Values and Model Violations...................................................121
8.1.3
Exploratory Efficacy..............................................................................121
8.1.3.1
Progression-Free Survival......................................................................121
8.1.3.2
Objective Response Rate .......................................................................122
8.1.3.3
Time to Tumor Progression ...................................................................122
8.1.3.4
Overall Survival.....................................................................................123
8.1.3.5
Duration of Overall Response................................................................123
8.1.3.6
ECOG Performance Status ....................................................................124
8.1.3.7
Reporting of Results ..............................................................................124
8.1.4
Safety .....................................................................................................124
8.2
Determination of Sample Size ...............................................................126
9.0
Ethics.....................................................................................126
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................126
9.2
Ethical Conduct of the Study.................................................................127
9.3
Subject Information and Consent...........................................................128
10.0
Source Documents and Case Report Form 
Completion ...........................................................................128
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
7
10.1
Source Documents .................................................................................128
10.2
Case Report Forms.................................................................................129
10.3
Extension Study Case Report Forms .....................................................130
11.0
Data Quality Assurance ......................................................130
12.0
Use of Information...............................................................131
13.0
Completion of the Study .....................................................132
14.0
Investigator's Agreement....................................................134
15.0
Reference List ......................................................................135
List of Tables
Table 1.
Schedule of Assessments – 14/21 Day Dosing (Phase 1)........................39
Table 2.
Schedule of Assessments – 21/21 Day Dosing with Lead-in 
Period (Phase 1) .......................................................................................42
Table 3.
Schedule of Assessments (Phase 2a) –21/21 Day Continuous 
Dosing Schedule with Lead-in Period .....................................................45
Table 4.
Schedule of Blood Collection for ABT-263 Assay 
(Pharmacokinetic Sampling) – Phase 1, Cycle 1.....................................48
Table 5.
Schedule of Blood Collection for ABT-263 Assay 
(Pharmacokinetic Sampling) – Phase 1, Cycle 2 and Beyond.................48
Table 6.
Schedule of Blood Collection for ABT-263 Assay 
(Pharmacokinetic Sampling) – Phase 2a, 21/21 Day Continuous 
Dosing Schedule ......................................................................................49
Table 7.
Clinical Laboratory Tests.........................................................................69
Table 8.
Schedule of Biomarker Sample Collection (Phase 1)..............................76
Table 9.
Schedule of Biomarker Sample Collection (Phase 2a)............................77
Table 10.
NCI-WG Criteria for Tumor Response (1996)........................................86
Table 11.
IWCLL Updated NCI-WG Criteria for Tumor Response (2008)............91
Table 12.
Identity of Investigational Products.........................................................98
List of Figures
Figure 1.
Phase 1 and Phase 2a Study Design.........................................................17
Figure 2.
Adaptive CRM Design.............................................................................20
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
8
Figure 3.
ABT-263 Dosing Schematic – Phase 1....................................................22
Figure 4.
21/21 Day Continuous Dosing Schedule for ABT-263 ...........................24
Figure 5.
Adverse Event Collection ......................................................................111
List of Appendices
Appendix A.
List of Abbreviations and Definitions of Terms....................................139
Appendix B.
List of Protocol Signatories....................................................................143
Appendix C.
Documents Required Prior to Initiation of the Study ............................144
Appendix D.
Responsibilities of the Clinical Investigator ..........................................146
Appendix E.
Sample List of Excluded and Cautionary Medications..........................148
Appendix F.
Simulations Comparing Fixed 3+3 Design Versus CRM-based 
Design ....................................................................................................150
Appendix G.
Extension Study - Assessments .............................................................161
Appendix H.
Protocol Amendment:  List of Changes.................................................163
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
9
3.0
Introduction
Bcl-2 Family Proteins
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway.  
The Bcl-2 oncogene was first identified in follicular lymphoma where the t(14;18) 
chromosomal translocation results in significant over-expression of this protein in B-cells.  
In contrast to other known oncogenes, Bcl-2 does not stimulate cellular proliferation, but 
rather inhibits programmed cell death by protecting cells from a wide variety of 
pro-apoptotic stimuli, including cytokine withdrawal, irradiation, cytotoxic drugs, heat 
and deregulated oncogenes.1  The Bcl-2 family of genes encodes a family of closely 
related proteins that possess either pro-apoptotic or anti-apoptotic activity and share up to 
four Bcl-2 Homology (BH) domains.2,3,4,5  The anti-apoptotic family members Bcl-XL, 
Bcl-2, Bcl-w, Bcl-B, A1 and Mcl-1 are characterized by four BH domains that are 
designated BH1-4.  The pro-apoptotic family members can be further subdivided into 
multidomain proteins (Bax, Bak) and the BH3-only proteins (Bad, Bik, Bid, Bim, Hrk, 
Bmf, Noxa, and Puma).  The interplay between these three groups of proteins serves as 
the gateway to the intrinsic apoptosis pathway.
The multidomain pro-apoptotic proteins Bax and Bak are direct mediators of apoptosis 
and are absolutely required for the initiation of the mitochondrial apoptosis pathway.6,7,8  
Anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2 and Bcl-XL) inhibit cytochrome 
C release by blocking Bax/Bak activation.9 The exact mechanism of action of Bcl-2 and 
Bcl-XL has not been completely elucidated, however it is known that it requires the ability 
to bind the pro-apoptotic Bcl-2 family members and that the ratio of pro-apoptotic to anti-
apoptotic proteins is associated with cell survival.10,11,12
ABT-263 Activity and Pharmacokinetic Profile
ABT-263 (navitoclax) is a small molecule Bcl-2 family protein inhibitor that binds with 
high affinity (Ki 1 nM) to multiple anti-apoptotic Bcl-2 family proteins including 
Bcl-XL, Bcl-2, Bcl-w, and Bcl-B.  ABT-263 displays potent mechanism-based 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
10
cytotoxicity (EC50 1 M) against human tumor cell lines derived from small cell lung 
carcinomas and lymphoid malignancies.  ABT-263 exhibits potent single agent activity 
against 10 of 22 leukemia and lymphoma cell lines spanning both B-cell and T-cell 
malignancies.
Pre-clinical experiments have been performed on primary patient derived chronic 
lymphocytic leukemia (CLL) samples with ABT-737, a first generation Bcl-2 family 
protein inhibitor.  Treatment with ABT-737 induced robust, concentration-dependent 
apoptosis in 47 of 50 patient-derived CLL specimens regardless of the presence of feeder 
cells.  These cells were highly sensitive with EC50 values of < 0.25 M.  Forty-two of the 
47 lines had EC50 values of < 0.01 M.  ABT-263, which has similar potency as 
ABT-737, would be expected to have similar efficacy.
The pharmacokinetic profile of ABT-263 was evaluated in multiple animal models 
including:  CD-1 mouse, Sprague-Dawley rat, beagle dog and cynomolgus monkey.  The 
pharmacokinetic profile of ABT-263 is characterized by very low plasma clearance and 
low volumes of distribution in all species studied, with terminal half-lives in the range of 
4.6 to 8.4 hours.  The oral bioavailability of the compound is formulation dependent, with 
values of 30% to 50% obtained from prototype solid dispersion and lipid-based 
formulations in dog.  In rat, [14C] ABT-263 is slowly absorbed, with clearance of the 
metabolites primarily in the bile.  Elimination of total radioactivity is rapid, with 90% of 
the dose recovered within 24-hours post-dose.  Parent drug is the major component in 
systemic circulation.
Based on preclinical evidence, potential treatment-related side effects may include drug 
interactions, lymphopenia, testicular effects and thrombocytopenia.  At the expected 
biologically effective plasma concentration in humans of 6.5 g/mL (Cmax), ABT-263 is 
likely to inhibit the metabolism of drugs that are substrates for CYP2C8 and CYP2C9 by 
greater than 50%.  Simulation of 350 mg q.d. dosing in humans describes an AUC of 
92 g•hr/mL at steady state, with a Cmax of ~6.5 g/mL.  Under these conditions, platelet 
values in patients with normal platelet values (~300 K/L) at baseline are expected to be 
~25 K/L at steady state.  At the lower end of the predicted efficacious range, an AUC of 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
11
53 g•hr/mL (predicted 200 mg q.d. dosing in humans) is expected to be attainable while 
still maintaining platelet values above 50 K/L at steady state.
ABT-263 induces apoptosis, rather than lysis of circulating platelets, which differs from 
typical chemotherapy induced thrombocytopenia related to myelosuppression.  Limited 
human clinical data are available to understand the response to infusion of exogenous 
platelets in the presence of circulating drug levels.  Platelet transfusion studies conducted 
in beagle dogs demonstrated that transfusion of one-day old platelets administered near 
the time of ABT-263 Cmax, resulted in higher platelet levels than dogs not receiving 
supplemental platelets.  Platelet concentrations remained higher after 24 hours with 
declining ABT-263 concentrations.  This study suggests that infusion of platelets may 
have beneficial effects in treating acute thrombocytopenia following oral dosing with 
ABT-263.
From the pre-clinical models, there may be an opportunity in the monotherapy setting to 
increase efficacy without additional platelet toxicity in the setting of continuous dosing.  
In murine xenograft models of SCLC, 21 days of continuous dosing achieves superior 
tumor growth inhibition, greater increase in life span, and greater incidence of complete 
and overall response rates compared to the intermittent dosing schedules or 14 days of 
dosing and 7 days off drug.  In a dog toxicology study, ABT-263 was delivered once daily 
for 28 days.  At doses that achieve plasma concentrations within the targeted efficacious 
exposure range, circulating platelet counts recovered to baseline within 14 days of dosing 
and remained at baseline for the subsequent 14 days of dosing.
This observation of platelet recovery during continued ABT-263 dosing has also been 
observed in the Phase 1 clinical studies.  Given that platelet nadirs typically occur in the 
first few days of dosing and circulating platelet counts recover during continued dosing, a 
lead-in period may help reduce the depth of platelet nadir.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
12
ABT-263 Toxicology
The safety of ABT-263 has been evaluated in single- and repeat-dose (up to 6 and 
9 months in duration in rats and dogs, respectively), reproductive (male and female 
fertility and embryo fetal development), safety pharmacology (cardiovascular, 
neurofunctional, and pulmonary), genetic (Ames, in vitro cytogenetics, and in vivo 
micronucleus), and special studies (guinea pig sensitization; lymphocyte 
immunophenotyping; and single-dose oral toxicity in male rats).  The primary effects of 
ABT-263 were on the hematopoietic system (platelets and lymphocytes) and the male 
reproductive system (germ cell depletion), and are believed to be based on inhibition of 
one or more members of the Bcl-2 family of antiapoptotic proteins.  Other findings 
included ovarian atrophy (rats only), and generally minimal and reversible liver changes 
(single-cell hepatocellular necrosis, increased mitotic index, and hypertrophy/hyperplasia 
and pigmentation of Kupffer cells) and single-cell necrosis in various tissues.  ABT-263 
was neither genotoxic, nor did it affect male or female fertility in rats or embryo-fetal 
development in rats and rabbits.  ABT-263-related effects were observed on brain, testes, 
and circulating platelets in juvenile rats.  Effects on the brain (cerebellar hypoplasia), 
which were not observed in adult rats, were the likely result of incomplete maturation of 
the blood-brain-barrier at the time dosing was initiated in the rat pups (post natal Day 7).
ABT-263 caused increases in pulmonary and peripheral vascular resistance and decreases 
in cardiac output in the dog following acute or multiple daily dosing.  Despite the 
increases in vascular resistance, there were no increases in blood pressure.  On Day 28 of 
the oral dosing study, these cardiovascular effects were associated with a mean Cmax value 
of 16.6 g/mL, whereas no statistically significant hemodynamic changes were associated 
with a mean Cmax of 11.4 g/mL.13  Similar systemic exposures induced these effects in 
the acute cardiovascular study.
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a 
progressive accumulation of functionally incompetent lymphocytes.  It is the most 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
13
common form of leukemia in adults in the Western World, accounting for nearly 25% of 
all leukemias.15  CLL primarily affects elderly individuals however approximately 
one-third of patients are less than sixty years of age at diagnosis.16  It is currently 
estimated that annually over 10,000 people will be diagnosed with CLL in the United 
States, and that almost 4,700 individuals will die of the disease.17  The approximate 5-year 
survival rate for patients with CLL is 73%.18
CLL presents with a variable clinical course.  Approximately one third of patients do not 
require treatment as they experience long survival and die of causes unrelated to disease.  
Another third have an initial indolent phase that is followed by rapid progression of the 
disease requiring therapy.  The remaining third have aggressive disease and require 
treatment at the time of diagnosis.  CLL patients will often have compromised bone 
marrow reserve due to their underlying disease.  The principal complication of CLL is 
immunodeficiency related to myelosuppression and as a result, infection is the major 
cause of death in patients with CLL.19
Treatment decisions for patients with CLL are made based upon considerations such as 
age, clinical staging, expected survival, and anticipated toxicities.  First line treatment 
options include alkylating agents, alkylator/anthracycline combination therapies and 
purine analogues such as fludarabine.  Improvement in treatment response rates occurred 
with the switch from historical single-agent usage to combination therapy, such as 
fludarabine and cyclophosphamide, with some combinations yielding overall response 
rates (ORR) in excess of 90%.  An alternative to combination therapy is sequential 
therapy.  The sequential regimen of fludarabine, cyclophosphamide, and rituximab (FCR) 
induced ORR of 88-95% with a high incidence of complete responses (53-70%).20-22
In previously treated/relapsed patients, fludarabine is the most active single-agent, with 
ORR ranging from 50-60%, and complete remission (CR) rates from 3-13%.23  Many 
patients treated previously with fludarabine can be retreated and will respond again to the 
same regimen.24  However, almost all CLL patients who are treated with single agent 
fludarabine or in combination will ultimately become fludarabine-refractory.25
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
14
The treatment options for patients with fludarabine-refractory disease are limited.  
Campath, a fully humanized monoclonal antibody directed against CD52, is the only 
approved therapy for CLL patients who have been treated with alkylating agents and who 
have failed fludarabine therapy.  Clinical trials in patients treated with Campath have 
demonstrated ORRs ranging from 21-33%.  Progression-free survival rates ranged 
between 4 and 7 months.26
Current chemotherapeutic agents elicit their anti-tumor response by inducing apoptosis 
through a variety of mechanisms.  However, many tumors ultimately become resistant to 
these agents.  Bcl-2 and Bcl-XL have been shown to confer chemotherapy resistance in 
both short-term survival assays in vitro and more recently, in vivo.  This suggests that 
therapies aimed at suppressing the function of Bcl-2 and Bcl-XL might potentially 
overcome this mechanism of chemotherapy resistance.27  Preclinical studies suggest that 
the Bcl-2 family protein inhibitor has single agent anti-tumor activity.
Based upon the preclinical profile of ABT-263, the role of Bcl-2 family proteins in 
hematological malignancies, and the lack of an existing therapy that provides a survival 
benefit in relapsed or refractory CLL patients, clinical investigation of ABT-263 is 
warranted.
ABT-263 Clinical Data
Preliminary aggregate clinical data from the 3 ongoing Phase 1 studies support that 
ABT-263 is tolerable at doses up to 250 mg in a 21/21 day continuous dosing schedule, 
which achieves exposures consistent with preclinical efficacy.  Anti-tumor activity has 
been noted in study subjects with CLL at doses 200 mg, suggesting that ABT-263 may 
provide a clinical benefit to subjects with CLL.
The cumulative preclinical toxicology, safety pharmacology, metabolism, 
pharmacokinetic, and preliminary clinical data indicate that ABT-263 has been adequately 
characterized and that treatment with ABT-263 represents an acceptable risk to adult 
subjects with cancer.  Consistent with the toxicological finding of a concentration 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
15
dependent decrease in circulating platelets in animal models, thrombocytopenia appears to 
be a DLT for ABT-263 in humans.  The ongoing clinical studies with ABT-263 will 
continue to evaluate its safety profile, DLT, MTD, bioavailability, pharmacokinetics, and 
efficacy.
This study will determine the dose limiting toxicity (DLT), the maximum-tolerated dose 
(MTD), and will assess the safety, pharmacokinetics, and preliminary efficacy of 
ABT-263 in subjects with relapsed or refractory CLL.  ABT-263 will be administered 
orally under two different dosing schedules (14/21 day dosing schedule and 21/21 day 
continuous dosing schedule).  The following 14/21 dose levels have been completed to 
date:  10 mg, 110 mg, 200 mg, and 250 mg.  The following 21/21 dose levels have been 
completed to date:  125 mg, 200 mg, 250 mg and 300 mg.
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Subjects receiving ABT-263 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 
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 CLL, no change to the benefit/risk balance for subjects in this study is
expected.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.14
4.0
Study Objectives
The objectives of the Phase 1 portion of the study include:
●
Safety assessment
●
Dose limiting toxicity (DLT) determination
●
Maximum tolerated dose (MTD) determination
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
16
●
Recommended Phase 2 Dose (RPTD) and schedule determination
●
Pharmacokinetic profile evaluation
The objectives of the Phase 2a portion of the study include:
●
Safety assessment at the recommended Phase 2 dose (RPTD) and schedule
●
Preliminary efficacy assessment including biomarker assessment
●
Pharmacokinetic profile evaluation
The objectives of the Extension Study portion of the study include:
●
Safety assessment
●
Evaluation of data regarding progression free survival (PFS) and overall 
survival (OS)
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 1/2a study evaluating the safety, PK, and preliminary efficacy of the orally 
administered Bcl-2 family protein inhibitor, ABT-263, in approximately 72 subjects with 
relapsed or refractory chronic lymphocytic leukemia.
The study will consist of three distinct portions.  The Phase 1 portion of the study will 
evaluate the pharmacokinetic profile and safety of ABT-263 administered under 
two different dosing schedules (14/21 day and 21/21 day) in up to 40 subjects with 
relapsed or refractory CLL following a dose escalation scheme in order to define the DLT 
and the MTD.  Subjects will be enrolled at approximately eight research sites for the 
Phase 1 portion of the study.  A continual reassessment methodology will be employed 
during Phase 1 to obtain a more precise estimate of the MTD and determine the 
recommended Phase 2 dose (RPTD).
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
17
The Phase 2a portion of the study will evaluate ABT-263 in approximately 32 subjects 
with CLL who have relapsed following any (but no more than 5) prior 
myelosuppressive/chemotherapy treatment regimen(s) at the defined RPTD and dosing 
schedule to obtain additional safety information and a preliminary assessment of efficacy 
as defined in Section 5.3.3.  Subjects in the Phase 2a portion of the study will be enrolled 
at approximately twelve research sites.
The Extension portion of the study will continue to evaluate the safety of ABT-263 
administered under two different dosing schedules (14/21 day and 21/21 day) in 
approximately 13 subjects with relapsed or refractory CLL.  Eligible subjects will be 
active subjects from the Phase 1 or Phase 2a portions of the study.
Figure 1 depicts the Phase 1 and Phase 2a study design.
Figure 1.
Phase 1 and Phase 2a Study Design
Dose Escalation:
14/21 day dosing
schedule
14/21 day dosing 
schedule: either
MTD or 
completion of 4th
dose level,
(whichever occurs
first)
Dose Escalation: continuous
dosing schedule
with dose titration lead-in
period
MTD and/or 
RPTD 
determined:
continuous
dosing
schedule
RPTD and 
schedule
defined
Phase 1
Phase 2a
 
 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
18
Continual Reassessment Method
The experimental design for the Phase 1 portion of the study is an adaptation of a 
continual reassessment method (CRM), which is based on the concept of maximizing the 
number of subjects at the best current estimation of the MTD given the previous 
observations.28,29  The CRM attempts to estimate the target MTD from a continuum of 
doses, whereas a fixed design merely selects a dose from a discrete set.  If the true target 
dose is not among the choices set out in advance by fixed designs, they can only 
approximate it.  A CRM based design uses a statistical model for dose and toxicity by 
including the accumulating data to guide selection of the next dose.  Simulations and 
literature have shown that compared to the conventional fixed 3+3 design, the CRM 
typically requires fewer subjects to find the MTD, does not greatly overshoot the MTD 
(that is, subjects are less likely to be treated with dangerously high doses), and does not 
greatly underestimate the MTD.  This design also minimizes the exposure of Phase 1 
subjects to lower, potentially inefficacious doses.
Escalation will continue to the estimated MTD.  The dose will be escalated by no more 
than an incremental increase of 100 mg or a 40% increase from the current dose level, 
whichever is greater.  A minimum of 3 subjects will be enrolled in each cohort.  
Additional eligible subjects may be enrolled at the current dose level at the discretion of 
the investigator and the AbbVie Medical Monitor.  If a cohort has enrolled more than 
3 subjects, dose escalation decisions may be made following the completion of Cycle 1 
for subjects in the intended cohort size of three.  However, available data from all subjects 
receiving study drug will be used in dose escalation decisions.  Predicted efficacious 
concentrations of ABT-263 are expected to occur in the dose range of 200 mg to 350 mg 
based on preclinical studies.
Subsequent dose levels will be selected based on an estimate from a statistical analysis.  
The statistical analysis will be a logistic regression model for the dose-toxicity 
relationship (i.e., the relationship between dose and the probability of DLT) and will 
incorporate data from the M06-814 study in lymphoid malignancies (with inclusion of 
CLL subjects) for initial modeling.  The first step will be to fit the logistic regression 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
19
model and obtain the estimate of the MTD.  Three subjects will be dosed at this estimated 
MTD.  After all three subjects complete Cycle 1, a logistic regression model will be fitted 
using all of the data cumulatively from this study, and an updated estimate of the MTD 
will be obtained.  Three more subjects will be dosed at the new estimated MTD, and the 
design will continue in this fashion, assigning subjects to the MTD as estimated from 
current results, until the estimated MTD changes by less than 10% or the predetermined 
sample size of 40 subjects is reached, whichever comes first.  Complete details on the 
CRM design for the Phase 1 portion of the study are provided in Section 8.1.1.  The 
following flowchart depicts the CRM design:
 




ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
21
A minimum of 3 subjects will be enrolled in each cohort.  Additional eligible subjects 
may be enrolled at the current dose level at the discretion of the investigator and the 
AbbVie Medical Monitor.  If a cohort has enrolled more than 3 subjects, dose escalation 
decisions may be made following the completion of Cycle 1 for subjects in the intended 
cohort size of three.  Dose adjustment decisions will be informed by subject tolerability 
and safety.  However, adverse events occurring after the first cycle and ongoing 
pharmacokinetic assessment may also be considered in dose escalation decisions.  If 
pharmacokinetic results indicate more than 25% of intersubject variability can be 
attributed to differences in body weight or body surface area (BSA), escalation will 
proceed with dosing normalized to body weight or BSA; therefore subsequent dose levels 
will be determined using average subject BSA or average subject weight.
If, in the opinion of the investigators and the AbbVie Medical Monitor, the observed dose 
limiting toxicities are likely to have resulted from a cumulative and continuous exposure 
to the study drug, an alternative dosing schedule for ABT-263 may be explored.  The 
alternative schedule will be jointly determined by the sponsor and investigator, based on 
pharmacokinetic data and the required recovery periods for the observed DLTs.  For 
example, an extended recovery period may be instituted or an every other day dosing 
schedule could be implemented.
Adjustments to the dose escalation schedule may also be made based upon preliminary 
pharmacokinetic and safety data obtained from concurrent dose escalation studies that are 
being conducted with ABT-263.  These decisions will be based on the judgment of the 
AbbVie Medical Monitor in consultation with the investigator.
Subject assessments for safety and clinical progression will continue weekly through the 
first 2 cycles (6 weeks).  Subsequently, subject assessments for safety and clinical 
progression will be performed once every cycle (every 3 weeks) or more frequently, as 
needed.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
22
Phase 1 -14/21 Day Dosing
ABT-263 will be administered for 14 consecutive days followed by 7 days off drug to 
complete a 21-day cycle.  Subjects will be instructed to self-administer ABT-263 orally 
once daily (QD) within 30 minutes after the completion of breakfast.
Figure 3.
ABT-263 Dosing Schematic – Phase 1
Additionally, a continuous dosing regimen will be evaluated and compared to the 
14/21 cyclic dosing regimen.
Phase 1 – 21/21 Day Continuous Dosing
Once either the MTD is defined or dosing in the 4th dose level is completed for the 
14/21 day dosing schedule, whichever occurs first, a continuous dosing schedule will be 
assessed.  Dosing with ABT-263 under the continuous dosing schedule (21/21 day) will 
begin at the dose estimated to provide exposure equivalent to the highest dosing level 
cleared (4th dose level) or the MTD from the 14/21 day schedule.  For example, if the 
highest dose level cleared or the MTD from the 14/21 day dosing schedule is 375 mg, the 
continuous starting dose (defined Cycle 1 Day 1 dose) would be (375 14)/21 or 250 mg.  
A minimum of three subjects will be enrolled in each cohort.  The ABT-263 dose will be 
ABT-263 once daily dosing
=
7
21
14
1
7 days off 
drug
15
x
x
All Cycles
 
  
  
 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
23
escalated using a modified CRM as described previously for the 14/21 day regimen 
(Figure 2).
Prior to beginning the assigned 21/21 day continuous dosing regimen, a 7-day lead-in 
dose titration period will be implemented.  In preclinical experiments in which stepwise 
increases in ABT-263 doses were administered to dogs every one or two weeks, the 
thrombocytopenic effect of higher doses was significantly attenuated.  These data 
combined with the clinically observed rebound in platelet counts from nadir during 
continued ABT-263 dosing suggest that a lead-in period may help reduce the depth of the 
initial platelet nadir and provide an additional margin of safety.
Subjects will begin dosing at 100 mg on Lead-in Day 1 (LD1).  This is the dose level at 
which a mean maximal platelet drop of approximately 60% from baseline with recovery 
during 14 days of dosing is expected based on observations in this study to date.  The 
lead-in titration dose may be adjusted if the defined dose level fails to significantly 
mitigate ABT-263-induced thrombocytopenia following the lead-in period or the defined 
dose level results in significant occurrence of DLT in the lead-in period.
A subject may only proceed from the lead-in period to the defined dose level for Cycle 1 
Day 1 and beyond if platelet count is ≥ 50,000/mm3 after Lead-in Day 7 and stable or 
increasing.  If the platelet count is < 50,000/mm3 after Lead-in Day 7, the visit day will be 
considered Lead-in Day 8 and the subject will continue to receive the lead-in dose until 
the platelet count is ≥ 50,000/mm3.
When the platelet count is ≥ 50,000/mm3, the subject will receive the lead-in dose that 
day, and the next day (defined as Cycle 1 Day 1) the subject will receive the defined dose 
for Cycle 1 Day 1, provided the pre-dose platelet count that day is ≥ 50,000/mm3 and 
platelets are stable or increasing.  For example, if a subject's platelet count is 
≥50,000/mm3 on Lead-in Day 9, the subject will take the lead-in dose on Day 9.  The 
next day will be considered Cycle 1 Day 1 and the subject will begin receiving the defined 
dose for Cycle 1 Day 1.  However, if the pre-dose platelet count is < 50,000/mm3 or 
 




ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
25
Intra-subject Dose Escalation in Phase 1
In order to maximize the collection of information at relevant doses and to minimize the 
exposure of individuals to sub-optimal doses, subjects may progressively escalate their 
current dose to the highest dose level tolerated through 2 cycles of ABT-263 
administration.  Individuals will need to complete at least two cycles at their originally 
assigned dose level, as well as subsequent dose levels, prior to any dose escalation.
All intra-subject dose escalation decisions will be based on the judgment of the 
investigator in coordination with the AbbVie Medical Monitor.  Once the MTD is 
declared and/or the RPTD determined, subjects who remain on study and continue to 
tolerate the drug may escalate to the dose level determined to be the RPTD or the dose 
level below the RPTD.  Phase 1 subjects will be allowed to switch their current dosing 
schedule to the recommended Phase 2a schedule once it has been declared.  The RPTD 
will be defined by observed DLTs and/or determination of MTD.
Subject assessments for safety (physical examination, vital signs, chemistry, hematology, 
urinalysis, ECOG performance score and adverse event assessment) will be performed 
weekly during the first cycle at the new escalated dose and then may resume to once every 
cycle.  All other procedures (platelet count, echocardiogram and ECG) will be performed 
according to the schedule of assessments as outlined in Table 1 and Table 2 for the 
subject's cumulative cycle.
Transition From Phase 1 Portion to Phase 2a Portion
Once the MTD and/or the RPTD is declared on the 21/21 day continuous dosing schedule, 
a safety analysis will be performed as described in Section 8.1.4.  The results of the safety 
analysis as well as the recommended Phase 2 dose and dosing schedule will be 
communicated to all participating research sites prior to the start of enrollment in the 
Phase 2a portion of the study.  Phase 1 subjects are not eligible for enrollment in the 
Phase 2a portion of the study, but may continue receiving ABT-263 monotherapy for up 
to 11 years after the last subject transitions to the Extension Study provided they continue 
to tolerate the drug, have no evidence of disease progression, and do not meet any of the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
26
criteria for subject discontinuation (Section 5.4).  Subjects who enter the Extension Study 
will continue taking ABT-263 at the same dose and schedule they were receiving in the 
Phase 1 portion of the study.
Subjects who enter the Extension Study must continue to meet all Inclusion and Exclusion 
criteria, with the exception of Laboratory Criteria.  However, subjects must meet 
laboratory criteria as stated in Section 5.2.5.
Phase 2a
In the Phase 2a portion of the study, 250 mg of ABT-263 will be administered under a 
21/21 day continuous dosing schedule.  All subjects will self-administer ABT-263 within 
30 minutes after the completion of breakfast unless specified otherwise.
A 7-day lead-in dose titration period will be implemented.  Subjects will begin dosing at 
100 mg on Lead-in Day 1 (LD1).  A subject may only proceed from the lead-in period to 
250 mg on Cycle 1 Day 1 and beyond if platelet count is ≥ 50,000/mm3 after Lead-in 
Day 7 and stable or increasing.  If the platelet count is < 50,000/mm3 after Lead-in Day 7, 
the visit day will be considered Lead-in Day 8 and the subject will continue to receive the 
lead-in dose until the platelet count is ≥ 50,000/mm3.
When the platelet count is ≥ 50,000/mm3, the subject will receive the lead-in dose that 
day, and the next day (defined as Cycle 1 Day 1) the subject will receive the defined dose 
for Cycle 1 Day 1, provided the pre-dose platelet count that day is ≥ 50,000/mm3 and 
platelets are stable or increasing.  For example, if a subject's platelet count is 
≥50,000/mm3 on Lead-in Day 9, the subject will take the lead-in dose on Day 9.  The 
next day will be considered Cycle 1 Day 1 and the subject will begin receiving the defined 
dose for Cycle 1 Day 1.  However, if the pre-dose platelet count is < 50,000/mm3 or 
platelets are decreasing, then the day becomes Lead-in Day 10 and the subject continues 
dosing at the lead-in dose.
If the platelet count is < 50,000/mm3 after 14 days at the lead in dose, the lead in dose will 
become the subject's dose for the duration of the study.  To change from the lead in dose 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
27
to a higher dose (for subjects who continue receiving the lead in dose beyond the lead in 
period), a discussion between the investigator and the AbbVie Medical Monitor is 
required.
For the purpose of subject assessments for safety and clinical progression under a 
21/21 day dosing schedule, a cycle will be defined as 21 days. These assessments for 
safety and clinical progression will continue weekly through the first two cycles (6 weeks) 
of ABT-263.  Subsequently, subject assessments for safety and clinical progression will 
be performed once every cycle (every 3 weeks) of ABT-263.
If, during Phase 2a, dose-limiting toxicities are observed at a frequency higher than the 
definition of MTD (> 30%), the principal investigator and the AbbVie Medical Monitor 
will review the data and jointly determine whether dosing should continue or a new, lower 
recommended Phase 2 dose or alternate dosing schedule should be defined.
Subjects with stable disease in the Phase 2a portion of the study may continue receiving 
ABT-263 monotherapy for up to 11 years after the last subject transitions to the Extension 
Study, provided they continue to tolerate the drug, have no evidence of disease 
progression, and do not meet any of the criteria for subject discontinuation (Section 5.4).  
Subjects who enter the Extension Study will continue taking ABT-263 at the same dose 
and schedule they were receiving in the Phase 2a portion of the study.
Subjects who enter the Extension Study must continue to meet all Inclusion and Exclusion 
criteria, with the exception of Laboratory Criteria.  However, subjects must meet 
laboratory criteria stated in Section 5.2.5.
5.2
Selection of Study Population
Subjects will undergo screening procedures within 14 days prior to initial study drug 
administration (Lead-in Day 1/Cycle 1 Day 1).  Adult male and female subjects with CLL 
who meet the inclusion criteria and who do not meet any of the exclusion criteria will be 
eligible for enrollment into the study.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
28
5.2.1
Phase 1 Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
The subject must be ≥ 18 years of age.
2.
The subject must have relapsed or refractory CLL and require treatment in the 
opinion of the investigator.
3.
The subject has an Eastern Cooperative Oncology Group performance score of 1.
4.
Subjects receiving Selective Serotonin Reuptake Inhibitor (SSRI) anti-depressants 
(e.g., Prozac) must be receiving a stable dose for at least 21 days prior to the 
first dose of study drug.
5.
The subject must have adequate bone marrow independent of growth factor support 
(with the exception of subjects with ANC < 1000/L and bone marrow heavily 
infiltrated with underlying disease [80% or more]), renal and hepatic function, per 
local laboratory reference range at Screening as follows:
●
Bone marrow:  Absolute Neutrophil count (ANC) ≥ 1000/L; 
Platelets ≥75,000/mm3 (entry platelet count must be independent of 
transfusion within 14 days of Screening), Hemoglobin ≥ 9.0 g/dL;
●
Renal function:  Serum creatinine 2.0 mg/dL or calculated creatinine 
clearance ≥ 50 mL/min;
●
Hepatic function and enzymes:  AST and ALT 3.0 the upper normal limit 
(ULN) of institution's normal range; Bilirubin 1.5 ULN.  Subjects with 
Gilbert's Syndrome may have a Bilirubin > 1.5 ULN;
●
Coagulation:  aPTT, PT, not to exceed 1.2 ULN.
6.
Female subjects must be surgically sterile, postmenopausal (for at least 1 year), or 
have negative results for a pregnancy test performed as follows:
●
At Screening on a serum sample obtained within 14 days prior to initial study 
drug administration, and
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
29
●
Prior to dosing on a urine sample obtained on Cycle 1 Day 1 or Lead-in Day 1 
(lead-in period) if it has been > 7 days since obtaining the serum pregnancy 
test results.
7.
All female subjects not surgically sterile or postmenopausal (for at least 1 year) and 
non-vasectomized male subjects must practice at least one of the following 
methods of birth control:
●
total abstinence from sexual intercourse (minimum one complete menstrual 
cycle);
●
a vasectomized partner;
●
hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months 
prior to study drug administration;
●
double-barrier method (including condoms, contraceptive sponge, diaphragm 
or vaginal ring with spermicidal jellies or cream).
8.
The subject 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.
5.2.2
Phase 1 Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
The subject has a history or is clinically suspicious for cancer-related Central 
Nervous System (CNS) disease.
2.
The subject has undergone an allogeneic or autologous stem cell transplant.
3.
The subject has a recent history (within 1 year prior to first dose of study drug) of 
an underlying, predisposing condition of bleeding or currently exhibits signs of 
bleeding.
4.
The subject has active peptic ulcer disease or other potentially hemorrhagic 
esophagitis/gastritis.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
30
5.
The subject has active immune thrombocytopenic purpura or a history of being 
refractory to platelet transfusions (within 1 year prior to the first dose of study 
drug).
6.
The subject has received aspirin within 7 days prior to the first dose of study drug.
7.
The subject is currently receiving or requires anticoagulation therapy or any drugs 
or herbal supplements that affect platelet function, with the exception of low-dose 
anticoagulation medications that are used to maintain the patency of a central 
intravenous catheter.
8.
Subject has received steroid therapy for anti-neoplastic intent within 7 days prior to 
the first dose of study drug with the exception of inhaled steroids for asthma, 
topical steroids, or replacement/stress corticosteroids.
9.
The subject has received any anti-cancer therapy including chemotherapy, 
immunotherapy, radiotherapy, hormonal (with the exception of hormones for 
thyroid conditions or estrogen replacement therapy [ERT]), or any investigational 
therapy within 14 days prior to the first dose of study drug, or has not recovered to 
less than grade 2 clinically significant adverse effect(s)/toxicity(ies) of the previous 
therapy.
10.
The subject has received a biologic within 30 days prior to the first dose of study 
drug.
11.
The subject has consumed grapefruit or grapefruit products within 3 days prior to 
the first dose of study drug.
12.
The subject has a significant history of cardiovascular disease (e.g., myocardial 
infarction [MI], thrombotic, or thromboembolic event in the last 6 months), renal, 
neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic 
disease that in the opinion of the investigator would adversely affect his/her 
participating in this study.
13.
A female subject is pregnant or breast-feeding.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
31
14.
The subject has tested positive for HIV (due to potential drug-drug interactions 
between anti-retroviral medications and ABT-263, as well as anticipated ABT-263 
mechanism based lymphopenia that may potentially increase the risk of 
opportunistic infections and potential drug-drug interactions with certain 
anti-infective agents).
15.
The subject has a history of other active malignancies within the past 3 years prior 
to study entry, with the exception of:
●
adequately treated in situ carcinoma of the cervix uteri;
●
basal or squamous cell carcinoma of the skin;
●
previous malignancy confined and surgically resected with curative intent.
16.
The subject exhibits evidence of other clinically significant uncontrolled 
condition(s) including, but not limited to:
●
Uncontrolled systemic infection (viral, bacterial, or fungal)
●
diagnosis of fever and neutropenia within 1 week prior to study drug 
administration.
5.2.3
Phase 2a Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
The subject must be ≥ 18 years of age.
2.
The subject must have CLL and require treatment in the opinion of the investigator.
3.
The subject has relapsed disease and has received no more than 5 prior 
myelosuppressive/chemotherapy regimens.
4.
Subject has an Eastern Cooperative Oncology Group performance score of 1.
5.
Subjects receiving Selective Serotonin Reuptake Inhibitor (SSRI) anti-depressants 
(e.g., Prozac) must be receiving a stable dose for at least 21 days prior to the 
first dose of study drug.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
32
6.
The subject must have adequate bone marrow independent of growth factor support 
(with the exception of subjects with ANC < 1000/L and bone marrow heavily 
infiltrated with underlying disease [80% or more]), renal and hepatic function, per 
local laboratory reference range at Screening as follows:
●
Bone marrow:  Absolute Neutrophil count (ANC) ≥ 1000/L; 
Platelets ≥75,000/mm3 (entry platelet count must be independent of 
transfusion within 14 days of Screening); Hemoglobin ≥ 9.0 g/dL;
●
Renal function:  Serum creatinine 2.0 mg/dL or calculated creatinine 
clearance ≥ 50 mL/min;
●
Hepatic function and enzymes:  AST and ALT 3.0 the upper normal limit 
(ULN) of institution's normal range; Bilirubin 1.5 ULN.  Subjects with 
Gilbert's Syndrome may have a Bilirubin > 1.5 ULN;
●
Coagulation:  aPTT, PT must not exceed 1.2 ULN.
7.
Female subjects must be surgically sterile, postmenopausal (for at least 1 year), or 
have negative results for a pregnancy test performed as follows:
●
At Screening on a serum sample obtained within 14 days prior to initial study 
drug administration, and
●
Prior to dosing on a urine sample obtained on Lead-in Day 1 if it has been 
> 7 days since obtaining the serum pregnancy test results.
8.
All female subjects not surgically sterile or postmenopausal (for at least 1 year) and 
non-vasectomized male subjects must practice at least one of the following 
methods of birth control:
●
total abstinence from sexual intercourse (minimum one complete menstrual 
cycle);
●
a vasectomized partner;
●
hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months 
prior to study drug administration;
●
double-barrier method (including condoms, contraceptive sponge, diaphragm 
or vaginal ring with spermicidal jellies or cream).
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
33
9.
The subject 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.
5.2.4
Phase 2a Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
The subject has a history or is clinically suspicious for cancer-related Central 
Nervous System (CNS) disease.
2.
The subject has a recent history (within 1 year prior to first dose of study drug) of 
an underlying, predisposing condition of bleeding or currently exhibits signs of 
bleeding.
3.
The subject has undergone an allogeneic or autologous stem cell transplant.
4.
The subject has active peptic ulcer disease or other potentially hemorrhagic 
esophagitis/gastritis.
5.
The subject has active immune thrombocytopenic purpura or a history of being 
refractory to platelet transfusions (within 1 year prior to the first dose of study 
drug).
6.
The subject is currently receiving or requires anticoagulation therapy or any drugs 
or herbal supplements that affect platelet function, with the exception of low-dose 
anticoagulation medications that are used to maintain the patency of a central 
intravenous catheter.
7.
The subject has received steroid therapy for anti-neoplastic intent within 7 days 
prior to the first dose of study drug with the exception of inhaled steroids for 
asthma, topical steroids or replacement/stress corticosteroids.
8.
The subject has received aspirin within 7 days prior to the first dose of study drug.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
34
9.
The subject has received any anti-cancer therapy including chemotherapy, 
immunotherapy, radiotherapy, hormonal (with the exception of hormones for 
thyroid conditions or estrogen replacement therapy [ERT]), or any investigational 
therapy within 14 days prior to the first dose of study drug, or has not recovered to 
less than grade 2 clinically significant adverse effect(s)/toxicity(ies) of the previous 
therapy.
10.
The subject has received a biologic within 30 days prior to the first dose of study 
drug.
11.
The subject has consumed grapefruit or grapefruit products within 3 days prior to 
the first dose of study drug.
12.
The subject has a significant history of cardiovascular disease (e.g., myocardial 
infarction [MI], thrombotic, or thromboembolic event in the last 6 months), renal, 
neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic 
disease that in the opinion of the investigator would adversely affect his/her 
participating in this study.
13.
A female subject is pregnant or breast-feeding.
14.
The subject has tested positive for HIV (due to potential drug-drug interactions 
between anti-retroviral medications and ABT-263, as well as anticipated ABT-263 
mechanism based lymphopenia that may potentially increase the risk of 
opportunistic infections and potential drug-drug interactions with certain 
anti-infective agents).
15.
The subject has a history of other active malignancies within the past 3 years prior 
to study entry, with the exception of:
●
adequately treated in situ carcinoma of the cervix uteri;
●
basal or squamous cell carcinoma of the skin;
●
previous malignancy confined and surgically resected with curative intent.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
35
16.
The subject exhibits evidence of other clinically significant uncontrolled 
condition(s) including, but not limited to:
●
uncontrolled systemic infection (viral, bacterial, or fungal);
●
diagnosis of fever and neutropenia within one week prior to study drug 
administration.
17.
The subject has received known CYP3A inhibitors (e.g., ketoconazole) within
7 days prior to first dose of study drug.
5.2.5
Extension Study Inclusion Criteria
Subjects who enter the Extension Study must continue to meet all Inclusion and Exclusion 
criteria (excluding laboratory parameters) from Phase 1 or in Phase 2a as listed above. 
Subjects entering the Extension Study must also have stable lab values per applicable 
laboratory reference ranges.
●
Subjects must meet the following hematology and coagulation lab criteria:
○
Platelet counts must be ≥ 25,000/mm3 (untransfused).  Platelet counts 
50,000/mm3 must be stable and monitored at an increased frequency at 
the discretion of the investigator.
○
Absolute Neutrophil count (ANC) ≥ 500/L.  ANC ≥ 500/µL and 
< 1,000/µL should be monitored at an increased frequency at the discretion 
of the investigator.
○
Hemoglobin of ≥ 8.0 g/dL.
○
aPTT, PT is not to exceed 1.2 ULN.
●
Subjects must meet the following chemistry criteria:
○
Subjects' chemistry values must not exceed Grade 2.  Grade 2 chemistry 
labs should be monitored at an increased frequency at the discretion of the 
investigator.
○
Serum creatinine 3.0 the upper normal limit (ULN) of institution's 
normal range.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
36
○
AST and ALT 5.0 the upper normal limit (ULN) of institution's normal 
range.
○
Bilirubin 3.0 ULN.  Subjects with Gilbert's Syndrome may be allowed 
to have a Bilirubin > 3.0 ULN based on a joint decision between the 
investigator and AbbVie medical monitor.
5.2.6
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medication, vitamins, 
and/or herbal supplements or if administration of any medication becomes necessary from 
the time of screening and throughout the study, the name of the medication, dosage 
information including dose and frequency, date(s) of administration including start and 
end dates, and reason for use must be recorded on the appropriate case report form (CRF).  
AbbVie will provide subject diaries to serve as a tool for the subjects to record 
concomitant medications and adverse events.
Steroid therapy, for anti-neoplastic intent, will not be allowed within 7 days prior to the 
first dose of study drug and during ABT-263 administration with the exception of inhaled 
steroids for asthma, topical steroids, or replacement/stress corticosteroids.
Aspirin will not be allowed within 7 days prior to the first dose of study drug or during 
ABT-263 administration.  However, subjects who have previously received aspirin 
therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) 
of aspirin if platelet counts are stable (≥ 50,000/mm3) through 2 Cycles of ABT-263 
administration.  All decisions regarding treatment with aspirin therapy will be determined 
by the investigator in conjunction with the AbbVie Medical Monitor.
CYP3A inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to 
the first dose of study drug or during ABT-263 administration.
Anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal 
(with the exception of hormones for thyroid conditions or estrogen replacement therapy 
[ERT]), and other investigational agents will not be allowed within 14 days prior to the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
37
first dose of study drug, or has not recovered to less than grade 2 clinically significant 
adverse effect(s)/toxicity(ies) of the previous therapy.  These agents will not be allowed 
during ABT-263 administration.
Biologics will not be allowed within 30 days prior to the first dose of study drug and 
during ABT-263 administration.
Colony stimulating factors (G-CSF, GM-CSF) or human erythropoietin will be considered 
during administration of ABT-263 if deemed necessary by the investigator and if mutually 
agreed upon by AbbVie Medical Monitor.
Best supportive care and treatment will be allowed for each subject (antiemetics, 
antibiotics, transfusions, nutritional support, pain control, etc.) with the exception of the 
following:
●
Plavix, ibuprofen, Aggrastat and other anticoagulants, drugs or herbal 
supplements that affect platelet function (due to expected dose limiting toxicity 
of thrombocytopenia).  Administration of heparin to keep subject's infusion 
lines patent is allowed.  Low-dose anticoagulation medications that are used to 
maintain the patency of a central intravenous catheter are allowed.
●
disulfiram (due to percentage of ethanol content in the drug formulation).
Concomitant medications of the following categories could potentially lead to adverse 
reaction(s).  It is important to assess whether potential study subjects are taking any of the 
cautionary medications.  If a potential study subject is taking any of the medications in the 
categories described below, the investigator will assess and document the use of 
medications known or suspected to fall in the following medication categories.  A sample 
list of medications that fall into the cautionary categories mentioned below can be found 
in Appendix E.  It is not possible to produce a 100% exhaustive list of medications that 
fall into the categories, so if in question, please refer to the appropriate product label.  If 
the investigator determines that such a medication is medically necessary, the investigator 
will notify the AbbVie Medical Monitor and discuss the investigator's use of these
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
38
medications and the investigator's plans to medically monitor the potential study subject 
under consideration.
●
CYP2C8 substrates such as glitazones and select statins (due to expected 
inhibition of the metabolism of CYP2C8 substrates).
●
CYP2C9 substrates such as phenytoin and tolbutamide (due to expected 
inhibition of the metabolism of CYP2C9 substrates).
●
CYP3A inducers such as rifampin and carbamazepine (due to possible 
induction of the metabolism of ABT-263).
If clinically indicated, anti-herpes and anti-PCP (Pneumocystis carinii pneumonia) 
prophylaxis should be considered.  Although there is a potential for drug-drug 
interactions, there is likely to be limited potential clinical effects, therefore Bactrim 
(trimethoprim-sulfamethoxazole) can be considered for PCP prophylaxis with close 
clinical monitoring.
A list of common medications in the excluded classifications described above is provided 
in Appendix E.  This is a partial list; all medications in these classifications are excluded.
Contact the AbbVie Medical Monitor identified in Section 6.5, if there are any questions 
regarding concomitant or prior therapies.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow
Chart
Study procedures will be performed as summarized in Table 1 through Table 6 below for 
the Phase 1 and Phase 2a portions of the study.
Study procedures for subjects in the Extension Study can be found in Appendix G.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
39
Table 1.
Schedule of Assessments – 14/21 Day Dosing (Phase 1)
Procedure
Screeninga
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 2 
(C1D2)
Cycle 1 
Day 3 
(C1D3)
Cycle 1
Day 14
(C1D14)
Weekly 
Through 
Cycle 2
Day 1 of Each 
Cycle 
After Cycle 2b
End of 
Every 3rd
Cycle
Final 
Visitr
30 Day Safety
Follow-Upr
Informed Consent
X
Physical Exam (including weight)
Xc
X
Xd
X
X
X
Medical History
X
X
Oncologic History
X
Vital Signs
X
X
X
X
X
X
12-lead ECGe
X
X
X
Xe
X
2D Echocardiogram with Dopplerf
X
X
X
Xf
X
Platelet Countg
X
X
X
X
X
X
X
X
X
Lymphocyte Enumerationh
X
X
X
X
Pregnancy Testi
X
X
Chemistryj
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
Urinalysisj
X
X
X
X
X
X
Performance Status (ECOG)
X
X
X
X
X
X
Tumor Assessmentsk
Xl
Xm,n
X
Bone Marrow Aspirate and 
Biopsyn
Xo
Adverse Event/Concomitant 
Medications Assessment
Xp
X
X
X
X
X
Xq
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
40
Table 1.
Schedule of Assessments – 14/21 Day Dosing (Phase 1) (Continued)
Procedure
Screeninga
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 2 
(C1D2)
Cycle 1 
Day 3 
(C1D3)
Cycle 1
Day 14
(C1D14)
Weekly 
Through 
Cycle 2
Day 1 of Each 
Cycle 
After Cycle 2b
End of 
Every 3rd
Cycle
Final 
Visitr
30 Day Safety
Follow-Upr
Dispense Meds/Subject Dosing 
Log
X
X
X
Collect Unused Study Drug
X
X
X
a.
Screening procedures must be performed within 14 days prior to study drug administration, except tumor assessment scans (if clinically indicated) and bone marrow 
aspirate/biopsy, which must be performed within 21 days prior to study drug administration.
b.
Study procedures (except platelets) may be performed within 72 hours prior to Day 1 for each cycle.  Platelets counts must be performed within 24 hours prior to dosing on 
Day 1 of each cycle.
c.
Height will be assessed at Screening only.
d.
A symptom directed physical exam may be performed weekly through Cycle 2.
e.
ECG will be performed at Screening, Day 1 and Day 14 of Cycle 1, Day 1 of each subsequent cycle and at the Final Visit for all subjects in the first 2 cohorts.  ECG will be 
performed at Screening, Day 1 and Day 14 of Cycle 1, Day 1 and Day 14 of Cycle 3 and at the Final Visit for subjects in subsequent cohorts.  Every effort should be made to 
obtain all ECGs approximately 4-8 hours post-dose (however, 6-8 hours post-dose is preferred), and if possible at approximately the same time of day.  If pharmacokinetic 
data indicates the Cmax of parent drug or a major metabolite occurs at a time different than this specified range, the timing of the ECG may be modified.  Repeat ECGs will be 
performed whenever clinically necessary.
f.
2D Echocardiogram with Doppler will be performed at Screening, Day 1 and Day 14 of Cycle 1, Day 1 of each subsequent cycle and at the Final Visit for all subjects in the 
first 2 cohorts.  Echocardiogram with Doppler will be performed at Screening, Day 1 and Day 14 of Cycle 1, Day 1 and Day 14 of Cycle 3 and at the Final Visit for subjects 
in subsequent cohorts.  Every effort should be made to obtain all echocardiograms approximately 4-8 hours post-dose (however, 6-8 hours post-dose is preferred), and if 
possible at approximately the same time of day.  If pharmacokinetic data indicates the Cmax of parent drug or a major metabolite occurs at a time different than this specified 
range, the timing of the echocardiogram may be modified.  Repeat echocardiograms will be performed whenever clinically necessary.
g.
Platelet counts will be performed Cycle 1:  Pre-dose on Days 1, 2, 3, 4, 5, 6, 8, 14 (in addition, at all PK time points per Table 4), Day 16 and as needed; Subsequent Cycles:  
Days 1, 3, 5, 8, 16 and as needed.  If the investigator and the AbbVie Medical Monitor jointly agree that platelet counts through Cycle 4 have been stable, then the frequency 
of platelet counts in Cycle 5 and beyond may be decreased to Day 1 of each cycle and as needed.  If platelet count performed on any given day is less than 50,000/mm3, 
additional platelet counts should be performed every day or at the discretion of the investigator.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
41
Table 1.
Schedule of Assessments – 14/21 Day Dosing (Phase 1) (Continued)
h.
Lymphocyte enumeration will be performed at Screening, Day 14 of Cycle 1, end of Cycle 4, the end of every 3rd cycle thereafter and at the Final Visit.
i.
For women of child bearing potential, a serum sample is to be tested at Screening and a urine sample (if it has been > 7 days since obtaining the serum pregnancy test results) 
is to be tested prior to dosing on Day 1 of the first cycle.
j.
The specific laboratory tests required for chemistry, hematology and urinalysis are listed in Table 7.  Triglycerides will only be collected at Screening and at the Final Visit.  
Amylase and lipase will be collected at Screening, Cycle 1 Day 14, and Final Visit.  For any subjects who are at high risk for tumor lysis syndrome (TLS) during Cycle 2 and 
beyond, additional samples for hematology and chemistry may be collected as per the management guidelines in Section 6.7.4.
k.
Assessment for tumor response will be performed at the end of Cycle 2, end of Cycle 4, end of every 4 cycles through Cycle 20 (i.e., C8, C12, C16, C20), end of every 
8 cycles thereafter (i.e., C28, C36, C44. . .) and at the Final Visit.  Analysis of peripheral blood for tumor response will be performed on Day 1 (pre-dose) of the following 
cycle for every tumor assessment.
l.
A CT scan will be performed at Screening (within 21 days prior to study drug administration).
m.
Assessments for tumor response will be repeated at least 2 months after NCI-WG criteria for a complete remission (CR or CRi) or partial remission (PR) are first met.
n.
If clinical and laboratory criteria for a CR or PR are met, a bone marrow aspirate/biopsy and CT scan should be performed at least 2 months after the criteria are first met in 
order to confirm a CR or PR.
o.
Bone marrow aspirate/biopsy will be done at Screening (within 21 days prior to study drug administration) unless a bone marrow aspirate and biopsy was obtained within 
12 weeks of starting study drug without intervening treatment and is representative of the subject's existing disease.
p.
Serious adverse event assessment will be performed at Screening after informed consent has been obtained.
q.
Adverse events will be followed until satisfactory clinical resolution of the adverse event is achieved.
r.
For subjects who continue in the Extension Study, the Final Visit and 30 Day Safety Follow-Up Visit procedures will be performed upon completion of the Extension Study.  
Refer to Appendix G for the Schedule of Assessments for subjects enrolled in the Extension Study.
Note:
A schedule of assessments for subjects enrolled in Phase 1 – 21/21 Day Dosing can be found in Table 2.  A schedule of assessments for subjects enrolled in Phase 2a can 
be found in Table 3.  Pharmacokinetic (PK) collection time points for Phase 1 are located in Table 4 and Table 5.  PK collection time points for Phase 2a are located in 
Table 6.  Biomarker collection time points for Phase 1 are in Table 8.  Biomarker collection time points for Phase 2a are located in Table 9.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
42
Table 2.
Schedule of Assessments – 21/21 Day Dosing with Lead-in Period (Phase 1)
Procedure
Screeninga
Lead-in 
Day 1
(LD1)
Lead-in 
Day 2
(LD2)
Lead-in 
Day 3
(LD3)
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 2 
(C1D2)
Cycle 1 
Day 3 
(C1D3)
Cycle 1
Day 14
(C1D14)
Weekly 
Through 
Cycle 2
Day 1 of 
Each 
Cycle 
After 
Cycle 2b
End of 
Every 3rd
Cycle
Final 
Visitr
30 Day 
Safety
Follow-Upr
Informed Consent
X
Physical Exam 
(including weight)
Xc
X
X
Xd
X
X
X
Medical History
X
X
Oncologic History
X
Vital Signs
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
X
2D Echocardiogram 
with Dopplerf
X
X
X
X
X
Platelet Countg
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte 
Enumerationh
X
X
X
X
Pregnancy Testi
X
X
Chemistryj
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
Urinalysisj
X
X
X
X
X
X
X
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
43
Table 2.
Schedule of Assessments – 21/21 Day Dosing with Lead-in Period (Phase 1) (Continued)
Procedure
Screeninga
Lead-in 
Day 1
(LD1)
Lead-in 
Day 2
(LD2)
Lead-in 
Day 3
(LD3)
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 2 
(C1D2)
Cycle 1 
Day 3 
(C1D3)
Cycle 1
Day 14
(C1D14)
Weekly 
Through 
Cycle 2
Day 1 of Each 
Cycle After 
Cycle 2b
End of 
Every 
3rd Cycle
Final 
Visitr
30 Day 
Safety
Follow-Upr
Performance Status (ECOG)
X
X
X
X
X
X
X
Tumor Assessmentsk
Xl
Xm,n
X
Bone Marrow Aspirate and 
Biopsyn
Xo
Adverse Event/Concomitant 
Medications Assessment
Xp
X
X
X
X
X
X
Xq
Dispense Meds/Subject Dosing 
Log
X
X
X
X
Collect Unused Study Drug
X
X
X
a.
Screening procedures must be performed within 14 days prior to study drug administration, except baseline tumor assessment (if clinically indicated) and bone marrow 
aspirate/biopsy, which must be performed within 21 days prior to study drug administration.
b.
Study procedures (except platelets) may be performed within 72 hours prior to Day 1 for each cycle.  Platelets counts must be performed within 24 hours prior to dosing on 
Day 1 of each cycle.
c.
Height will be assessed at Screening only.
d.
A symptom directed physical exam may be performed weekly through Cycle 2.
e.
ECG will be performed at Screening, Lead-in Day 1, Day 1 and Day 14 of Cycle 1, Day 1 and Day 14 of Cycle 3 and at the Final Visit.  Every effort should be made to obtain 
all ECGs approximately 4-8 hours post-dose (however, 6-8 hours post-dose is preferred), and if possible at approximately the same time of day.  If pharmacokinetic data 
indicates the Cmax of parent drug or a major metabolite occurs at a time different than this specified range, the timing of the ECG may be modified.  Repeat ECGs will be 
performed whenever clinically necessary.
f.
2D Echocardiogram with Doppler will be performed at Screening, Lead-in Day 1, Day 1 and Day 14 of Cycle 1, Day 1 and Day 14 of Cycle 3 and at the Final Visit.  Every 
effort should be made to obtain all echocardiograms approximately 4-8 hours post-dose (however, 6-8 hours post-dose is preferred), and if possible at approximately the same 
time of day.  If pharmacokinetic data indicates the Cmax of parent drug or a major metabolite occurs at a time different than this specified range, the timing of the 
echocardiogram may be modified.  Repeat echocardiograms will be performed whenever clinically necessary.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
44
Table 2.
Schedule of Assessments – 21/21 Day Dosing with Lead-in Period (Phase 1) (Continued)
g.
Platelet counts will be performed at Screening, Lead-in Days 1, 2, 3, 5 and 7 and then daily if the lead-in period extends beyond Day 7.  Cycle 1:  Pre-dose on Days 1, 2, 3, 5, 
8, 14 (in addition, at all PK time points per Table 4), Day 16, and as needed.  Subsequent Cycles:  Weekly and as needed.  If the investigator and the AbbVie Medical Monitor 
jointly agree that platelet counts through Cycle 4 have been stable, then the frequency of platelet counts in Cycle 5 and beyond may be decreased to Day 1 of each cycle and 
as needed.  If platelet count on any given day is less than 50,000/mm3, additional platelet counts should be performed every day or at the discretion of the investigator.
h.
Lymphocyte enumeration will be performed at Screening, Day 14 of Cycle 1, end of Cycle 4, the end of every 3rd cycle thereafter and at the Final Visit.
i.
For women of child bearing potential, a serum sample is to be tested at Screening and a urine sample is to be tested (if it has been > 7 days since obtaining the serum 
pregnancy test results) prior to dosing on Lead-in Day 1 (lead-in period).
j.
The specific laboratory tests required for chemistry, hematology and urinalysis are listed in Table 7.  Triglycerides will only be collected at Screening and at the Final Visit.  
Amylase and lipase will be collected at Screening, Cycle 1 Day 14, and Final Visit.  For any subjects who are at high risk for tumor lysis syndrome (TLS) during Cycle 2 and 
beyond, additional samples for hematology and chemistry may be collected as per the management guidelines in Section 6.7.4.
k.
Assessment for tumor response will be performed at the end of Cycle 2, end of Cycle 4, end of every 4 cycles through Cycle 20 (i.e., C8, C12, C16, C20), end of every 
8 cycles thereafter (i.e., C28, C36, C44. . .) and at the Final Visit.  Analysis of peripheral blood for tumor response will be performed on Day 1 (pre-dose) of the following 
cycle for every tumor assessment.
l.
A CT scan will be performed at Screening (within 21 days prior to study drug administration).
m.
Assessments for tumor response will be repeated at least 2 months after NCI-WG criteria for a complete remission (CR or CRi) or partial remission (PR) are first met.
n.
If clinical and laboratory criteria for a CR or PR are met, a bone marrow aspirate/biopsy and CT scan should be performed at least 2 months after the criteria are first met in 
order to confirm a CR or PR.
o.
Bone marrow aspirate/biopsy will be done at Screening (within 21 days prior to study drug administration) unless a bone marrow aspirate and biopsy was obtained within 
12 weeks of starting study drug without intervening treatment and is representative of the subject's existing disease.
p.
Serious adverse event assessment will be performed at Screening after informed consent has been obtained.
q.
Adverse events will be followed until satisfactory clinical resolution of the adverse event is achieved.
r.
For subjects who continue in the Extension Study, the Final Visit and 30 Day Safety Follow-Up Visit procedures will be performed upon completion of the Extension Study.  
Refer to Appendix G for the Schedule of Assessments for subjects enrolled in the Extension Study.
Note:
A schedule of assessments for subjects enrolled in Phase 1 – 14/21 Day Dosing can be found in Table 1.  A schedule of assessments for subjects enrolled in Phase 2a can 
be found in Table 3.  Pharmacokinetic (PK) collection time points for Phase 1 are located in Table 4 and Table 5.  PK collection time points for Phase 2a are located in 
Table 6.  Biomarker collection time points for Phase 1 are in Table 8.  Biomarker collection time points for Phase 2a are in Table 9.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
45
Table 3.
Schedule of Assessments (Phase 2a) –21/21 Day Continuous Dosing Schedule with Lead-in Period
Procedure
Screeninga
LD1
LD2
LD3
C1
D1
C1
D2
C1
D3
C1
D15
Weekly 
Through 
C2
D1 of Each 
Cycle After 
C2b
End of 
Every 3rd
Cycle
C5
D1
C9
D1
Final 
Visits
30 Day 
Safety
Follow-
Ups
Post-
Treatment
Informed Consent
X
Physical Exam (including weight)
Xc
X
X
Xd
X
X
X
Medical History
X
X
Oncologic History
X
Vital Signs
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
X
2D Echocardiogram with Dopplerf
X
X
X
X
X
Platelet Countg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte Enumerationh
X
X
X
X
Pregnancy Testi
X
X
Chemistryj
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
Urinalysisj
X
X
X
X
X
X
X
Performance Status (ECOG)
X
X
X
X
X
X
X
Tumor Assessmentsk
Xl
Xm,n
X
Bone Marrow Aspirate/Biopsyn
Xo
Clinical Disease Progression 
Assessment
X
X
X
Adverse Event/Concomitant 
Medications Assessment
Xp
X
X
X
X
X
X
Xq
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
46
Table 3.
Schedule of Assessments (Phase 2a) – 21/21 Day Continuous Dosing Schedule with Lead-in Period 
(Continued)
Procedure
Screeninga
LD1
LD2
LD3
C1
D1
C1
D2
C1
D3
C1
D15
Weekly 
Through 
C2
D1 of Each 
Cycle After 
C2b
End of 
Every 3rd
Cycle
C5
D1
C9
D1
Final 
Visits
30 Day 
Safety
Follow-
Ups
Post-
Treatment
Dispense Meds/Subject Dosing 
Log
X
X
X
X
Collect Unused Study Drug
X
X
X
Survival Assessment(s)r
X
C = Cycle; D = Day; L = Lead-in
a.
Screening procedures must be performed within 14 days prior to study drug administration, except baseline tumor assessment scans (if clinically indicated) and bone marrow 
aspirate/biopsy, which must be performed within 21 days prior to study drug administration.
b.
Study procedures (except platelets) may be performed within 72 hours prior to Day 1 for each cycle.  Platelet counts must be performed within 24 hours prior to dosing on 
Day 1 of each cycle.
c.
Height will be assessed at Screening only.
d.
A symptom directed physical exam may be performed weekly through Cycle 2.
e.
Every effort should be made to obtain all ECGs approximately 4 to 8 hours post-dose (however, 6 to 8 hours post-dose is preferred), and if possible at approximately the same 
time of day.  Repeat ECGs will be performed whenever clinically necessary.  If necessary, ECGs may be performed within 3 days of the visit, except Screening, which must 
be performed within 14 days prior to study drug administration.  
f.
Every effort should be made to obtain all echocardiograms approximately 4 to 8 hours post dose (however, 6 to 8 hours post dose is preferred), and if possible at 
approximately the same time of day.  Repeat echocardiograms will be performed whenever clinically necessary.  If necessary, ECHOs may be performed within 3 days of the 
visit, except Screening, which must be performed within 14 days prior to study drug administration.
g.
Platelet counts will be performed at Screening, Lead-in Days 1, 2, 3, 5 and 7 and then daily if the lead-in period extends beyond Day 7.  Cycle 1:  Pre-dose on Days 1, 2, 3, 5, 
8, 15 and as needed.  Subsequent Cycles:  Weekly and as needed.  If platelet count on any given day is less than 50,000/mm3, additional platelet counts should be performed 
every day or at the discretion of the investigator.  If the investigator and the AbbVie Medical Monitor jointly agree that platelet counts through Cycle 4 have been stable, then 
the frequency of platelet counts in Cycle 5 and beyond may be decreased to Day 1 of each Cycle and as needed.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
47
Table 3.
Schedule of Assessments (Phase 2a) – 21/21 Day Continuous Dosing Schedule with Lead-in Period 
(Continued)
h.
Lymphocyte enumeration will be performed at Screening, Day 15 of Cycle 1, end of Cycle 4, the end of every 3rd cycle thereafter and at the Final Visit.
i.
For women of childbearing potential, a serum sample is to be tested at Screening and a urine sample is to be tested (if it has been > 7 days since obtaining the serum 
pregnancy test results) prior to dosing on Lead-in Day 1 (lead-in period).
j.
The specific laboratory tests required for chemistry, hematology and urinalysis are listed in Table 7.  Triglycerides will only be collected at Screening and at the Final Visit.  
Amylase and lipase will be collected at Screening, Cycle 1 Day 15, and Final Visit.  For any subjects who are at high risk for tumor lysis syndrome (TLS) during Cycle 2 and 
beyond, additional samples for hematology and chemistry may be collected as per the management guidelines in Section 6.7.4.
k
Assessment for tumor response will be performed at the end of Cycle 2, end of Cycle 4, end of every 4 cycles through Cycle 20 (i.e., C8, C12, C16, C20), end of every 
8 cycles thereafter (i.e., C28, C36, C44. . .) and at the Final Visit.  Analysis of peripheral blood for tumor response will be performed on Day 1 (pre-dose) of the following 
cycle for every tumor assessment.
l.
A CT scan will be performed at Screening (within 21 days prior to study drug administration).
m.
Assessments for tumor response will be repeated 2 months after NCI-WG (1996) criteria for a complete remission (CR) are first met and/or at least 2 months after IWCLL 
updated NCI-WG (2008) criteria for a complete remission (CR or CRi) or partial remission (PR) are first met.
n.
If clinical and laboratory criteria for a CR or PR are met), a bone marrow aspirate/biopsy and CT scan should be performed at least 2 months after the criteria are first met in 
order to confirm a CR or PR.  A bone marrow aspirate/biopsy will be performed at the end of Cycle 8 (for all subjects regardless of response) if the subject is continuing to 
receive ABT-263.
o.
Bone marrow aspirate/biopsy will be done at Screening (within 21 days prior to study drug administration) unless a bone marrow aspirate and biopsy was obtained within 
12 weeks of starting study drug without intervening treatment and is representative of the subject's existing disease.
p.
Serious adverse event assessment will be performed at Screening after informed consent has been obtained.
q.
Adverse events will be followed until satisfactory clinical resolution of the adverse event is achieved.
r.
Survival assessments will be collected every 3 months for 2 years following discontinuation from the study (including the extension portion of the study).  In Protocol 
Amendment #12 this information will no longer be collected.
s.
For subjects who continue in the Extension Study, the Final Visit and 30 Day Safety Follow-Up Visit procedures will be performed upon completion of the Extension Study.  
Refer to Appendix G for the Schedule of Assessments for subjects enrolled in the Extension Study.
Note:
A schedule of assessments for subjects enrolled in Phase 1 can be found in Table 1 and Table 2.  Pharmacokinetic (PK) collection time points for Phase 1 are located in 
Table 4 and Table 5.  PK collection time points for Phase 2a are located in Table 6.  Biomarker collection time points for Phase 1 are in Table 8.  Biomarker collection 
time points for Phase 2a are located in Table 9.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
48
Table 4.
Schedule of Blood Collection for ABT-263 Assay (Pharmacokinetic Sampling) – Phase 1, Cycle 1
Phase
Cycle 1
Day 1
Cycle 1
Day 2
Cycle 1
Day 14
Phase 1 – 14/21 day schedule
0 (pre-dose)
2, 4, 6, 8 hours post-dose
24 hours post-dose Day 1 
(pre-dose Day 2)
0 (pre-dose)
2, 4, 6, 8 hours post-dose
Phase 1 – 21/21 day schedule – with lead-in
0 (pre-dose) 
2, 4, 6, 8 hours post-dose
24 hours post-dose Day 1 
(pre-dose Day 2)
0 (pre-dose)
2, 4, 6, 8 hours post-dose
All 0 hour (pre-dose) PK samples will be collected around the same time for platelet sample collection.
Note:
In addition, serial pharmacokinetic samples will be obtained from subjects who develop Grade 4 thrombocytopenia (< 25,000/mm3).  The first pharmacokinetic sample 
should be collected as soon as possible after determination of the Grade 4 thrombocytopenia and then 24 and 48 hours thereafter.
Table 5.
Schedule of Blood Collection for ABT-263 Assay (Pharmacokinetic Sampling) – Phase 1, Cycle 2 and Beyond
Phase
Cycle 2
Day 3
Cycle 2
Day 8
Cycle 2
Day 14
Cycle 3
Day 1
Cycle 3
Day 14
Day 14 of Cycles 6, 
9, 12 and 15
Phase 1 – 14/21 day schedule
0 hour (pre-dose)
0 hour (pre-dose)
0 hour (pre-dose)
4 to 8 hours post-dose 
(immediately after ECG)
0 hour (pre-dose) and 
4 to 8 hours post-dose 
(immediately after ECG)
0 (pre-dose)
Phase
Cycle 2
Day 3
Cycle 2
Day 8
Cycle 2
Day 14
Cycle 3
Day 1
Cycle 3
Day 14
Day 1 of Cycles 6, 9, 
12 and 15
Phase 1 – 21/21 day schedule 
– with lead-in
0 hour (pre-dose)
0 hour (pre-dose)
0 hour (pre-dose)
4 to 8 hours post-dose 
(immediately after ECG)
0 hour (pre-dose) and 
4 to 8 hours post-dose 
(immediately after ECG)
0 (pre-dose)
All 0 hour (pre-dose) PK samples will be collected around the same time for platelet sample collection.
Note:
In addition, serial pharmacokinetic samples will be obtained from subjects (including subjects in the Extension Study) who develop Grade 4 thrombocytopenia 
(< 25,000/mm3).  The first pharmacokinetic sample should be collected as soon as possible after determination of the Grade 4 thrombocytopenia and then 24 and 
48 hours thereafter.  Starting with Protocol Amendment 13, PK samples will NOT be collected.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
49
Table 6.
Schedule of Blood Collection for ABT-263 Assay (Pharmacokinetic Sampling) – Phase 2a, 21/21 Day 
Continuous Dosing Schedule
Procedure
Cycle 1
Day 15
Cycle 3
Day 1
Day 1 of Cycles 5 and 9
Phase 2a
0 (pre-dose) and 4 to 8 hours post-dose 
(immediately after ECG)
0 (pre-dose)
0 (pre-dose) and 4 to 8 hours post-dose 
(immediately after ECG)
All 0 hour (pre-dose) PK samples will be collected around the same time for platelet sample collection.
Note:
In addition, serial pharmacokinetic samples will be obtained from subjects (including subjects in the Extension Study) who develop Grade 4 thrombocytopenia 
(< 25,000/mm3).  The first pharmacokinetic sample should be collected as soon as possible after determination of the Grade 4 thrombocytopenia and then 24 and 
48 hours thereafter.  Starting with Protocol Amendment 13, PK samples will NOT be collected.
 
 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
50
5.3.1.1
Study Procedures
For subjects who continue in the Extension Study, the Final Visit, and 30 Day Safety 
Follow-Up Visit procedures will be performed only once upon completion of the 
Extension Study.
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. Additional details are provided 
in the subsequent section. Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study. If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow the updates 
below how to proceed.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, if it is not possible for all study procedures to be 
performed as specified due to travel restrictions or other reasons, the following 
modifications are allowed:
●
If permitted by local regulations, the IRB/IEC and the subject, the subject 
visits may be conducted in the subject's home residence.
●
Some study visits and/or activities may be performed by phone/virtually.  
These are indicated by a hashtag (#) in the activity table (Appendix G)
○
During a virtual visit, activities that do not need to be performed are 
indicated by a (#) in the activity table (Appendix G).
●
Study visits and/or activities may be performed by a local 
clinic/hospital/laboratory. All procedures performed at local facilities must be 
performed by appropriately qualified personnel.
●
Study Visits and/or activities should be performed as scheduled whenever 
possible. If it is not possible to do so due to the pandemic, perform the activity 
at the earliest feasible opportunity. Laboratory draws must be obtained within 
24 hours from the scheduled visit.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
51
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative 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 the pharmacodynamic (PD) and 
pharmacogenetic (PG) sampling portions of the study.  A separate informed consent will 
be required for subjects entering the Extension Study.  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.
Medical History
The following will be collected during the Screening Visit:
●
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
●
Any surgical procedures
●
Treatments administered (including dates and type of modality)
At each visit, the subject's medical history will be reviewed and any changes from 
baseline will be recorded on the adverse event CRF.  On Cycle 1 Day 1 (14/21 day dosing 
schedule), any changes observed from the Screening assessments prior to dosing will be 
recorded in the subject's medical history.  During the lead-in period, any changes from the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
52
Screening assessment prior to dosing will be recorded in the subject's history on Lead-in 
Day 1 (21/21 day dosing schedule).  All medication (prescription or over-the-counter, 
including vitamins and/or herbal supplements) will be recorded beginning with the 
Screening Visit and continuing until 30 days following the last dose of ABT-263.
Physical Examination
A physical examination (including weight) will be performed at Screening, Day 1 of 
Cycle 1, Day 1 of each subsequent cycle (or within 72 hours prior), at the Final Visit and 
at the Safety Follow-up Visit.  During the lead-in period (21/21 day dosing schedule), a 
physical examination (including weight) will also be performed at Lead-in Day 1.  A 
symptom-directed physical examination may be performed weekly through the 
first 2 cycles and when necessary.  Height will be measured only at Screening.  The 
physical examination performed at Screening will serve as the baseline physical 
examination for clinical assessment.  For the Extension Study, a physical examination will 
be performed at Day 1, every 4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final 
Visit and at the Safety Follow-up Visit.  Any significant physical examination findings 
after dosing will be recorded as adverse events.
Vital Signs
Body temperature (oral or tympanic), blood pressure and pulse will be measured at 
Screening, Day 1 of Cycle 1, weekly through the first 2 cycles, Day 1 of each subsequent 
cycle (or within 72 hours prior), at the Final Visit and at the Safety Follow-up Visit.  
During the lead-in period (21/21 day dosing schedule), body temperature (oral), blood 
pressure and pulse will also be measured at Lead-in Day 1.  The vital signs measurements 
at Screening will serve as the baseline measurements for clinical assessment.  For the 
Extension Study, body temperature, blood pressure and pulse will be measured at Day 1, 
every 4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final Visit and at the Safety 
Follow-up Visit.
In Phase 1, blood pressure and pulse rate will be measured approximately 30 to 
60 minutes after study drug administration.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
53
Blood pressure and pulse rate will be measured after the subject has been sitting for at 
least 5 minutes on days study drug is administered in the clinic.
COVID-19 Pandemic-Related Acceptable Protocol Modifications 
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, weight, and vital signs measurements may be performed 
by the subject or caregiver as needed.
Platelet Count
The platelet count measurement obtained on Cycle 1 Day 1 (pre-dose) will serve as the 
baseline for clinical assessment for the 14/21 day dosing schedule.  The platelet count 
measurement obtained on Lead-in Day 1 (pre-dose) will serve as the baseline for clinical 
assessment for the 21/21 day dosing schedule with lead-in period.
If platelet count on any given day is less than 50,000/mm3, additional platelet counts 
should be performed every day or at the discretion of the investigator.
If a platelet transfusion is deemed necessary, a post-transfusion platelet count should be 
obtained within 10 to 60 minutes.
Platelet counts < 25,000/mm3 should be confirmed the same day by manual reading and a 
separate peripheral draw.  Additional platelet counts will be obtained from a subject if 
ABT-263 is either held or interrupted per the management guidelines in Section 6.7.1 and 
Section 6.7.2.
All platelet count measurements obtained during Cycle 1 through Cycle 4 in the Phase 1 
portion of the study will be either entered immediately on the eCRF or faxed to the 
Oncology Safety Management Team within 24 hours of report availability via the contact 
information provided in Section 6.5.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
54
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. If laboratory samples cannot be obtained, study drug 
administration may be continued provided the investigator has reviewed all prior 
laboratory results and confirms and discusses with the subject that there is no safety 
concern for the subject to continue use of the study drug in the absence of current labs. 
The subject should be scheduled for laboratory draws as soon as feasible within 14 days 
from the scheduled visit.
The platelet count schedule of assessment may be modified as information is obtained 
regarding the expected decrease in platelets in response to study drug administration.  
This will be based upon discussion between the investigator and the AbbVie Medical 
Monitor.
Platelet count assessments will be performed stat and assessed by the investigator prior to 
study drug administration as follows:
Phase 1 – 14/21 Day Dosing Schedule:
Screening
Cycle 1:
●
Days 1, 2, 3, 4, 5, 6, 8, 14 and 16 
●
Platelet counts performed in Cycle 1 can be obtained within 24 hours prior to 
the visit, except on Days 1 and 14 when platelet counts are required at all of 
the pharmacokinetic sampling time points as indicated in Table 4 and Table 5.
●
As needed
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
55
Subsequent Cycles:
●
Days 1, 3, 5, 8 and 16
●
As needed
●
If the investigator and the AbbVie Medical Monitor jointly agree that platelet 
counts through Cycle 4 have been stable, then the frequency of platelet counts 
in Cycle 5 and beyond may be decreased to Day 1 of each cycle and as needed.
Final Visit and Safety Follow-up Visit
For the Extension Study, platelet count assessments will be performed at Day 1, every 
4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final Visit and at the Safety Follow-up 
Visit.
Phase 1 – 21/21 Day Dosing Schedule:
Screening
During the lead-in period, the following platelet counts will be obtained:
●
Lead-in Days 1, 2, 3, 5 and 7
●
Daily if lead-in period extends beyond Day 7 (i.e., Lead-in Days 8-14)
Cycle 1:
●
Days 1, 2, 3, 5, 8, 14 and 16
●
Platelet counts performed in Cycle 1 can be obtained within 24 hours prior to 
the visit, except on Days 1 and 14 when platelet counts are required at all of 
the pharmacokinetic sampling time points as indicated in Table 4.
●
As needed
Subsequent Cycles:
●
Weekly
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
56
●
As needed
●
If the investigator and the AbbVie Medical Monitor jointly agree that platelet 
counts through Cycle 4 have been stable, then the frequency of platelet counts 
in Cycle 5 and beyond may be decreased to Day 1 of each cycle and as needed.
Final Visit and Safety Follow-up Visit
For the Extension Study, platelet count assessments will be performed at Day 1, every 
4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final Visit and at the Safety Follow-up 
Visit.
Phase 2a:
Screening
During the lead-in period, the following platelet counts will also be obtained:
●
Lead-in Days 1, 2, 3, 5 and 7
●
Daily if lead-in period extends beyond Day 7 (i.e., Lead-in Days 8-14)
Cycle 1:
●
Days 1, 2, 3, 5, 8 and 15 
●
As needed
Subsequent Cycles:
●
Weekly
●
As needed
●
If the investigator and the AbbVie Medical Monitor jointly agree that platelet 
counts through Cycle 4 have been stable, then the frequency of platelet counts 
in Cycle 5 and beyond may be decreased to Day 1 of each cycle and as needed.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
57
Final Visit and Safety Follow-up Visit
For the Extension Study, platelet count assessments will be performed at Day 1, every 
4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final Visit and at the Safety Follow-up 
Visit.
Lymphocyte Enumeration
Lymphocyte enumeration to identify B and T cell lymphocyte subpopulations will be 
performed at Screening, Day 14 of Cycle 1 (14/21 day dosing schedule), Day 15 of 
Cycle 1 (21/21 day dosing schedule), end of Cycle 4, at the end of every 3rd cycle 
thereafter, and at the Final Visit for each subject.  The lymphocyte enumeration results 
from Screening will serve as the baseline for clinical assessment.  For the Extension 
Study, lymphocyte enumeration will be performed if deemed necessary by the 
investigator and at the Final Visit.
All lymphocyte enumeration results obtained in the Phase 1 portion of the study will be 
either entered immediately on the eCRF or faxed to the Oncology Safety Management 
Team within 24 hours of report availability via the contact information provided in 
Section 6.5.
ECOG Performance Status
The ECOG performance status39 will be assessed at Screening, Day 1 of Cycle 1, weekly 
through the first 2 cycles, Day 1 of each subsequent cycle (or within 72 hours prior), at the 
Final Visit and at the Safety Follow-up Visit.  For the Extension Study, the ECOG 
performance status will be assessed at the Final Visit and Safety Follow-up Visit.
Grade
Description
0
Fully active, able to carry on all pre-disease 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.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
58
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.
During the lead-in period, ECOG performance status will also be assessed on Lead-in 
Day 1 (21/21 day dosing schedule).
The ECOG performance status assessed at Screening will serve as the baseline for clinical 
assessment.
12-Lead Electrocardiogram (ECG) (Phase 1)
A 12-lead resting ECG will be performed for all subjects in the first 2 cohorts of the study 
at Screening, Day 1 and Day 14 of Cycle 1, Day 1 of each subsequent cycle and at the 
Final Visit.  For subsequent cohorts, an ECG will be performed at Screening, Day 1 and 
Day 14 of Cycle 1, Day 1 and Day 14 of Cycle 3 and at the Final Visit.  For the Extension 
Study, a 12-lead resting ECG will be performed at the Final Visit.
If necessary, the Cycle 1 Day 14 and Cycle 3 Day 14 ECGs may be performed within 
3 days prior to Day 14.  During the lead-in period, an ECG will also be performed on 
Lead-in Day 1.  The test results will be assessed for each subject on an ongoing basis by 
the AbbVie Medical Monitor and an independent cardiology expert, and monitoring may 
be adjusted depending on the observation of any clinically significant findings.
Every effort should be made to obtain all ECGs approximately 4-8 hours post-dose 
(however, 6-8 hours post-dose is preferred), and if possible at approximately the same 
time of day.  If pharmacokinetic data indicates the Cmax of parent drug or a major 
metabolite occurs at a time different than this specified range, the timing of the ECG may 
be modified.  A qualified physician will sign and date the ECGs, determine if any findings 
outside normal physiological variation are clinically significant (in consultation with a 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
59
cardiologist, if necessary) and document this on the appropriate CRF.  The original ECG 
tracing with physician assessment will be retained in the subject's records at the study site 
and a copy will be faxed to the Oncology Safety Management Team within 24 hours of 
report availability via the contact information provided in Section 6.5.  The ECG 
measurement obtained at Screening will be used to document baseline status of the subject 
so that safety comparisons can be made, if necessary.  Repeat ECGs will be performed 
whenever clinically necessary.
12-Lead Electrocardiogram (ECG) (Phase 2a)
A 12-lead resting ECG will be performed for all subjects in Phase 2a at the following 
visits:
●
Screening
●
Cycle 1 Day 15
●
Cycle 5 Day 1
●
Cycle 9 Day 1
●
Final Visit
For the Extension Study, a 12-lead resting ECG will be performed at the Final Visit.
If necessary, ECGs may be performed within 3 days of the visit, except Screening, which 
must be performed within 14 days prior to study drug administration.
The test results will be assessed for each subject on an ongoing basis by the AbbVie 
Medical Monitor and an independent cardiology expert, and monitoring may be adjusted 
depending on the observation of any clinically significant findings.
Every effort should be made to obtain all ECGs approximately 4-8 hours post-dose 
(however, 6-8 hours post-dose is preferred), and if possible at approximately the same 
time of day.  If pharmacokinetic data indicates the Cmax of parent drug or a major 
metabolite occurs at a time different than this specified range, the timing of the ECG may 
be modified.  A qualified physician will sign and date the ECGs, determine if any findings 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
60
outside normal physiological variation are clinically significant (in consultation with a 
cardiologist, if necessary) and document this on the appropriate CRF.  The original ECG 
tracing with physician assessment will be retained in the subject's records at the study site 
and a copy will be faxed to the Oncology Safety Management Team within 5 days of 
report availability via the contact information provided in Section 6.5.  The QT, QTc and 
heart rate will be recorded for all ECGs on the eCRF.  The ECG measurement obtained at 
Screening will be used to document baseline status of the subject so that safety 
comparisons can be made, if necessary.  Repeat ECGs will be performed whenever 
clinically necessary.
2D Echocardiogram with Doppler (Phase 1)
A 2D echocardiogram with Doppler will be performed for all subjects in the 
first 2 cohorts at Screening, Day 1 and Day 14 of Cycle 1, Day 1 of each subsequent cycle 
and at the Final Visit.  For subsequent cohorts, an echocardiogram with Doppler will be 
performed at Screening, Day 1 and Day 14 of Cycle 1, Day 1 and Day 14 of Cycle 3 and 
at the Final Visit.  If necessary, the Cycle 1 Day 14 and Cycle 3 Day 14 echocardiograms 
may be performed within 3 days prior to Day 14.  During the lead-in period, an 
echocardiogram will also be performed on Lead-in Day 1.  For the Extension Study, a 
2D echocardiogram with Doppler will be performed at the Final Visit.
The test results for each subject will be assessed on an ongoing basis by the AbbVie 
Medical Monitor and an independent cardiology expert, and monitoring may be adjusted 
depending on the observation of any clinically significant findings.
Every effort should be made to obtain all echocardiograms approximately 4-8 hours 
post-dose (however, 6-8 hours post-dose is preferred), and if possible at approximately the 
same time of day.  If pharmacokinetic data indicates the Cmax of parent drug or a major 
metabolite occurs at a time different than this specified range, the timing of the 
echocardiogram may be modified.  A qualified physician will sign and date the 
echocardiogram reports, determine if any findings outside normal physiological variation 
are clinically significant and document this on the appropriate CRF.  The original 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
61
echocardiogram report with physician assessment will be retained in the subject's records 
at the study site and a copy will be faxed to the Oncology Safety Management Team 
within 24 hours of report availability via the contact information provided in Section 6.5.  
In addition, AbbVie (or designee) will require access to the recording of the 
echocardiogram as necessary.  The echocardiogram results obtained at Screening will be 
used to document baseline status of the subject so that safety comparisons can be made, if 
necessary.  Repeat echocardiograms will be performed whenever clinically necessary.
2D Echocardiogram with Doppler (Phase 2a)
A 2D echocardiogram with Doppler will be performed for all subjects in Phase 2a at the 
following visits:
●
Screening
●
Cycle 1 Day 15
●
Cycle 5 Day 1
●
Cycle 9 Day 1
●
Final Visit
For the Extension Study, a 2D echocardiogram with Doppler will be performed at the 
Final Visit.
If necessary, ECHOs may be performed within 3 days of the visit except Screening, which 
must be performed within 14 days prior to study drug administration.
The test results for each subject will be assessed on an ongoing basis by the AbbVie 
Medical Monitor and an independent cardiology expert, and monitoring may be adjusted 
depending on the observation of any clinically significant findings.
Every effort should be made to obtain all echocardiograms approximately 4-8 hours 
post-dose (however, 6-8 hours post-dose is preferred), and if possible at approximately the 
same time of day.  If pharmacokinetic data indicates the Cmax of parent drug or a major 
metabolite occurs at a time different than this specified range, the timing of the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
62
echocardiogram may be modified.  A qualified physician will sign and date the 
echocardiogram reports, determine if any findings outside normal physiological variation 
are clinically significant and document this on the appropriate CRF.  The original 
echocardiogram report with physician assessment will be retained in the subject's records 
at the study site and a copy will be faxed to the Oncology Safety Management Team 
within 5 days of report availability via the contact information provided in Section 6.5.  In 
addition, AbbVie (or designee) will require access to the recording of the echocardiogram 
as necessary.  The echocardiogram results obtained at Screening will be used to document 
baseline status of the subject so that safety comparisons can be made, if necessary.  
Repeat echocardiograms will be performed whenever clinically necessary.  The sponsor 
(AbbVie) may choose to introduce performance of serial echocardiograms to be evaluated 
by an independent cardiologist.
Bone Marrow Aspirate and Biopsy
A bone marrow aspirate and biopsy will be done at Screening (within 21 days prior to the 
first dose of study drug) unless a bone marrow aspirate and biopsy was obtained within 
12 weeks of starting study drug without intervening treatment and is representative of the 
subject's existing disease.  The bone marrow aspirate and biopsy should be performed 
after all other eligibility criteria have been met, unless otherwise obtained through 
standard of care.  Bone marrow aspirates and biopsies performed as standard of care 
throughout the study should also be captured on a case report form.
In the Phase 2a portion of the study, a bone marrow aspirate/biopsy will be performed at 
the end of Cycle 8 (for all subjects regardless of response) if the subject is continuing to 
receive ABT-263.
If a subject meets all the clinical and laboratory criteria for a complete remission (CR), a 
bone marrow aspirate and biopsy should be performed at least 2 months after the criteria 
are first met in order to confirm a CR.  In the Phase 2a portion of the study, a bone 
marrow aspirate and biopsy should be performed at least 2 months after the IWCLL 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
63
updated NCI-WG (2008) criteria are first met and 2 months after NCI-WG (1996) criteria 
are first met in order to confirm a CR.
Computed Tomography (CT) Scans and Magnetic Resonance Imaging (MRI)
A CT scan of involved anatomic regions (or MRI, if medically indicated) will be done at 
Screening (within 21 days prior to the first dose of study drug).  CT scans and MRIs 
performed as standard of care throughout the study should also be captured on a case 
report form.
Phase 1
If a subject meets all the clinical and laboratory criteria for a complete remission (CR) or 
a partial remission (PR), a CT scan should be performed at least 2 months after the criteria 
are first met in order to confirm a CR or PR.
Phase 2a
If a subject meets all the clinical and laboratory criteria for a complete remission (CR) or 
a partial remission (PR), a CT scan should be performed at least 2 months after the criteria 
are first met in order to confirm a CR or PR.
Tumor Assessments
Analysis of peripheral blood, physical examination, bone marrow aspirate and biopsy, 
CT scan of involved anatomic regions and MRI (if medically indicated), will be utilized 
for disease assessment as described above.
Phase 1
Subjects will be evaluated against the IWCLL updated NCI-WG (January 2008) criteria31
(physical examination/CT/MRI) at the end of Cycle 2, the end of Cycle 4, end of every 
4 cycles through Cycle 20 (i.e., C8, C12, C16, C20), end of every 8 cycles thereafter 
(i.e., C28, C36, C44. . .) and at the Final Visit.  For the Extension Study, subjects will be 
evaluated against the IWCLL updated NCI-WG (January 2008) criteria (physical 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
64
examination/CT/MRI) at the Final Visit.  Analysis of peripheral blood will be evaluated 
against the NCI-WG criteria for tumor response assessment on Day 1 (pre-dose) of the 
following cycle for every tumor assessment.  For example, when a subject completes 
Cycle 2, the laboratory values from Day 1 of Cycle 3 (pre-dose) will be used to assess 
tumor response.
The tumor assessment performed at Screening will serve as the baseline for clinical 
assessment.  Assessments for tumor response will be repeated at least 2 months after 
NCI-WG criteria for complete remission (CR or CRi) are first met.  Assessments for 
tumor response will be repeated at least 2 months after criteria for a partial remission (PR) 
are first met.  Response criteria will be assessed while subjects continue treatment with 
ABT-263.  Response criteria definitions are outlined in Section 5.3.3.1.
Phase 2a
Subjects will be evaluated against the NCI-WG (1996) criteria30 and the IWCLL updated 
NCI-WG (January 2008) criteria31 (physical examination/CT/MRI) at the end of Cycle 2, 
the end of Cycle 4, end of every 4 cycles through Cycle 20 (i.e., C8, C12, C16, C20), end 
of every 8 cycles thereafter (i.e., C28, C36, C44. . .) and at the Final Visit.  For the 
Extension Study, subjects will be evaluated against the NCI-WG (1996) criteria and the 
IWCLL updated NCI-WG (January 2008) criteria (physical examination/CT/MRI) at the 
Final Visit.  Analysis of peripheral blood will be evaluated against the NCI-WG criteria 
for tumor response assessment on Day 1 (pre-dose) of the following cycle for every tumor 
assessment.  For example, when a subject completes Cycle 2, the laboratory values from 
Day 1 of Cycle 3 (pre-dose) will be used to assess tumor response.
The tumor assessment performed at Screening will serve as the baseline for clinical 
assessment.  Assessments for tumor response will be repeated 2 months after NCI-WG 
(1996) criteria for complete remission (CR) are first met and/or at least 2 months after the 
IWCLL updated NCI-WG (2008) criteria for complete remission (CR or CRi) are 
first met.  Assessments for tumor response will be repeated at least 2 months after criteria 
for a partial remission (PR) are first met.  Response criteria will be assessed while 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
65
subjects continue treatment with ABT-263.  Response criteria definitions are outlined in 
Section 5.3.3.1.
Disease Progression Assessment (Extension Study)
Subjects should be evaluated for disease progression at a minimum of every 4 cycles and 
as deemed appropriate by the investigator per standard of care for tumor assessments.  At 
each visit, the investigator should assess whether or not there is evidence of disease 
progression and record the date of progression on the paper Case Report Form if 
applicable.  If a CT scan, MRI, or bone marrow aspirate or biopsy is performed per 
standard of care, the data should be recorded on the appropriate paper Case Report Form.  
Subjects exhibiting disease progression should be discontinued from the study per 
Section 5.4.1.
Pregnancy Test
For female subjects of childbearing potential, the local reference laboratory will perform a 
serum pregnancy test at Screening and a urine pregnancy test before dosing on Cycle 1 
Day 1 (14/21 day dosing schedule) or Lead-in Day 1 (21/21 day dosing schedule), if it has 
been > 7 days since obtaining the serum pregnancy test results.  The test results must be 
reviewed and determined to be negative prior to dosing.
Subjects considered not of childbearing potential must be documented as being surgically 
sterile or post-menopausal (for at least 1 year).
Survival (Phase 2a)
Survival information (i.e., the date and cause of death, post-treatment cancer therapies, 
etc.) will be collected at 3 month intervals after the last study visit for a period of 2 years 
after the subject has discontinued from the study.  In Protocol Amendment #12 this 
information will be no longer collected.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
66
Clinical Laboratory Tests
Phase 1
In the Phase 1 portion of the study, local laboratories will be utilized to process and 
provide results for the clinical laboratory tests.  Subjects who move into the Extension 
Study from Phase 1 will continue to use local laboratories for the clinical laboratory tests.  
The principal investigator or sub-investigator will review, initial and date all laboratory 
results.  The laboratory test results will be collected on the electronic Case Report Forms.  
The laboratory test results from the Extension Study will be collected on paper Case 
Report Forms.
Hematology, chemistry and urinalysis samples will be collected at Screening, Cycle 1 
Day 1, Cycle 1 Days 2 and 3 (chemistry and hematology only), weekly through the 
first 2 cycles, Day 1 of each subsequent cycle (or within 72 hours prior), at the Final Visit 
and at the Safety Follow-up Visit.
For the Extension Study, hematology and chemistry will be collected at Day 1, every 
4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final Visit and at the Safety Follow-up 
Visit.
During the lead-in period, hematology, chemistry and urinalysis samples will also be 
collected on Lead-in Day 1 and Lead-in Days 2 and 3 (chemistry and hematology only).
For any subjects who are at high risk for tumor lysis syndrome (TLS) during Cycle 2 and 
beyond, additional samples for hematology and chemistry may be collected as per the 
management guidelines in Section 6.7.4.  ANC ≥ 500/µL and < 1,000/µL should be 
monitored at an increased frequency at the discretion of the investigator.  Grade 2 
chemistry labs should be monitored at an increased frequency at the discretion of the 
investigator.
The laboratory test results from Screening (except platelet count) will serve as the 
baseline for clinical assessment.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
67
All laboratory measurements obtained through Day 1 of Cycle 2 in the Phase 1 portion of 
the study will be either entered on the eCRF or faxed to the Oncology Safety Management 
Team within 24 hours of report availability via the contact information provided in 
Section 6.5.
Phase 2a
Hematology, chemistry and urinalysis samples will be collected at Screening, Cycle 1 
Day 1, Cycle 1 Days 2 and 3 (chemistry and hematology only), weekly through the 
first 2 cycles, Day 1 of each subsequent cycle (or within 72 hours prior), at Final Visit and 
at the Safety Follow-up Visit.
For the Extension Study, hematology and chemistry will be collected at Day 1, every 
4 cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, etc.), Final Visit and at the Safety Follow-up 
Visit.
During the lead-in period (21/21 day dosing schedule), hematology, chemistry and 
urinalysis samples will also be collected on Lead-in Day 1 and Lead-in Days 2 and 3 
(chemistry and hematology only).
For any subjects who are at high risk for tumor lysis syndrome (TLS) during Cycle 2 and 
beyond, additional samples for hematology and chemistry may be collected as per the 
management guidelines in Section 6.7.4.  ANC ≥ 500/µL and < 1,000/µL should be 
monitored at an increased frequency at the discretion of the investigator.  Grade 2 
chemistry labs should be monitored at an increased frequency at the discretion of the 
investigator.
Local laboratories will be utilized in Phase 2a to process and provide results for the 
hematology samples.  The principal investigator or sub-investigator will review, initial 
and date all laboratory results.  The hematology test results will be collected on the 
electronic Case Report Forms.  All other (i.e., lymphocyte enumeration, chemistry and 
urinalysis) clinical laboratory samples obtained in Phase 2a will be assessed using a 
certified central laboratory (Quest Diagnostics).  The central laboratory for this study will 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
68
provide instructions regarding the collection, processing and shipping of these samples.  
All laboratory samples, except hematology samples, should be shipped to the central 
laboratory.
Starting with Protocol Amendment 13, subjects in the Extension Study from Phase 2a will 
use local laboratories for all clinical laboratory samples.  
The local laboratory test results from the Extension Study will be collected on paper Case 
Report Forms.
A certified local reference laboratory may perform chemistry tests for immediate subject 
management in Phase 2a; however split or concurrent samples must be drawn and sent to 
the central laboratory for analysis.
Local laboratories will be utilized to process and provide results for all platelet counts.  
Platelet count results must be available and reviewed prior to dosing.  The laboratory test 
results from Screening (except platelet count) will serve as the baseline for clinical 
assessment.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
69
Table 7.
Clinical Laboratory Tests
Hematology
Clinical Chemistrya,b
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
Mean platelet volume (MPV)
Mean corpuscular hemoglobin 
(MCH)
Mean corpuscular volume 
(MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Reticulocyte count
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 acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Amylase (only at Screening, 
  C1D14 or C1D15 and Final Visit)
Lipase (only at Screening, C1D14 
  or C1D15 and Final Visit)
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination (as 
indicated)
a.
Chemistry tests should be obtained under fasting conditions if possible.
b.
Triglycerides will only be performed at Screening and Final Visit.
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator may repeat the test to verify the out-of-range value.
●
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 or requires a subject to receive treatment will be recorded as an adverse 
event.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
70
Assignment of Subject Numbers
Phase 1
The results of all screening and pre-dose Study Day 1 (or Lead-in Day 1 for lead-in 
period) evaluations must be within clinically acceptable limits (per inclusion criteria in 
Section 5.2.1), upon review by the investigator with the concurrence of the AbbVie 
Medical Monitor or designee, before a subject can be administered study drug.  Screening 
results will be faxed to the Clinical Team Leader as indicated in Section 7.0.  Subjects 
will not be enrolled in the study if laboratory or other screening results are not within 
clinically acceptable limits.  Subjects who meet the inclusion criteria and do not meet any 
of the exclusion criteria will be assigned a unique subject number by AbbVie, as 
described in Section 5.5.3.
Phase 2a
The results of all screening and pre-dose Lead-in Day 1 evaluations must be within 
clinically acceptable limits (per inclusion criteria in Section 5.2.1), upon review by the 
investigator before a subject can be administered study drug.  Subjects will not be enrolled 
in the study if laboratory or other screening results are not within clinically acceptable 
limits.  Subjects who meet the inclusion criteria and do not meet any of the exclusion 
criteria will be assigned a unique subject number by AbbVie, as described in 
Section 5.5.3.
Extension Study
Subjects who meet the inclusion criteria and do not meet any of the exclusion criteria 
(refer to Section 5.2) and who continue in the Extension Study will retain the subject 
number that was assigned in the Phase 1 or Phase 2a portion of the study.
5.3.1.2
Meals and Dietary Requirements
Subjects will self-administer ABT-263 orally once daily (QD) within 30 minutes 
following the completion of breakfast, unless otherwise specified.  Subjects may not 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
71
consume grapefruit or grapefruit products within the 3-day period prior to initial study 
drug administration and until the last treatment cycle is completed due to possible CYP3A 
mediated metabolic interaction.
5.3.1.3
Blood Samples for Pharmacogenetic Analyses
DNA
All Sites
Phase 1 and 2a:  Optional
One 4 mL blood sample for DNA isolation will be collected at Screening (preferred) or 
prior to treatment on Lead-in Day 1 (21/21 day dosing schedule) or Cycle 1 Day 1 
(14/21 day dosing schedule) from each subject who consents to provide samples for 
pharmacogenetic analysis.  The collection, processing, and shipping of the specimens 
should be performed as described in the M06-873 laboratory manual.
Samples will be shipped to AbbVie for DNA extraction and long-term storage.  AbbVie 
or a designated laboratory will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality.
If pharmacogenetic testing is performed, results from individual subjects will be kept 
coded and confidential.  Samples will be coded so that subject identities will not be 
available to the scientists conducting the genotyping analysis.  The samples will be 
retained while research on ABT-263 or Bcl-2 inhibitors continues.  Upon completion of 
the research, the samples will be destroyed.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
72
5.3.1.4
Specimens for Pharmacodynamic Analyses
Blood Collection for Proteomics
All Sites
Phase 1:  Optional
Approximately 4 mL of blood will be collected by venipuncture into one 4 mL EDTA 
(purple top) tube at Screening (preferred) or prior to treatment on Day 1, Cycle 1 Day 14, 
Cycle 2 Day 14, and an additional sample will be prepared at Final Visit, including the 
Final Visit of the Extension Study, from all subjects who consent to participate.  The 
collection, processing, and shipping of the specimens should be performed as described in 
the M06-873 laboratory manual.  The complete process of centrifugation, transfer to 
cryovial, and freezing should be accomplished in less than 1 hour from blood draw.
Phase 2a:  Required
Approximately 6 mL of blood will be collected by venipuncture into one 6 mL EDTA 
(purple top) tube at Screening (preferred) or prior to treatment on Day 1, Cycle 1 Day 15, 
Cycle 2 Day 15 and an additional sample will be prepared at Final Visit.  Including the 
Final Visit of the Extension Study.  In Protocol Amendment #12 this sample will no 
longer be required to be collected from subjects in the extension study.  The collection, 
processing, and shipping of the specimens should be performed as described in the M06-
873 laboratory manual.  The complete process of centrifugation, transfer to cryovial, and 
freezing should be accomplished in less than 1 hour from blood draw.
Blood Collection and Storage for Bcl-2 Family Analysis
All Sites
Phase 1 and 2a:  Required
Approximately 2 mL of blood will be collected by venipuncture into pediatric EDTA 
tubes at Screening (preferred) or prior to treatment on Lead-in Day 1 (21/21 day dosing 
schedule) or Cycle 1 Day 1 (14/21 day dosing schedule), Cycle 1 Day 14 (14/21 day 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
73
dosing schedule), or Cycle 1 Day 15 (21/21 day dosing schedule), end of Cycle 4, and 
Final Visit.  Including the Final Visit of the Extension Study.  In Protocol 
Amendment #12 this sample will no longer be required to be collected from subjects in 
the extension study.
The collection, processing, and shipping of the specimens should be performed as 
described in the M06-873 laboratory manual.  It is preferable for the process of inversion, 
fixing, mixing and freezing occur within 30 minutes of the blood draw.
ACD Tube of Blood for ZAP70/CD38-Ship Day of Draw
US Sites Only
Phase 1:  Optional
Phase 2a:  Required
Approximately 6 mL of blood will be collected by venipuncture into appropriately labeled 
6 mL ACD tube (yellow top) at Screening (preferred) or prior to treatment on Lead-in 
Day 1 (21/21 day dosing schedule) or Cycle 1 Day 1 (14/21 day dosing schedule), end of 
Cycle 4 and an additional sample will be prepared at Final Visit.  The specimen must be 
shipped Monday-Thursday and on the same day of collection.  The collection, processing, 
and shipping of the specimens should be performed as described in the M06-873 
laboratory manual.
Heparin Tube of Blood for CGH/FISH-Ship Day of Draw
Australian Sites and US Sites
Phase 1 and 2a:  Required
Approximately 6 mL of blood will be collected by venipuncture into appropriately labeled 
6 mL heparin tube (green top) at Screening (preferred) or prior to treatment on Lead-in 
Day 1 (21/21 day dosing schedule) or Cycle 1 Day 1 (14/21 day dosing schedule), end of 
Cycle 4 and at Final Visit including the Final Visit of the Extension Study.  In Protocol 
Amendment #12 this sample will no longer be required to be collected from subjects in 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
74
the extension study.  The collection, processing, and shipping of the specimens should be 
performed as described in the M06-873 laboratory manual.
Bone Marrow Aspirate/Biopsy Collection
All Sites
Phase 2a Only:  Required
Bone Marrow Aspirate
Bone marrow aspirates should be drawn at baseline into a green top heparin tube in 
conjunction with the diagnostic biopsy for all subjects in Phase 2a at Screening and at the 
end of Cycle 8 if the subject is continuing to receive ABT-263.  If a bone marrow aspirate 
was obtained within 12 weeks of starting study drug without intervening treatment and is 
representative of the subject's existing disease, a Screening sample does not need to be 
obtained.  A portion of the aspirate may be processed according to the institutional 
standard procedures (for tumor assessment) and a portion must be processed according to 
the M06-873 lab manual for pharmacodynamic analysis of tumor cells.  If a procedure 
other than what is described in the M06-873 lab manual is used, a description of the 
procedure should be provided to AbbVie.
Bone Marrow Core Biopsy
If bone marrow aspirate is not collected, a bone marrow core biopsy may be obtained at 
Screening and the end of Cycle 8 for Phase 2a.  The core may be processed according to 
the institutional standard procedures or per the M06-873 lab manual.  If a procedure other 
than what is described in the M06-873 lab manual is used, a description of the procedure 
should be provided to AbbVie.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
75
Bcl-2/Bim Ratio-Ship Day of Draw
Australian Sites and US Sites
Phase 1 and 2a:  Optional
Approximately 4 mL of blood will be collected by venipuncture into an appropriately 
labeled 4 mL heparin tube (green top) at Screening (preferred) or prior to treatment on 
Lead-in Day 1 (21/21 day dosing schedule) or Cycle 1 Day 1 (14/21 day dosing schedule), 
end of Cycle 4 and Final Visit.  The specimen must be shipped Monday-Thursday and on 
the same day of collection.  The collection, processing, and shipping of the specimens 
should be performed as described in the M06-873 laboratory manual.
Assays for in vivo Apoptosis of CLL Cells-Ship Day of Draw
Australian Sites Only
Phase 1 and 2a:  Optional
Approximately 6 mL of blood (and/or 1 mL of bone marrow aspirate, if patient is 
undergoing a bone marrow biopsy) will be collected by venipuncture (or aspirate) into an 
appropriately labeled 6 mL heparin tube (green top) at Screening (preferred) or prior to 
treatment on Lead-in Day 1 (21/21 day dosing schedule) or Cycle 1 Day 1 (14/21 day 
dosing schedule), Cycle 1 Day 7 or Cycle 1 Day 8, Cycle 1 Day 14 or Cycle 1 Day 15, 
Cycle 2 Day 1, Cycle 2 Day 7 or Cycle 2 Day 8, and Cycle 2 Day 14 or Cycle 2 Day 15.  
The collection, processing, and shipping of the specimens should be performed as 
described in the M06-873 laboratory manual.
Assays for in vitro Sensitivity of CLL Cells-Ship Day of Draw
Australian Sites Only
Phase 1 and 2a:  Optional
Approximately 10 mL of blood (and/or 1 mL of bone marrow aspirate, if patient is 
undergoing a bone marrow biopsy) will be collected by venipuncture (or aspirate) into an 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
76
appropriately labeled 10 mL EDTA tube (pink top) at Screening (preferred) or prior to 
treatment on Lead-in Day 1 (21/21 day dosing schedule) or Cycle 1 Day 1 (14/21 day 
dosing schedule), Cycle 1 Day 14 or Cycle 1 Day 15 and Cycle 3 Day 1 (prior to 
treatment).  The collection, processing, and shipping of the specimens should be 
performed as described in the M06-873 laboratory manual.
Table 8.
Schedule of Biomarker Sample Collection (Phase 1)
Screeninga
C1D7
C1D14
C2D1
C2D7
C2D14
C3D1
End of 
C4
Final 
Visitf
Pharmacogeneticsb
4 mL
Proteomics-plasmab
4 mL
4 mL
4 mL
4 mL
CD38/ZAP 70b,c
6 mL
6 mL
Bcl-2 Family analysis
2 mL
2 mL
2 mL
2 mL
CGH/FISHd
6 mL
6 mL
Bcl-2/Bim Ratiob,d
4 mL
4 mL
Markers of 
apoptosisa,b,e
6 mL
6 mL
6 mL
6 mL
6 mL
6 mL
In vitro sensitivitya,b,e
10 mL
10 mL
10 mL
C = Cycle; D = Day
a.
Screening samples not collected at the time of screening should be collected pre-dose on Lead-in Day 1 (21/21 day 
dosing) or Cycle 1 Day 1 (14/21 day dosing), however, every effort should be made to collect at screening to 
decrease the blood volumes obtained on Lead-in Day 1/Cycle 1 Day 1.
b.
Blood collection is optional in the Phase 1 portion of the study.
c.
Study will only be performed in the US.
d.
Studies will only be performed in US and Australia.
e.
Studies will only be performed in Australia.
f.
For subjects who continue in the Extension Study, the Final Visit procedures will be performed upon completion of 
the Extension Study.  Refer to Appendix G for the Schedule of Assessments for subjects enrolled in the Extension 
Study.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
77
Table 9.
Schedule of Biomarker Sample Collection (Phase 2a)
Screeninga
C1D7
C1D15
C2D1
C2D7 C2D15
C3D1
End of 
C4
End of 
C8
Final 
Visith
Pharmacogeneticsb
4 mL
Proteomics-plasma
6 mL
6 mL
6 mL
6 mL
CD38/ZAP 70c
6 mL
6 mL
Bcl-2 Family 
analysis
2 mL
2 mL
2 mL
2 mL
CGH/FISHd
6 mL
6 mL
6 mL
Bcl-2/Bim Ratiob,d
4 mL
4 mL
Markers of 
apoptosisa,b,e
6 mL
6 mL
6 mL
6 mL
6 mL
6 mL
In vitro 
sensitivitya,b,e
10 mL
10 mL
10 mL
Tumor cells bone 
marrow aspirate
2 mLf
2 mLg
C = Cycle; D = Day
a.
Screening samples not collected at the time of screening should be collected pre-dose on Lead-in Day 1, however, 
every effort should be made to collect at Screening to decrease the blood volumes obtained on Lead-in Day 1.
b.
Blood collection is optional in the Phase 2a portion of the study.
c.
Study will only be performed in the US.
d.
Studies will only be performed in US and Australia.
e.
Studies will only be performed in Australia.
f.
If a bone marrow aspirate was obtained within 12 weeks of starting study drug without intervening treatment and is 
representative of the subject's existing disease, a Screening sample does not need to be obtained.
g.
A bone marrow aspirate/biopsy will be performed at the end of Cycle 8, if the subject is continuing to receive 
ABT-263.
h.
Prior to Amendment 12, subjects who continue in the Extension Study, the Final Visit procedures were performed 
upon completion of the Extension Study, collection of these specimens are no longer required.  Refer to 
Appendix G for the Schedule of Assessments for subjects enrolled in the Extension Study.
5.3.1.5
Disposition of Samples for 
Pharmacogenetic/Pharmacodynamic Analyses
The blood samples for pharmacogenetic and pharmacodynamic analyses will be shipped 
from the study site to AbbVie or designate according to instructions from AbbVie.  The 
samples should be labeled with the drug number name, type of sample (e.g., blood), the 
protocol number, the subject number, the study cycle and day and/or collection date.  An 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
78
inventory of the samples included will accompany the package.  Arrangements will be 
made with AbbVie for the shipment of stored samples to: 
Attn:  AbbVie Sample Receiving
c/o:  Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL  60085
Phone: (847) 937-0889
Fax:
(847) 938-9898
Email:
sample.receiving@abbvie.com
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood Samples for ABT-263 Assay
Phase 1 – 14/21 Day Dosing Schedule
Blood samples for ABT-263 assay will be collected by venipuncture into 3 mL evacuated 
potassium EDTA-containing collection tubes during Cycle 1 at the following times:  
Day 1, pre-dose (0 hour) and at 2, 4, 6, 8 and 24 (C1D2 pre-dose) hours after dosing; 
Day 14, pre-dose (0 hour) and at 2, 4, 6 and 8 hours after dosing.  Sufficient blood will be 
collected to provide approximately 1 mL plasma from each sample.  A total of 11 blood 
samples (approximately 33 mL) will be collected per subject for pharmacokinetic analysis 
during Cycle 1.  Blood samples will be collected in subsequent cycles as follows:  
pre-dose on Cycle 2, Days 3, 8 and 14; Cycle 3, Day 1 (4-8 hours post-dose immediately 
after ECG) and Day 14 (pre-dose and 4-8 hours post-dose immediately after ECG).  
Additional blood samples will be collected pre-dose (0 hour) on Day 14 of Cycles 6, 9, 12 
and 15.  See Table 4 and Table 5 for a schedule of the blood collection for ABT-263 
assay.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
79
Phase 1 - 21/21 Day Dosing Schedule
Blood samples for ABT-263 assay will be collected by venipuncture into 3 mL evacuated 
potassium EDTA-containing collection tubes during Cycle 1 at the following times:  
Day 1, pre-dose (0 hour) and at 2, 4, 6, 8 and 24 (C1D2 pre-dose) hours after dosing; 
Day 14, pre-dose (0 hour) and at 2, 4, 6 and 8 hours after dosing.  Sufficient blood will be 
collected to provide approximately 1 mL plasma from each sample.  A total of 11 blood 
samples (approximately 33 mL) will be collected per subject for pharmacokinetic analysis 
during Cycle 1.  Blood samples will be collected in subsequent cycles as follows:  
pre-dose on Cycle 2, Days 3, 8 and 14; Cycle 3, Day 1 (4-8 hours post-dose immediately 
after ECG) and Day 14 (pre-dose and 4-8 hours post-dose immediately after ECG).  
Additional blood samples will be collected pre-dose (0 hour) on Day 1 of Cycles 6, 9, 12 
and 15.
See Table 4 and Table 5 for a schedule of the blood collection for ABT-263 assay.
Phase 2a
Blood samples for ABT-263 assay will be collected by venipuncture into 3 mL evacuated 
potassium EDTA-containing collection tubes during Cycle 1 at the following times:  
Day 15 (pre-dose [0 hour] and 4-8 hours post-dose immediately after ECG).  Sufficient 
blood will be collected to provide approximately 1 mL plasma from each sample.  A total 
of 2 blood samples (approximately 6 mL) will be collected per subject for 
pharmacokinetic analysis during Cycle 1.  Additional blood samples will be collected 
pre-dose (0 hour) on Cycle 3 Day 1 and pre-dose (0 hour) and 4-8 hours post-dose 
(immediately after ECG) on Day 1 of Cycles 5 and 9.
See Table 6 for a schedule of the blood collection for ABT-263 assay.
Phase 1, Phase 2a and Extension Study
In addition, serial pharmacokinetic samples will be obtained from subjects who develop 
Grade 4 thrombocytopenia (< 25,000/mm3).  The first pharmacokinetic sample should be 
collected as soon as possible after determination of the first Grade 4 thrombocytopenia 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
80
event and then 24 and 48 hours thereafter.  Starting with Protocol Amendment 13, PK 
samples will NOT be collected.
Blood and plasma samples must be protected from direct sunlight during collection, 
processing and storage.  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.  In addition, the date and time (to the nearest minute) of dose and whether or 
not doses were taken within 30 minutes of completing breakfast for the pre-dose (0 hour) 
PK sampling day and for the 2 days prior to each PK sampling day will be recorded on the 
eCRF.  Sites should ensure that the data are captured via source document (e.g., subject
calendar, clinic notes).
5.3.2.2
Handling/Processing of Samples
Blood Samples for ABT-263 Assay
The processing of all pharmacokinetic specimens should be performed as described in the 
M06-873 laboratory manual.
5.3.2.3
Disposition of Samples for ABT-263 Assay
Samples should be labeled using the labels provided by AbbVie with the drug number 
name, type of sample (plasma), the protocol number, the subject number, the study cycle 
and day and the planned time of sampling relative to dosing.  The frozen plasma samples 
for ABT-263 assay will be packed in dry ice sufficient to last during transport and shipped 
from the study site to AbbVie according to instructions from AbbVie.  An inventory of 
the samples included will accompany the package.  Arrangements will be made with 
AbbVie for the shipment of samples to:
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
81
Attn:  AbbVie Sample Receiving
c/o Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL  60085
Phone: (847) 937-0889
Fax:
(847) 938-9898
Email: sample.receiving@abbvie.com
5.3.2.4
Measurement Methods
Analysis of Plasma Samples
Plasma concentrations of ABT-263 will be determined under the supervision of the Drug 
Analysis Department at AbbVie.
5.3.3
Efficacy Variables
For the Phase 2a portion of the study, all efficacy analyses are exploratory in nature.  The 
exploratory efficacy endpoints include tumor response (determined using NCI-WG 
Criteria), progression free survival (PFS), time to tumor progression (TTP), overall 
survival (OS), duration of overall response and ECOG performance status.  Analyses of 
these endpoints are described in Section 8.1.3.
5.3.3.1
NCI-WG Criteria for Tumor Response
Only subjects with active disease requiring treatment (in the opinion of the investigator) 
will be enrolled in the study.  Response over the course of therapy will be evaluated using 
the 1996 National Cancer Institute Working Group Guidelines for Chronic Lymphocytic 
Leukemia (NCI-WG) criteria30 and the International Workshop for Chronic Lymphocytic 
Leukemia (IWCLL) updated 2008 National Cancer Institute Working Group Guidelines 
(NCI-WG) for Chronic Lymphocytic Leukemia criteria.31  Response criteria will be 
assessed while subjects continue treatment with ABT-263.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
82
5.3.3.1.1
NCI-WG Criteria - 1996
Methods of Measurement
Disease response and progression will be assessed by analysis of peripheral blood, clinical 
examination, radiographic techniques when clinically indicated (e.g., splenomegaly, 
lymphadenopathy), and bone marrow aspirate and biopsy (if needed to confirm active 
disease at baseline and to confirm a CR).
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes).  For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is required.
The diameter, in two planes, of the largest palpable nodes in each of the following sites 
should be measured:  cervical, axillary, supraclavicular, inguinal, and femoral.
CT is the preferred method to measure lesions selected for response assessment.  MRI 
may be used if medically indicated (e.g., severe contrast allergy).  Conventional CT and 
MRI should be performed with cuts of 7 mm or less in slice thickness contiguously.
For accurate objective response evaluation, ultrasound (US) should not be used to 
measure tumor lesions.  However, US is a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.  US might 
also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
83
Cytology and histology can be used to differentiate between partial remission (PR) and 
complete remission (CR) in rare cases (e.g., after treatment to differentiate between 
residual benign lesions and residual malignant lesions in tumor types such as germ cell 
tumors).
Assessment of response will be performed by the investigator and documented on the 
appropriate CRF.
Complete Remission (CR) requires all of the following for a period of at least 2 months:
1.
Absence of lymphadenopathy by physical examination and appropriate 
radiographic techniques.
2.
No hepatomegaly or splenomegaly by physical examination and appropriate 
radiographic techniques.
3.
Absence of constitutional symptoms.
4.
Normal CBC as exhibited by:
●
Polymorphonuclear leukocytes ≥ 1,500/L.
●
Platelets > l00,000/L.
●
Hemoglobin > 11.0 g/dL (untransfused).
5.
Bone marrow aspirate and biopsy should be performed 2 months after clinical and 
laboratory results demonstrate that all of the requirements above have been met to 
demonstrate that a CR has been achieved.  The marrow sample must be at least 
normocellular for age, with less than 30% of nucleated cells being lymphocytes.  
Lymphoid nodules should be absent.  If the bone marrow is hypocellular, a repeat 
determination should be made in 4 weeks.  Samples should be re-reviewed in 
conjunction with the prior pathology.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
84
Partial Remission (PR) requires all of the following for a period of at least 2 months:
1.
≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment 
baseline value.
2.
≥ 50% reduction in lymphadenopathy.
3.
≥ 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy).
In addition one or more of the following criteria must be met:
●
Polymorphonuclear leukocytes ≥ 1,500/L or 50% improvement over baseline.
●
Platelets > l00,000/L or 50% improvement over baseline.
●
Hemoglobin > 11.0 g/dL or 50% improvement over baseline without 
transfusions.
Progressive Disease (PD) requires at least one of the following:
1.
≥ 50% increase in the sum of the products of at least two lymph nodes on 
two consecutive determinations 2 weeks apart (at least one node must be ≥ 2 cm); 
appearance of new palpable lymph nodes.
2.
≥ 50% increase in the size of the liver and/or spleen as determined by measurement 
below the respective costal margin; appearance of palpable hepatomegaly or 
splenomegaly, which was not previously present.
3.
≥ 50% increase in the absolute number of circulating lymphocytes with at least 
5,000/L.
4.
Transformation to a more aggressive histology (e.g., Richter's syndrome or PLL 
with > 55% prolymphocytes).
Subjects who have not achieved a CR or a PR, or who have not exhibited PD will be 
considered to have Stable Disease (SD).
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
85
Subjects who meet the criteria above for a CR but exhibit persistent bone marrow 
lymphoid infiltration will be referred to as nodular PRs (nPR).  In addition, subjects who 
meet the criteria above for a CR but exhibit persistent thrombocytopenia or anemia 
unrelated to disease activity and attributable to a persistent drug toxicity will be 
considered PR's.
A summary of the criteria described above is included in Table 10.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
86
Table 10.
NCI-WG Criteria for Tumor Response (1996) 
Criteria
Complete 
Remission (CR)
Nodular Partial 
Remission (nPR)#
Partial 
Remission (PR)
Progressive 
Disease (PD)
Symptoms
Absent
Absent
Absent or present
Not specified
Lymphadenopathy
Absent
Absent
≥ 50% reduction
≥ 50% increase* or 
new nodes
Hepatomegaly 
and/or 
Splenomegaly
Absent
Absent
≥ 50% reduction
≥ 50% increase or 
new hepatomegaly 
and/or 
splenomegaly
Neutrophils/ 
Polymorphonuclear 
Leukocytes 
(109/L)
≥ 1.5
≥ 1.5
≥ 1.5 or ≥ 50% 
improvement from 
baseline
Not specified
Lymphocytes 
(109/L) 
< 4
< 4
≥ 50% reduction 
from baseline
≥ 50% increase 
with at least
5 109/L
Platelets (109/L)
> 100
> 100
> 100 or ≥ 50% 
improvement from 
baseline
Not specified
Hemoglobin (g/dL) 
untransfused
> 11
> 11
> 11 or ≥ 50% 
improvement from 
baseline
Not specified
Bone Marrow 
Aspirate/Biopsy
Normocelluar 
< 30% 
lymphocytes; No 
intestinal or 
nodular infiltrates
Normocelluar 
< 30% 
lymphocytes; 
Nodular infiltrates
May be normal 
(i.e., < 30% 
lymphocytes 
without interstitial 
or nodular 
infiltrates) or 
persistent disease
Not specified
Other
NA
NA
NA
Transformation to 
RS or PLL
NA = not applicable; RS = Richter syndrome; PLL = Prolymphocytic Leukemia (with > 55% prolymphocytes); # = nPR 
is no longer applicable due to the utilization of immunohistochemistry; * = sum of products of at least 2 lymph nodes
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
87
5.3.3.1.2
IWCLL Updated NCI-WG Criteria – 2008
Methods of Measurement
Disease response and progression will be assessed by analysis of peripheral blood, clinical 
examination, radiographic techniques to assess splenomegaly, lymphadenopathy and/or 
bone marrow aspirate and biopsy to confirm active disease at baseline and if needed to 
confirm a CR.
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes).  For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is required.
The diameter, in two planes, of the largest palpable nodes in each of the following sites 
should be measured:  cervical, axillary, supraclavicular, inguinal, and femoral.
CT is the preferred method to measure lesions selected for response assessment.  MRI 
may be used if medically indicated (e.g., severe contrast allergy).  Conventional CT and 
MRI should be performed with cuts of 7 mm or less in slice thickness contiguously.
For accurate objective response evaluation, ultrasound (US) should not be used to 
measure tumor lesions.  However, US is a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.  US might 
also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
88
Assessment of response will be performed by the investigator and documented on the 
appropriate CRF.
Complete Remission (CR) requires all of the following for a period of at least 2 months:
1.
Absence of clonal lymphocytes in the peripheral blood.
2.
Absence of significant lymphadenopathy by physical examination and appropriate 
radiographic techniques.  A CT scan of the abdomen, pelvis and thorax should be 
performed if previously abnormal.  Lymph nodes should not be larger than 1.5 cm 
in diameter.
3.
No hepatomegaly or splenomegaly by physical examination.  A CT scan of the 
abdomen should be performed at response assessment if found to be abnormal prior 
to the start of study drug or if physical exam is inconclusive at the time of 
evaluation.
4.
Absence of constitutional symptoms.
5.
Normal CBC as exhibited by:
●
Polymorphonuclear leukocytes ≥ 1,500/L without G-CSF support.
●
Platelets > 100,000/L.
●
Hemoglobin > 11.0 g/dL (untransfused or without erythropoietin support).
Bone marrow aspirate and biopsy should be performed at least 2 months after clinical and 
laboratory results demonstrate that all of the requirements above have been met to 
demonstrate that a CR has been achieved.  The marrow should be analyzed by flow 
cytometry and/or immunochemistry to demonstrate that the marrow is free of clonal 
B-CLL cells.  Note:  cases with residual CLL cells by conventional flow cytometry or 
immunohistochemistry are defined as a PR.
Subjects who fulfill all the criteria for a CR, but who have persistent anemia, 
thrombocytopenia or neutropenia apparently unrelated to CLL, but related to drug toxicity 
should be considered as a different category of remission, CR with incomplete bone 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
89
marrow recovery (CRi).  The marrow evaluation should be performed with scrutiny and 
not show any clonal infiltrate.  Subjects should be monitored prospectively to determine 
whether or not their outcome differs from that of patients with detectable residual disease 
or with non-cytopenic PR.
Partial Remission (PR) requires at least two of the following for a period of at least 
2 months:
1.
≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment 
baseline value.
2.
≥ 50% reduction in lymphadenopathy (assessed by CT scan):
●
In the sum of products of up to 6 lymph nodes, or
●
In one lymph node diameter if only a single lymph node was present at 
baseline.
3.
No increase in any lymph node, and no new enlarged lymph node.  In small lymph 
nodes (< 2 cm), an increase of < 25% is not considered to be significant.
4.
≥ 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy) 
as defined by CT scan.
In addition one or more of the following criteria must be met:
●
Polymorphonuclear leukocytes ≥ 1,500/L or 50% improvement over baseline 
without G-CSF support.
●
Platelets > 100,000/L or 50% improvement over baseline.
●
Hemoglobin > 11.0 g/dL or 50% improvement over baseline without 
transfusions or erythropoietin support.
Progressive Disease (PD) requires at least one of the following:
1.
Appearance of any new lesions such as enlarged lymph nodes (> 1.5 cm), 
splenomegaly, hepatomegaly or other organ infiltrates.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
90
2.
≥ 50% increase in the sum of the products of diameters of multiple nodes
3.
≥ 50% in the greatest determined diameter of any previous site.  A lymph node of 
1-1.5 cm must increase by ≥ 50% to a size greater than 1.5 cm in the longest axis.  
A lymph node of more than 1.5 cm must increase to more than 2.0 cm in the 
longest axis.
4.
≥ 50% increase in the size of the liver and/or spleen or the de novo appearance of 
hepatomegaly or splenomegaly.
5.
≥ 50% increase in the absolute number of blood lymphocytes with at least 
5,000 B-lymphocytes per L.
6.
Transformation to a more aggressive histology (e.g., Richter's syndrome or PLL 
with > 55% prolymphocytes).
7.
Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to 
CLL.
●
The progression of any cytopenia (unrelated to autoimmune cytopenia), as 
documented by a decrease of Hb levels by more than 2 g/dL or to less than 
10 g/dL, or by a decrease of platelet counts by more than 50% or to less than 
100,000/L, defines disease progression, if the marrow biopsy demonstrates an 
infiltrate of clonal CLL cells.
Subjects who have not achieved a CR or a PR, or who have not exhibited PD will be 
considered to have Stable Disease (SD).
A summary of the criteria described above is included in Table 11.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
91
Table 11.
IWCLL Updated NCI-WG Criteria for Tumor Response (2008)
Criteria
Complete 
Remission (CR)
Partial Remission 
(PR)
Progressive 
Disease (PD)
Stable Disease 
(SD)
Lymphadenopathy
None above 
1.5 cm
≥ 50% reduction
≥ 50% increase
Change of –49% 
to +49%
Hepatomegaly and/or 
Splenomegaly
Absent
≥ 50% reduction
≥ 50% increase 
or new 
hepatomegaly 
and/or 
splenomegaly
Change of –49% 
to +49%
Constitutional Symptoms
Absent
Present
Present
Present
Polymorphonuclear Leukocytes
≥ 1500/L
≥ 1500/L or 
> 50% 
improvement over 
baseline without 
G-CSF support
Not specified
Not specified
Circulating clonal 
B-lymphocytes
None
≥ 50% reduction 
from baseline
≥ 50% increase 
over baseline
Change of –49% 
to +49%
Platelets
> 100,000/L
> 100,000/L or 
≥50% 
improvement from 
baseline
Decrease of 
≥50% from 
baseline 
secondary to 
CLL
Change of –49% 
to +49%
Hemoglobin
> 11 g/dL 
(untransfused and 
without 
erythropoietin)
> 11 g/dL or 
≥50% 
improvement from 
baseline
Decrease of 
> 2 g/dL from 
baseline 
secondary to 
CLL
Increase 
< 11 g/dl or 
< 50% over 
baseline or 
decrease 
< 2 g/dL
Bone Marrow Aspirate/Biopsy
Normocellular, 
< 30% 
lymphocytes, no 
B-lymphoid 
nodules, 
Hypocellular 
marrow defines 
CRi
≥30% 
lymphocytes, or 
B-lymphoid 
nodules, or not 
done
Increase of 
lymphocytes to 
more than 30% 
from normal
No change in 
marrow infiltrate
5.3.3.1.3
Definition of Clinical Disease Progression (Phase 2a)
Clinical disease progression is defined as determined by the investigator only, which may 
be characterized as, but is not limited to:
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
92
●
Constitutional symptoms attributable to CLL progression (e.g., unintentional 
weight loss, significant fatigue [e.g., ECOG performance score ≥ 2], persistent 
fevers without signs of infection or night sweats)
●
Requirement for palliative radiation, chemotherapy, surgery, immunotherapy 
or biologics
●
Death from disease progression
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring, vital signs, physical examination, platelet counts, lymphocyte enumeration, 
ECG, echocardiogram, and laboratory assessments.
5.3.5
Pharmacokinetic Variables
Values for the pharmacokinetic parameters of ABT-263, including the maximum 
observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the terminal 
phase elimination rate constant (), terminal elimination half-life (t1/2), the area under the 
plasma concentration-time curve (AUC) from time 0 to 24 hours (AUC0-24) for the dose 
on C1D1 in Phase 1 will be determined using noncompartmental methods.  For C1D14 in 
Phase 1, values will be determined for Cmax, Tmax and AUC from time 0 to 8 hours 
(AUC0-8).
5.3.6
Pharmacogenetic Variables
DNA samples may be analyzed for genetic factors contributing to the subject's response to 
ABT-263 in terms of pharmacokinetics, efficacy and safety.  The samples may also be 
used for the development of a diagnostic test for such a drug response.  Such genetic 
factors may include, for example, drug metabolizing enzymes, drug transport proteins, 
and Bcl-2 family members.  Genetic studies in general may include determination of the 
relationship of genetic haplotypes and drug metabolism, transport, therapeutic response 
and adverse events.  If clear differences of pharmacokinetics, safety or efficacy are noted 
during the clinical development of ABT-263 and believed to have a genetic basis, these 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
93
samples may be analyzed as part of a multicenter, multi-study project to identify genetic 
factors involved in the response to study drugs.  The samples may also be used for the 
development of a diagnostic test for drug response.
5.3.7
Pharmacodynamic Variables
Several putative biomarkers of efficacy and response will be evaluated in this protocol 
with the goal of defining the relationship between drug concentration and disease status.
Examination of the proteomic profiles of patients in the ABT-263 clinical trials may 
reveal patterns of protein/peptide concentrations that may be further evaluated in future 
clinical studies to determine any prognostic value and any correlation with clinical 
response.  Plasma samples will be analyzed for predictive or drug-responsive proteomic 
markers.  In addition circulating tumor-derived DNA or RNA may be extracted from 
plasma and assessed for expression or methylation and mutational status of genes relevant 
to either the disease status or ABT-263 mechanism of action.
In the event that any plasma or serum samples are unused, remaining samples will be 
banked for use in diagnostic test development efforts.  Measurement of relevant RNAs 
and proteins including the Bcl-2 family members in CLL cells in the blood, pre-treatment, 
during therapy and at time of relapse, may be examined for putative stratification markers 
for correlation with efficacy.  Additional studies may include determination of the 
Bcl-2/Bim ratio at the mitochondrial level, a highly predictive marker of sensitivity to the 
Bcl-2 family inhibitors.  For sites in Australia, additional studies may include assays to 
measure in vivo apoptosis and in vitro studies of patient CLL cell sensitivity to ABT-263.
Fluorescent In-situ Hybridization (FISH) may be conducted on CLL whole blood samples 
from patients participating in this study to assess amplifications and translocations in the 
Bcl-2 gene and other genes which may prove to be informative including standard CLL 
cytogenetic markers.  Whole genome analysis by CGH array may also be performed on 
CLL samples to identify genomic markers of CLL.  The potential relationship between 
amplification of these genes and the clinical outcome in these patients will be examined as 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
94
a stratification tool.  Biospecimens collected during the course of this study may be 
banked and used in the future to investigate new scientific questions related to this study.
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.
●
The subject experiences toxicities that require more than a 3-week dose 
interruption.
●
The subject requires more than two dose reductions, in the absence of 
objective response to ABT-263.
●
The subject requires radiotherapy, cancer-related surgery, or alternate 
anti-neoplastic agents during the study period.
●
The subject becomes pregnant or begins breastfeeding.
●
The occurrence of an adverse event that precludes further investigational drug 
administration.
●
Noncompliance with the protocol.
●
The subject requires anti-coagulant or anti-platelet therapy during the study 
period.
In addition, subjects in the Extension Study may also be discontinued for following 
reasons:
●
The Extension Study has been ongoing for 11 years since the transition of the 
last subject into the Extension Study.
●
ABT-263 becomes commercially available.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
95
●
AbbVie no longer pursues ABT-263 in this indication.
The investigator will inform AbbVie prior to discontinuing a subject from the study by 
contacting the Clinical Team Leader as identified in Section 7.0.
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.
The investigator should contact the sponsor medical contact before discontinuing a subject
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
All subjects will be included for analysis of safety data.  Subjects in the Phase 1 portion of 
the study who withdraw from the study will not be replaced unless they are not evaluable.  
Evaluable subjects are defined as those subjects who:
●
Experience a DLT
●
Complete at least 80% of dosing in the first cycle (of either 14/21 or 21/21 day 
dosing schedule)
In the event that a subject withdraws or is discontinued from the study, reason(s) for the 
discontinuation from the study will be recorded.  A physical examination, ECG, 
echocardiogram, vital signs measurement, laboratory analyses, performance status 
assessment, collection of unused study drug, an assessment of adverse events and tumor 
assessment (if needed) will be performed as soon as possible after discontinuation from 
the study.
A Safety Follow-up Visit should be performed for all subjects approximately 30 days 
following discontinuation of ABT-263 and then as clinically appropriate for safety 
assessment.  The subject will be followed until a satisfactory clinical resolution of the 
adverse event(s) is achieved.  If the subject refuses a follow-up visit or the visit is not 
performed, the reason should be noted in the subject's source documentation.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
96
In the event of a positive pregnancy test for a subject during the study, the administration 
of study drug to that subject must be discontinued immediately.  The investigator will 
report the positive pregnancy test result by telephone within 1 working day to the contact 
listed in Section 6.5.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study, either in its entirety or at a study site provided that 
written notice is submitted at a reasonable time in advance of the intended termination.  
The following procedures for discontinuation will be followed:
●
If the sponsor has decided to prematurely discontinue the study, the sponsor 
will promptly notify in writing the investigator as well as regulatory authorities 
of the decision and give detailed reasons for the discontinuation.
●
The investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation.
●
The investigator 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
Subjects will self-administer ABT-263 orally once daily (QD).  Each dose will be taken 
with approximately 240 mL of water.  On days that pre-dose pharmacokinetic sampling is 
required, dosing will occur in the morning (approximately 8 AM) in the clinic to facilitate 
pharmacokinetic sampling.  All subjects will self-administer ABT-263 within 30 minutes 
after the completion of breakfast.  The effect of food on pharmacokinetics will be 
evaluated outside of this study protocol and changes will be initiated if fasting conditions 
are superior.
On dosing days with PK collection (per Table 4 through Table 6), the time of each drug 
administration will be recorded to the nearest minute.  On all other days, subjects will be 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
97
instructed to record the date and time they take study drug.  Subject diaries will be 
provided by AbbVie.
During the Study Drug Dosing Period, a subject with confirmed (viral test positive) or 
suspected COVID-19 infection can only be dosed with study drug if the following 
COVID-19 viral clearance criteria are met:
●
Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 10 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 10 days have passed since prior positive result (note:  
subjects who develop symptoms will follow guidance above for symptomatic 
subjects)
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects 
must be discussed with the AbbVie medical contact, along with the possibility of 
premature discontinuation from the study drug dosing period.  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.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 12.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
98
Table 12.
Identity of Investigational Products
Study Drug
Trademark*
Formulation
Route of 
Administration
Manufacturer
ABT-263
(Navitoclax)
N/A
ABT-263 Stabilized Oral 
Solution (25 mg/mL, 
90 mL/bottle)
Oral
AbbVie/Abbott
ABT-263
(Navitoclax)
N/A
Tablets (25 mg)
Oral
AbbVie/Abbott
ABT-263
(Navitoclax)
N/A
Tablets (100 mg)
Oral
AbbVie/Abbott
*
N/A = Not Applicable
ABT-263 Stabilized Oral Solution
AbbVie (or designee) will supply, at a minimum:
●
ABT-263 Stabilized Oral Solution packaged in amber glass bottles containing 
a solution of 25 mg/mL concentration of ABT-263 per bottle. Each bottle will 
be supplied in a carton.
●
Written instructions for dosing and handling of drug supplies for the subject.
●
Written instructions for preparation and dispensing of prefilled syringes by the 
site pharmacist (or designee).
Ancillary Materials:
●
Amber oral syringes with caps.
●
Child-resistant syringe cartons.
●
Adapt-a-Caps (for bottles of stabilized oral solution).
●
Dispensing labels for prefilled syringes and corresponding child-resistant 
cartons.
●
Insulated cooler bags with freezable gel packs, to allow subject to transport of 
syringe cartons under recommended cold storage conditions.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
99
ABT-263 Tablets
ABT-263 tablets and any applicable ancillary materials will be provided by AbbVie.
5.5.2.1
Packaging and Labeling
ABT-263 Stabilized Oral Solution (25 mg/mL) will be packaged in amber glass bottles 
containing 90 mL solution per bottle.  Each bottle will be supplied in a carton.
ABT-263 tablets will be packaged in HDPE (high density polyethylene) plastic bottles.
Each bottle and carton will be labeled as required per country requirement.  Labels must 
remain affixed to the bottles and cartons.  Blank spaces on the label will be completed by 
the site.
ABT-263 Stabilized Oral Solution
The pharmacist (or designee) will prepare (prefill) the appropriate size oral syringes 
according to the dosing schedule and instructions provided.  Prefilled syringes will be 
placed in a child resistant carton for the subject to take home.  All prefilled syringes and 
child resistant cartons provided to the subject will also contain a label (completed by the 
site pharmacist or designee).  Each syringe and child resistant carton will be labeled as 
required per country requirements.  Labels must remain affixed to the syringes and child 
resistant cartons.  AbbVie will provide detailed instructions and training for the handling 
of study supplies to the study site.
5.5.2.2
Storage and Disposition of Study Drug
The investigational products supplied in this study are for investigational use only, and are 
to be used only within the context of this study.  All clinical supplies must be maintained 
under adequate security until dispensed for subject use, destroyed or returned to AbbVie.  
All clinical supplies must be stored per the conditions specified on the label.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
100
ABT-263 Stabilized Oral Solution
ABT-263 Stabilized Oral Solution (25 mg/mL) must be stored at 15° to 25°C (59° to 
77°F).  For additional oral solution storage information, please refer to labeled storage 
conditions.  Prefilled syringes must be stored at 2° to 8°C (36° to 46°F) and protected 
from light.
ABT-263 Tablets
ABT-263 tablets must be stored at 15° to 25°C (59° to 77°F) and protected from moisture 
and light.
5.5.2.3
Preparation/Reconstitution of Dosage Form
Written instructions for the preparation of ABT-263 oral solution and syringes will be 
provided to the site pharmacists as separate documents outside of this protocol.
5.5.3
Method of Assigning Subjects to Treatment Groups
As they are enrolled in the Phase 1 portion of the study, subjects will be assigned a dose 
and unique consecutive subject number, beginning with 501.  A detailed description for 
the methodology of allocating subjects to treatment groups according to the continual 
assessment methodology is provided in Section 8.1.1.  As the study progresses, subjects 
may progressively escalate to the highest dose level tolerated through 2 cycles of 
ABT-263 administration.  These decisions will be based on the judgment of the 
investigator in coordination with the AbbVie Medical Monitor.  As they are enrolled in 
the Phase 2a portion of the study, subjects will be assigned a unique consecutive subject 
number, beginning with 601.  The site, in conjunction with the sponsor, will be 
responsible for assignment of all unique subject numbers and dose assignments.  Subjects 
who continue in the Extension Study will retain the subject number that was assigned in 
the Phase 1 or Phase 2a portion of the study.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
101
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.  All subjects will receive ABT-263 within 
30 minutes following the completion of breakfast, unless specified otherwise.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
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 (or subject's caregiver) at home
●
Subject agrees to have the study drug shipped directly to their home
●
Shipments may also include other study supplies (e.g., drug dosing diaries).  
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.  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.
●
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.
5.5.5
Blinding
This is an open-label study.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
102
5.5.6
Treatment Compliance
To document compliance with the treatment regimen, subjects will be instructed to return 
all prefilled drug syringes or bottles, even if empty, and any other study related items as 
necessary, to the appropriate study site personnel at scheduled clinic visit.  Compliance 
will be monitored and documented by the study site personnel on the appropriate form.  
The study site personnel will question the subject regarding adherence to the dosing 
regimen, record either the number of prefilled syringes returned in the carton or the 
number of bottles returned, the date returned and determine treatment compliance before 
dispensing new medication to the study 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 ABT-263 will be kept by the site and will include lot number, Proof 
of Receipt number(s), bottle numbers, number of prefilled syringes or bottles dispensed, 
and the date on which study drug is administered or dispensed to the subject.  An overall 
accountability of the study drug will be performed and verified by the AbbVie designated 
monitors throughout the study and at the study site closeout visit.  Subjects will be 
instructed to return all prefilled syringes or bottles at each study visit, used or unused.  
The site will maintain a current and accurate inventory of supplies returned by the subject, 
whether used or unused.  Upon completion or termination of the study, all original 
containers (containing unused study drug) will be returned to AbbVie according to 
instructions from AbbVie.  If pre-arranged between AbbVie and the site, destruction of 
used and unused study drug bottles and syringes will be performed at the site.  Empty 
bottles will be destroyed at the site per the site's destruction policy.  Labels must remain 
attached to the containers.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
103
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Phase 1
For the Phase 1 portion of the study, the experimental design is an adaptation of the 
continual reassessment method (CRM).  The CRM is expected to locate the MTD 
efficiently.  The MTD is defined as the dose at which 30% of subjects experience a DLT 
during the first cycle.  The CRM attempts to estimate the target MTD from a continuum 
of doses, whereas a fixed design merely selects a dose from a discrete set.  If the true 
target dose is not among the choices set out in advance by fixed designs, they can only 
approximate it.  A CRM based design uses a statistical model for dose and toxicity by 
including the accumulating data to guide selection of the next dose.  Simulations and 
literature have shown that compared to the conventional fixed 3+3 design, the CRM 
typically requires fewer subjects to find the MTD, does not greatly overshoot the MTD 
(that is, subjects are not expected to be treated with dangerously high doses), and does not 
greatly underestimate the MTD.
During Phase 1, this study will employ a CRM design.32,33  Dosing with ABT-263 will 
begin at 10 mg with a cohort of three subjects.  The study drug dose will be escalated to 
the CRM estimated MTD, not to exceed an increase of more than 100 mg or 40% increase 
from the current dose level.  A minimum of three subjects will be treated per dose level to 
account for potential inter-subject variability.  The study design will be based on the 
concept of entering every subject at the best current statistical estimation of the MTD 
given the previous observations.  The dose escalation strategy will be based on a dose and 
probability of DLT response model.  The model will be adjusted using all of the available 
data and a new estimate of MTD will be projected from the updated model.  There are no 
control groups in this study.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
104
Phase 2a
The Phase 2a portion of the study will be open-label at the recommended Phase 2 dose 
(RPTD) and dosing schedule.  The RPTD will be defined by observed DLTs and/or 
determination of MTD from the Phase 1 portion of the 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 CLL will be selected to participate in this study.  
Pre-clinical findings support the possibility of efficacy in this patient population.  Due to 
the expected mechanism based, potentially dose-limiting thrombocytopenia, the study 
eligibility requirements take into consideration a potential subject's baseline platelet 
count, history of bleeding or active bleeding, coagulation parameters, CNS metastasis, 
ongoing immune thrombocytopenic purpura, and transplant history.
5.6.4
Selection of Doses in the Study
The starting dose in this Phase 1/2a trial is derived from the results obtained in the 
ABT-263 1-month rat and dog toxicity studies.  The initial starting dose of 10 mg was 
obtained by applying a safety factor of 10 to the lowest dosage used in the 1-month rat 
study (10 mg/kg/day) and the second-lowest dosage used in the 1-month dog study 
(3 mg/kg/day).  Although mild changes in platelets were noted in the rats and mild to 
moderate changes in platelets and lymphocytes were noted in dogs at these doses, the 
degree of platelet and lymphocyte decrease was well tolerated.  At all dosages, the 
decrease in platelets was readily reversible upon discontinuation of ABT-263.  
Additionally, at the dosages of 10 mg/kg/day in the rat or 3 mg/kg/day in the dog, 
platelets returned to baseline or near baseline values in the face of continued dosing.  
Given the ability to monitor the anticipated dose-limiting toxicity (thrombocytopenia) and 
the intended subject population, the safety factor of 10 provides an appropriate margin of 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
105
safety and safeguard against variability when extrapolating between species.  The 
conversion of the 10 mg/kg dose in rats and the 3 mg/kg dose in dogs to the human 
equivalent dose of approximately 10 mg was made using body surface area scaling for a 
60 kg human.  Projections of human pharmacokinetic data suggest that the proposed dose 
of 10 mg taken once daily to a 60 kg human would be expected to produce at steady state 
a Cmax in plasma of 0.2 g/mL and an AUC over a dosing interval (AUC24) of 
2.6 g•hr/mL.  These predicted values are below those concentrations that resulted in a 
No-Observed-Adverse-Effect-Level (NOAEL) in the dog or a tolerated dose in the rat.  
An AUC value of at least 53 g•hr/mL-88 g•hr/mL is projected to provide an efficacious 
concentration.  Subsequent to the 10 mg dose, the study drug dose will be escalated to the 
estimated MTD not to exceed an increase of 100 mg or a 40% increase from the current 
dose level, whichever is greater.
Phase 1
Selection of doses will be based on CRM by using a dose and probability of DLT 
response model.  A prior model will be employed based on preclinical and clinical data.  
Estimates of the model parameters and the probability of toxicity will be updated at each 
dose level.  The methodology for fitting the dose-toxicity response model is described in 
Section 8.1.1.  Subjects will be assigned to the dose level that estimates the targeted 
MTD, defined as the dose to reflect 30% rate of DLT according to the model.  The design 
is adaptive because at each dose level, the model will be updated using all of the previous 
available data and a new estimate of MTD will be projected from the updated model.  
A minimum of three subjects will be enrolled to warrant reasonable accuracy for the 
estimates.  The modeling process provides flexibility so that the new estimated MTD may 
be escalated or decreased from the previous dose.  The design continues in this fashion by 
assigning subjects to the MTD as estimated from current results.  When the next predicted 
MTD is within 10% of the current dose, the model is considered to have converged and 
MTD will be declared.  However, dose-determination will stop if the predetermined 
sample size of subjects is reached, based on operational considerations.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
106
Once either the MTD is defined or dosing in the 4th dose level is completed for the 
14/21 day dosing schedule, whichever occurs first, a continuous dosing schedule will be 
assessed.  Dosing with ABT-263 under the continuous dosing schedule (21/21 day) will 
begin at the dose estimated to provide exposure equivalent to the highest dosing level 
cleared (4th dose level) or the MTD from the 14/21 day schedule.
The starting dose for continuous dosing will be determined by calculating a dose of 
equivalent exposure from a 14/21 day schedule to a 21/21 day schedule (MTD 14)/21.  
For example if the highest tolerated dose is determined to be 375 mg then ABT-263 will 
be dosed at 250 mg once daily (375 mg 14/21 = 250 mg).
A 7 day period of dosing with a lead-in dose of ABT-263 will be explored with the 
21/21 day dosing schedule in order to interrogate whether higher doses may then be given 
with overall less reduction in platelet counts.  Subjects will begin dosing at 100 mg on 
Lead-in Day 1 (LD1).  This is the dose level at which a mean maximal platelet drop of 
approximately 60% from baseline with recovery during 14 days of continued dosing is 
expected based on observations in this study to date.  The lead-in titration dose may be 
adjusted if the defined dose level fails to significantly mitigate ABT-263-induced 
thrombocytopenia following the lead-in period or the defined dose level results in 
significant occurrence of DLT in the lead-in period.
Phase 2a
Once the MTD and/or RPTD is declared on the Phase 1-21/21 day continuous dosing 
schedule, a safety analysis will be performed as described in Section 8.1.4.  The results of 
the safety analysis as well as the recommended Phase 2 dose and dosing schedule will be 
communicated to all participating research sites prior to the start of enrollment in the 
Phase 2a portion of the study.
6.0
Adverse Events
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 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
107
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course, outcome, relationship of the adverse event to study 
drug, and any action(s) taken.  For serious adverse events not considered "probably 
related" to study drug, the investigator will provide an Other cause of the event.  For 
adverse events to be considered 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
Definitions
6.1.1
Adverse Event
An adverse event (AE) 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.  
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, meets protocol specific criteria (see Section 6.7 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 preexisting condition and 
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 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
108
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
Hospitalization for the purpose of TLS prophylaxis (e.g., for I.V. hydration) 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.
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.
6.1.2
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 (SAE) 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).
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
109
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).  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.
Spontaneous Abortion
Miscarriage experienced by study subject.
Elective Abortion
Elective abortion performed on study subject.
6.2
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, Version 3.0 
(NCI CTCAE).34
If a reported adverse event increases in severity the initial adverse event should be given 
an outcome date and a new adverse event reported to reflect the change in severity.  For 
all reported serious adverse events that increase in severity, the supplemental eCRFs 
(paper CRFs for the Extension Study) also need to be updated to reflect the change in 
severity.
For adverse events not captured by the Common Terminology Criteria, the following 
should be used:
Grade 1 (Mild)
The adverse event is transient and easily tolerated by the 
subject.
Grade 2 (Moderate)
The adverse event causes the subject discomfort and interrupts 
the subject's usual activities.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
110
Grade 3/4 (Severe)
The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating or 
life-threatening.
Grade 5
The adverse event resulted in death of the subject.
6.3
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:
Probably Related
An adverse event has a strong temporal relationship to study 
drug or recurs on re-challenge and an Other cause of event is 
unlikely or significantly less likely.
Possibly Related
An adverse event has a strong temporal relationship to the 
study drug and an Other cause of event is equally or less likely 
compared to the potential relationship to study drug.
Probably Not 
Related
An adverse event has little or no temporal relationship to the 
study drug and/or a more likely Other cause of event exists.
Not Related
An adverse event is due to an underlying or concurrent illness 
or effect of another drug and is not related to the study drug 
(e.g., has no temporal relationship to study drug or has a much 
more likely Other cause of event).
For causality assessments, events meeting the categories of probably or possibly will be 
considered "associated."  Events that are probably not or not related will be considered 
"not associated."  In addition, when the investigator has not reported a causality or 
deemed it not assessable, AbbVie will consider the event associated.
If an investigator's opinion of possibly, probably not, or not related to study drug is given, 
an Other cause of event must be provided by the investigator for the serious adverse 
event.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
111
6.4
Adverse Event Collection Period
All serious and non-serious adverse events reported from the time of study drug 
administration until 30 days following discontinuation of study drug administration will 
be collected, whether elicited or spontaneously reported by the subject.
Serious adverse events occurring after the study-specific informed consent is signed but 
prior to the initial dose of the investigational product will be collected only if they are 
considered by the investigator to be causally related to the study required procedures.
For subjects in the Extension Study, all adverse events that occur after Day 1 visit in the 
Extension Study should be captured in the Extension Study paper Case Report Forms.
Adverse event information will be collected as shown in Figure 5.
Figure 5.
Adverse Event Collection
Participation-
related
SAEs*
SAEs and Nonserious AEs
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.
6.5
Adverse Event Reporting
In the event of a serious adverse event, whether related to study drug or not, the 
investigator will notify Oncology Safety Management within 24 hours of the site being 
made aware of the serious adverse event by faxing the appropriate serious adverse event 
forms to the AbbVie Oncology Safety Management Team.
FAX to:  +1 (847) 785-8224
Email:  SafetyManagement_Oncology@abbvie.com
 




ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
113
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:
●
COVID-19 Supplemental Signs/symptoms
●
COVID-19 Status Form
6.6
Pregnancy
In the event of a positive pregnancy test, subjects must immediately discontinue study 
drug and must be discontinued from the study.  The investigator must report the positive 
pregnancy test to the appropriate contact listed in protocol Section 6.5 within 1 working 
day of the site becoming aware of the pregnancy.
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  The investigator must follow the pregnancy to completion 
and provide an update to AbbVie after delivery.
Male subjects should be informed that contraceptive measures should be taken by their 
female partners.  If the subject's partner should become pregnant during the study, this 
should also be reported and data may be collected.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.7
Toxicity Management
6.7.1
Definition - Dose Limiting Toxicity
Dose-limiting toxicities for dose-escalation purposes will be determined during the 
first cycle.  Adverse events occurring following the first cycle will also be evaluated by 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
114
the investigator and the AbbVie Medical Monitor and may be considered as dose limiting.  
Any of the following events, which are considered possibly or probably related to the 
administration of ABT-263, will be considered a dose limiting toxicity (DLT).
●
Thrombocytopenia:
○
Grade 4 thrombocytopenia (< 25,000/mm3)
●
Platelet counts < 25,000/mm3 should be confirmed the same day by manual 
reading and a separate peripheral draw.  If the repeat platelet count is 
≥25,000/mm3, this will not be considered a DLT.  If the repeat platelet count 
cannot be obtained within the same day as the initial measurement of 
< 25,000/mm3, then the initial measurement will constitute a DLT.
●
Grade 2 or higher bleeding associated with thrombocytopenia
●
All other Grade 3, 4 or 5 adverse events will be considered a DLT.  Exceptions 
include:
○
Grade 3, 4 Afebrile Neutropenia less than 7 days
○
Grade 3, 4 Leukopenia
○
Grade 3, 4 Lymphopenia
○
Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment
○
Grade 2 toxicity that requires dose modification or delay of > 1 week, will 
be considered a DLT (e.g., peripheral neuropathy)
Any DLT will require an interruption and possible discontinuation of ABT-263.  
ABT-263 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.  Following a DLT of thrombocytopenia, 
ABT-263 may be reintroduced, but only at a reduced dose, if the platelet toxicity grade 
returns to Grade 2 (≥ 50,000/mm3).  Any reduced dose level will be jointly defined by 
the investigator and the AbbVie Medical Monitor.  The dose may be increased thereafter 
upon joint determination of the investigator and the AbbVie Medical Monitor.  This dose 
is not to exceed the highest tolerated dose level.
For the Phase 1 portion of the study, all decisions regarding continued dosing for 
individual subjects will be medically managed by the investigator, in conjunction with the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
115
AbbVie Medical Monitor, as appropriate.  These decisions will be driven by the definition 
of DLTs as described above.
6.7.2
Management of Thrombocytopenia
ABT-263 induces apoptosis, rather than lysis, of circulating platelets, which differs from 
typical chemotherapy induced thrombocytopenia related to myelosuppression.
All decisions regarding continued ABT-263 dosing for individual subjects will be 
determined by the investigator, in conjunction with the AbbVie Medical Monitor, as 
appropriate.  These decisions should be guided by the following:
Administration of ABT-263 will be interrupted or discontinued for:
●
Any pre-dose platelet count < 25,000/mm3
●
Any clinically significant bleeding, defined as Grade 2 or higher hemorrhage
If ABT-263 is held, it may be restarted, but only at a reduced dose to be jointly defined by 
the investigator and the AbbVie Medical Monitor, once the subject's platelet count is 
≥50,000/mm3.  The dose may be increased (not to exceed the highest tolerated dose) 
thereafter upon joint determination of the AbbVie Medical Monitor and the investigator.
After any Grade 4 platelet count < 25,000/ mm3 is observed for the first time in a subject, 
serial PK samples will be collected.  PK samples will be collected as soon as possible 
after the Grade 4 platelet count is determined and then 24 and 48 hours after the event.  
Starting with Protocol Amendment 13, PK samples will NOT be collected.
Limited human clinical data are available to understand the response to infusion of 
exogenous platelets in the presence of circulating drug levels.  Platelet transfusion studies 
conducted in beagle dogs demonstrated that transfusion of one-day old platelets 
administered near the time of ABT-263 Cmax, resulted in higher platelet levels than dogs 
not receiving supplemental platelets.  Platelet concentrations remained higher after 
24 hours with declining ABT-263 concentrations.  This study suggests that infusion of 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
116
platelets may have beneficial effects in treating acute thrombocytopenia following oral 
dosing with ABT-263.
If platelet transfusions are required in response to active bleeding, dosing of ABT-263 
should be suspended.  It should be noted that platelet response with transfusions may not 
follow typical platelet kinetics of thrombocytopenia as with typical chemotherapy induced 
myelosuppression.  Procedures consistent with local institutional blood banking 
guidelines regarding platelet transfusions should be followed.
Platelet Transfusion Recommendations:
If a platelet transfusion is deemed necessary, the treating physician should be aware of the 
following:
●
Due to the rapid apoptotic effect of ABT-263 on mature platelets, the initial 
increase in platelets post-transfusion may be smaller and the duration of 
response may be shorter.  For this reason, donor platelets collected as recently 
as possible prior to transfusion should be considered.
●
A post-transfusion platelet count should be obtained within 10 to 60 minutes.
●
Additional transfusions may be necessary to achieve the desired platelet 
response.
6.7.3
Management of Lymphopenia
There is a potential for clinically significant lymphopenia in this study.  If clinically 
indicated, anti-infective prophylaxis should be implemented at the investigator's 
discretion, including appropriate prophylaxis for viral, fungal, bacterial or Pneumocystis 
carinii pneumonia (PCP) infections.  Potential for drug-drug interactions should be 
considered.  See Appendix E for a description of excluded and cautionary medications.
6.7.4
Management of Tumor Lysis Syndrome
There is a potential for tumor lysis in subjects with various tumor types in the presence of 
the following risk factors:  bulky disease, elevated pre-treatment LDH levels, elevated 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
117
leukocyte count and dehydration.  Adequate hydration, careful monitoring of laboratory 
values and an agent to reduce the uric acid level should be considered for subjects at high 
risk during the Lead-in and subsequent cycles.  Please discuss with the AbbVie Medical 
Monitor, as appropriate.
6.7.5
Determination of the MTD
The MTD is defined as the dose at which 30% of subjects experience a DLT during the 
first cycle.  At each dose level, MTD will be estimated based on actual observations from 
subjects to construct a dose and toxicity rate model using the maximum likelihood 
method.  As data accumulate and the reassessment continues, the MTD will be determined 
based on the convergence criteria described in Section 5.6.4.  The recommended Phase 2 
dose (RPTD) will be defined by observed DLTs and/or determination of MTD.
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 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), the investigator 
is responsible for notifying independent ethics committee (IEC)/independent review board 
(IRB), regulatory authorities (as applicable), and AbbVie.
 




ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
119
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided p-value < 0.05.
8.1.1
Demographics and Treatment Allocation
Demographics
Descriptive statistics will be provided for baseline demographic variables for the Phase 1 
and the Phase 2a portion of the study separately.  Age, height and weight will be 
summarized with means, medians, standard errors, standard deviations and ranges.  
Frequencies and percentages will be provided for gender and race.
Treatment Allocation
One of the objectives of the Phase 1 portion of this study is to determine the MTD, and 
the dose allocation process will be conducted according to a continual reassessment 
method (CRM).35,36,37  A two-parameter logistic regression model will be employed to 
characterize dose and toxicity rate relationship.  A prior model based on preclinical and 
clinical data will be employed to estimate doses with approximately 30% and 90% 
probability of inducing a DLT.  The MTD is the dose that reflects a 30% rate of DLT.  
The dose associated with 90% DLT rate will be incorporated for future model fitting to 
stabilize the high dose-toxicity portion of the model.  For each subject, the response will 
be defined as 0 (no DLT event) or 1 (DLT).  Along with the actual observed data, 
10 imputed subjects will be added with 9 subjects having DLT and 1 without DLT at the 
dose associated with 90% DLT rate.  A small weight of 0.025 will be assigned to these 
imputed data to reflect a small degree of certainty, and at the same time to stabilize the 
model fitting process as shown in the simulations.  To estimate the dose corresponding to 
approximately 30% probability of inducing DLT, one out of the three subjects in the 
160 mg dosing cohort from the M06-814 study will be utilized with a small weight of 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
120
0.083 assigned to these prior data.  For the actual observations, a unity weight will be 
assigned.  The maximum likelihood method will be employed to estimate the parameters 
and probability of DLT within the framework of the logistic regression analysis.  The 
fitted model will be inverted to estimate the target dose associated with 30% chance of 
DLT, or the MTD.  The next cohort of subjects will then be assigned to the projected 
MTD and evaluated.  The outcome will be incorporated to update the logistic regression 
model using all the cumulative information.  The design will continue to adapt data from 
current results and assign subjects to the projected MTD until the target dose changes by 
less than 10%, or a sample size of 40 subjects is reached.  Simulations to compare the 
conventional fixed 3+3 design and the CRM based design are provided in Appendix F.
8.1.2
Pharmacokinetics
8.1.2.1
Tabulations and Summary Statistics
Plasma concentrations of ABT-263 and pharmacokinetic parameter values will be 
tabulated for each subject and each dose level, and summary statistics will be computed 
for each sampling time and each parameter.
8.1.2.2
Model and Tests
Dose Proportionality
For subjects who participate in the Phase 1 14/21 day dosing portion of the study, an 
analysis will be performed on pharmacokinetic variables for C1D1 dose to simultaneously 
explore for demographic variables that explain some of the variability in 
pharmacokinetics and to address questions of dose proportionality and linear kinetics.  An 
analysis will be performed for dose-normalized Cmax, Tmax, and dose-normalized AUCt 
(AUC0-24), provided that they can be adequately determined from the data.  The model 
used for the statistical analyses will include dose 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 potentially 
formulation (if applicable), as well as others that might explain some of the variability in 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
121
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 level 0.10.  The 
natural logarithmic transformation will be employed for Cmax and AUCt 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.
A corresponding analysis will also be performed on pharmacokinetic variables of the dose 
on C1D14 for both the Phase 1 14/21 and 21/21 day dosing schedules.  The variables will 
include dose-normalized Cmax, Tmax, and dose-normalized AUCt (AUC0-8).
Additional analyses will be performed if useful and appropriate.
8.1.2.3
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue will be 
addressed.  Normally values of pharmacokinetic 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 
pharmacokinetic 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.
8.1.3
Exploratory Efficacy
The following exploratory efficacy analyses will be performed on the data collected from 
the Phase 2a portion of the study.
8.1.3.1
Progression-Free Survival
The distribution of PFS will be estimated using Kaplan-Meier methodology.  Median time 
to PFS and the corresponding 95% confidence interval will be estimated.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
122
For a given subject, PFS will be defined as the number of days from the date the subject 
started study drug to the date the subject experiences an event of disease progression, as 
defined in Section 5.3.3, or to the date of death if disease progression is not reached.  
All events of disease progression will be included, regardless of whether the event 
occurred while the subject was still taking study drug or had previously discontinued 
study drug.  Events of death will be included for subjects who had not experienced disease 
progression provided the death occurred within 2 cycles (42 days) of the date of the last 
available tumor evaluation.  If a subject has not experienced an event of disease 
progression or death as defined above, then the subject's data will be censored at the date 
of the last available evaluation for disease progression.  The date of the last available 
evaluation will be the date of the last study visit at which a tumor assessment was 
performed.
8.1.3.2
Objective Response Rate
The proportion of subjects with a complete remission (CR), complete remission with 
incomplete bone marrow recovery (CRi) or partial remission (PR) based on the NCI-WG 
criteria in Section 5.3.3.1 will be estimated and the corresponding 95% confidence 
interval for the proportion will be constructed.  The exact binomial distribution will be 
used to construct this confidence interval.
A subject will be classified as a complete remission (CR), complete remission with 
incomplete bone marrow recovery (CRi), partial remission (PR) or as having PD based on 
the definition in Section 5.3.3.1.  The objective response rate (CR, CRi, PR) will be 
computed for all subjects with active disease at baseline (in the opinion of the 
investigator).
8.1.3.3
Time to Tumor Progression
Time to tumor progression for a given subject will be defined as the number of days from 
the date the subject started study drug to the date of the subject's tumor progression.  Time 
to tumor progression may be collected up to 2 cycles (42 days) following the date of the 
last available tumor evaluation.  All events of tumor progression will be included, 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
123
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 progressed, then the data 
will be censored at the date of the last study visit at which a tumor assessment was 
performed.
The distribution of the time to tumor progression will be estimated using Kaplan-Meier 
methodology.  Median time to tumor progression and the corresponding 95% confidence 
interval will be estimated.
8.1.3.4
Overall Survival
Time to death for a given subject will be defined as the number of days from the date the 
subject started study drug to the date of the subject's death.  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 died, then the data 
will be censored at the date of the last study visit, the last contact date, or the date the 
subject was last known to be alive, whichever is last.  The date of the last study visit will 
be determined by selecting the last available date of the following study procedures for a 
subject:  physical examination, vital signs assessment, blood chemistry, hematology, and 
urinalysis collection.
The distribution of the time to death will be estimated using Kaplan-Meier methodology.  
Median survival time and the corresponding 95% confidence interval will be estimated.
8.1.3.5
Duration of Overall Response
The duration of overall response for a given subject will be defined as the number of days 
from the day the criteria are met for CR, CRi or PR (whichever is recorded first) to the 
date that PD is objectively documented.  The reference for PD will be the smallest 
measurements recorded since the treatment started.  If a subject is still responding then the 
subject's data will be censored at the last study visit at which a tumor assessment was 
performed.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
124
The distribution of the duration of overall response will be estimated using Kaplan-Meier 
Methodology.
8.1.3.6
ECOG Performance Status
For the ECOG performance scale, descriptive statistics will be summarized for each 
assessment.  In addition, a mean change from baseline to each assessment will be 
summarized.
8.1.3.7
Reporting of Results
All subjects enrolled will be assessed for response to treatment based on the NCI-WG 
criteria in Section 5.3.3.1.  Each subject will be assigned to one of the following 
categories:  1) complete remission, 2) complete remission with incomplete bone marrow 
recovery, 3) partial remission, 4) stable disease, 5) progressive disease, 6) early death 
from malignant disease, 7) early death from toxicity, 8) early death because of other 
cause, or 9) unknown (not assessable, insufficient data).
Subjects in response categories 5-8 will be considered as failing to respond to treatment 
(disease progression).  Thus, an incorrect treatment schedule or drug administration will 
not result in exclusion from the analysis of a response.
Sub-analyses may be performed on the subset of subjects for whom major protocol 
deviations have not been reported (e.g., early discontinuation of treatment, major protocol 
violations, etc.).  The reasons for excluding subjects from the analysis will be clearly 
reported.
8.1.4
Safety
Safety summaries will include all subjects participating in the study unless otherwise 
indicated.  A safety analysis will be performed for all subjects in the Phase 1 portion of 
the study once the MTD is reached and/or RPTD is determined, after the last enrolled 
subject completes one cycle of drug, and prior to enrollment of subjects into the Phase 2a 
portion of the study.  A second safety analysis will be performed for all subjects in the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
125
Phase 1 and Phase 2a portions of the study upon completion of the study.  The following 
will be included in these analyses:
Adverse Events
The number and percentage of subjects having treatment-emergent adverse events will be 
tabulated by MedDRA system organ class and preferred term.38  The tabulations will also 
be provided with further breakdowns by NCI CTCAE toxicity grade and relationship to 
study drug.  Serious adverse events, events leading to discontinuation of treatment, and 
events leading to death, will be summarized.  For subjects who participate in Cycle 1 of 
Phase 1 of the study, all summaries will be done by dose.  For the study as a whole, 
summaries will be provided with a breakdown as appropriate.
Platelet Counts
Platelet counts will be explored for trends with dose and time and summarized as 
appropriate.  The baseline value (last measurement before the beginning of study drug 
administration) will be included in the statistical analysis and changes from baseline will 
be addressed.
A repeated measures model with dose level as a classification variable will be performed 
for values in Cycle 1 of the platelet counts for which multiple measurements will be 
taken.  A transformation of a variable will be used if it clearly provides more nearly 
symmetric probability distribution and/or more nearly homogenous variances across dose 
levels.
The relationship between drug concentration variables and platelet counts will be 
explored.  The dependence of observations from the same subject will be appropriately 
taken into account in all of the above analyses.
Other Safety Measurements
Laboratory test results, lymphocyte enumeration results, vital signs, echocardiogram 
results, and ECG interval measurements results will be explored for trends with dose and 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
126
time and summarized as appropriate.  The baseline values (Screening values) will be 
included in the statistical analysis and changes from baseline will be addressed.  Changes 
from baseline at the recommended Phase 2a dose will be analyzed with a t-test at each 
scheduled visit.  Where applicable, blood chemistry and hematology determinations will 
be categorized according to NCI CTCAE (Version 3.0) grades, and shifts from baseline 
NCI CTCAE grades to maximum and final post-baseline grades for each treatment group 
will be assessed.  Vital signs values will be evaluated for possible clinical significance 
using criteria developed at AbbVie.  Additional analyses will be performed if useful and 
appropriate.
8.2
Determination of Sample Size
The sample size was based on simulations for CRM, clinical justification and subject 
enrollment numbers historically used for the testing of new oncology compounds.
During the dose-toxicity modeling process, a minimum of three subjects per cohort will 
be included to warrant reasonable accuracy for the estimates.  The total number of 
subjects required for the Phase 1 portion of this study will depend upon the toxicities 
observed as the trial progresses.  The total number of subjects for Phase 1 is not likely to 
exceed 40 based on operational considerations.  For the Phase 2a portion of the study, 
approximately 32 subjects with relapsed disease was chosen to further characterize safety 
and assess preliminary evidence of efficacy with the RPTD in this population.
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.  IEC/IRB approval of the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
127
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 prior to implementation 
of any changes made to the study design.  A list of the documents required prior to 
initiation of the study can be found in Appendix C.
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.
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will 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.
In all cases, these alternative measures must be allowed by local regulations and permitted 
by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures are taken 
to protect the subjects against any immediate hazard.
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.  The investigator must ensure that the study is conducted in accordance with the 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
128
provisions as stated in the FDA regulations and complies with prevailing local laws and 
customs.  Responsibilities of the clinical investigator are specified in Appendix D.
9.3
Subject Information and Consent
Prior to the initiation of any screening or study-specific procedures, the investigator or 
his/her representative will explain the nature of the study to the subject and answer all 
questions regarding this study.  Subjects who provide blood or tissue samples for 
pharmacogenetic or pharmacodynamic analyses will also sign an informed consent 
regarding the collection of these samples.  Each informed consent will be reviewed, 
signed and dated by the subject or his/her legal representative and the person who 
administered the informed consent.  A copy of each informed consent will be given to the 
subject and each 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.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' 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 on the 
appropriate source documents.
The investigator(s)/institution(s) 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.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
129
10.2
Case Report Forms
Case report forms must be completed for each subject 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 will be collected with an Electronic 
Data Capture (EDC) tool called InForm provided by the technology vendor Phase 
Forward of Waltham, MA, USA.  In addition, this study will use the Central Coding tool 
provided by Phase Forward to code event and medication terms.  The EDC system and the 
study-specific eCRFs will be in compliance with Title 21 CFR Part 11.  The 
documentation related to the validation of the EDC tool is available through the vendor, 
Phase Forward, while the validation of the study-specific eCRFs will be conducted by 
AbbVie and be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own patient files.  These patient 
files will serve as source data for the trial.  eCRF data required by this protocol will be 
recorded by investigative site personnel in the EDC tool.  Data entered into the eCRF 
should be supported by source documentation.
If eCRF corrections are necessary they will be made by the investigator or by an 
authorized member of the investigator's staff to the eCRFs.  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 CRFs 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/her electronic signature and date to eCRFs as 
evidence thereof.
Access to the EDC system will be provided by Phase Forward 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 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
130
EDC tool will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of his eCRF entries.  It will be possible for the 
investigator to make paper printouts from that media.
10.3
Extension Study Case Report Forms
Case report forms must be completed for each subject enrolled in this study.  These forms 
will be used to transmit information collected during the study to AbbVie and regulatory 
authorities, as applicable.  Each CRF will be printed on 2-part NCR paper: the white copy 
will be retrieved by AbbVie or its designee, and the pink copy will be retained by the site.
All information written on the CRFs must also be reflected in the subject source 
documents.  All CRFs must be legible and completed in indelible ballpoint ink.  Any 
necessary corrections are to be made by drawing a single line through the incorrect entry 
and writing in the revision, which must be initialed and dated by the investigator or 
designee.  Data are not to be obliterated by blacking out, correction fluid, or by erasing the 
original entry.  If the reason for the correction is not obvious, a brief explanation 
(e.g., "transcription error") should accompany the change.  Once a CRF has been 
separated, all changes must be made via addenda.  All addenda must be signed and dated 
by the investigator.
The principal investigator will review the case report forms for completeness and 
accuracy and sign and date the set of case report forms where indicated.
Case report forms will be reviewed periodically against source documents for 
completeness, legibility, and acceptability by AbbVie Laboratories personnel or its 
designee.
11.0
Data Quality Assurance
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 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
131
documents, performance of study procedures, case report form completion and specimen 
collection methods.  The personnel at the study site will be trained on the study 
procedures, when applicable, by AbbVie (or designee).
The AbbVie designated monitor will monitor the study site throughout the study.  A 
100% 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, continuous review of the data will be 
conducted by a physician or representative at AbbVie.
Computer logic checks will be run to identify such items as inconsistent study dates.  Any 
necessary corrections will be made to the electronic CRF.
Routine hematology, serum chemistry and urinalysis tests will be conducted using a 
certified clinical laboratory.  Laboratory reference ranges will be obtained prior to the 
initiation of the study.  The AbbVie designated monitor, the investigator and other 
appropriate personnel from AbbVie will conduct a review of all laboratory results.
12.0
Use of Information
All information concerning ABT-263 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 ABT-263.  
This information may be disclosed as deemed necessary by AbbVie to other clinical 
investigators, other pharmaceutical companies, to the FDA and to other 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 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
132
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 pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature.  Hence, neither the investigator, the subject nor the subject's 
physician (if different than the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic 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 pharmacogenetic 
information from this study may also be used in scientific publications or presented at 
medical conventions.  Pharmacogenetic information will be published or presented only in 
a way that does not identify any individual subject.
AbbVie agrees that before it publishes any results of this study, it shall provide the 
investigator a pre-publication manuscript for review prior to the submission of the 
manuscript to the publisher.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
133
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.
AbbVie may terminate this study either in its entirety or at a study site provided that 
written notice is submitted at a reasonable time in advance of the intended termination.  
The investigator may also terminate the study at his/her study site after providing written 
notice to AbbVie at a reasonable time 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, it will immediately notify the investigator 
by telephone and subsequently provide written instructions for study termination.
AbbVie will select the signatory coordinating investigator from the investigators who 
participate in each multi-center 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 scheduled visit or the 
actual date of follow-up contact, whichever is longer.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
134
14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator Brochure for ABT-263.
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.
Protocol Title:
A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics, and 
Efficacy of ABT-263 in Subjects with Relapsed or Refractory Chronic 
Lymphocytic Leukemia
Protocol Date:
03 September 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
135
15.0
Reference List
1.
Korsmeyer SJ.  BCL-2 gene family and the regulation of programmed cell death.  
Cancer Res.  1999;59:1693s-1700s.
2.
Cory S, Adams JM.  The Bcl-2 family:  regulators of the cellular life-or-death 
switch.  Nature Reviews.  Cancer 2002;2:647-656.
3.
Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death 
decisions.  Molecular Immunology.  2003;39:615-647.
4.
Cory S, Huang DCS, Adam JM.  The Bcl-2 family:  roles in cell survival and 
oncogenesis.  Oncogene.  2003;22:8590-8607.
5.
Willis S, Day CL, Hinds MG, et al.  The Bcl-2 regulated apoptotic pathway.  
Journal of Cell Science.  2003;116:4053-4056.
6.
Wei MC, Zong WX Cheng EHY, et al.  Proapoptotic BAX and BAK:  a requisite 
gateway to mitochondrial dysfunction and death.  Science.  2001;292:727-730.
7.
Lindsten T, Ross AJ, King A, et al.  The combined functions of proapoptotic Bcl-2 
family members Bak and Bax are essential for normal development of multiple 
tissues.  Molecular Cell.  2000;6:1389-1399.
8.
Degenhardt K, Sundararajan R, Lindsten T, et al.  Bax and Bak independently 
promote cytochrome c release from mitochondria.  Journal of Biological 
Chemistry.  2002;277:14127-14134.
9.
Adams JM, Cory S.  Life or death decisions by the Bcl-2 protein family [Review].  
Trends in Biochemical Sciences.  2001;26:61-66.
10.
Fadeel B, Zhivotovsky B, Orrenius S.  All along the watchtower:  on the regulation 
of apoptosis regulators [Review].  FASEB Journal.  1999;13:1647-1657.
11.
Tsujimoto Y, Shimizu S.  Bcl-2 family:  life-or-death switch [Review].  FEBS 
Letters.  2000;466:6-10.
12.
Yang E, Korsmeyer SJ.  Molecular thanatopsis:  a discourse on the Bcl-2 family 
and cell death.  Blood.  1996;88:386-401.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
136
13.
Cordynamics.  R&D/08/1639.  Cardiovascular assessment of systemic and 
pulmonary hemodynamic parameters in dogs after 28 days of dosing with 
A-855071 (ABT-263).  2008.
14.
AbbVie.  ABT-263 (A-855071) Investigator's Brochure Edition 15.  
29 August 2019.
15.
Diehl LF, Karnell LH, Menck HR, the American College of Surgeons Commission 
on Cancer and The American Cancer Society.  The National Cancer Data Base 
report on age, gender, treatment, and outcomes of patients with chronic 
lymphocytic leukemia.  Cancer.  1999;86:2684-2692.
16.
Zwiebel JA, Cheson BD.  Chronic lymphocytic leukemia:  staging and prognostic 
factors.  Seminars in Oncology.  1998;25:42-59.
17.
Ries LAG, Harkins D, Krapcho M, et al.  SEER Cancer Statistics Review, 
1975-2003, National Cancer Institute.  Bethesda, MD 
http://seer.cancer.gov/csr/1975_2003/, based on November 2005 SEER data 
submission, posted to the SEER web site 2006.
18.
Jemal A, Clegg LX, Ward E, et al.  Annual report to the nation on the status of 
cancer, 1975-2001, with a special feature regarding survival.  Cancer.  
2004;101:3-27.
19.
Francis S, Karanth M, Pratt G, et al.  The effect of immunoglobulin VH gene 
mutation status and other prognostic factors on the incidence of major infections in 
patients with chronic lymphocytic leukemia.  Cancer.  2006;107:1023-1033.
20.
Lamanna N, Weiss MA, Maslak PG, et al.  Sequential therapy with fludarabine, 
high dose cyclophosphamide, and rituxamib induces a high incidence of complete 
response in patients with chronic lymphocytic leukemia (CLL).  Proc Am Soc Clin.  
2003;22:580.
21.
Keating MJ, O'Brien S, Albitar M, et al.  Early results of a chemoimmunotherapy 
regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for 
chronic lymphocytic leukemia.  J Clin Oncol.  2005;23(18):4079-4088.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
137
22.
Yee KWL and O'Brien SM.  Chronic lymphocytic leukemia:  diagnosis and 
treatment.  Mayo Clin Proc.  2006;81:1105-1129.
23.
Hallek M, Schmitt B, Wilhelm M, et al.  Fludarabine plus cyclophosphamide is an 
efficient treatment for advanced chronic lymphocytic leukaemia (CLL):  results of 
a phase II study of the German CLL Study Group.  Br J Haematol.  
2001;114:342-348.
24.
Keating MJ, O'Brien S, Kantarjian H, et al.  Long-term follow-up of patients with 
chronic lymphocytic leukemia treated with fludarabine as a single agent.  Blood.  
1993;81:2878-2884.
25.
Byrd JC, Stilgenbauer S, Flinn IW.  Chronic lymphocytic leukemia.  Hematology 
2004; 163-183.
26.
Campath [package insert].  Cambridge, MA:  Genzyme Corp; 2005.
27.
Fujita, N.  In vivo veritas:  Bcl-2 and Bcl- XL mediate tumor cell resistance to 
chemotherapy Drug Resistance Updates 2000, 3 (149-154).
28.
Schoffski P, Riggert S, Fumoleau P, et al.  Phase 1 trial of intravenous aviscumine 
(rViscumin) in patients with solid tumors:  a study of the European Organization 
for Research and Treatment of Cancer New Drug Development Group.  Annals of 
Oncology 2004;15(12):1816-1824.
29.
O'Quigley J, Zohar S.  Experimental designs for phase I and phase I/II dose-finding 
studies.  British Journal of Cancer 2006;94:609-613.
30.
Cheson BD, Bennett, MG, Kay N, et al.  National Cancer Institute-Sponsored 
Working Group Guidelines for Chronic Lymphocytic Leukemia:  Revised 
Guidelines for Diagnosis and Treatment.  Blood.  1996;12:4990-4997.
31.
Hallek, M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, 
Dohner H, et al.  Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia:  a report from the International Workshop on chronic lymphocytic 
leukemia (IWCLL) updating the National Cancer Institute-Working Group (NCI-
WG) 1996 guidelines.  Blood.  E pub 2008 Jan 23.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
138
32.
Storer BE.  An evaluation of phase I clinical trial designs in the continuous 
dose-response setting.  Stats Med 2001;20:2399-2408.
33.
Potter DM.  Adaptive dose finding for phase I clinical trials of drugs used for 
chemotherapy of cancer.  Stats Med 2002;21:1805-1823.
34.
Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, 
NIH, DHHS.  August 9, 2006.  Available at:  
http://ctep.cancer.gov/reporting/ctc_v30.html.  Accessed November 2006.
35.
O'Quigley J, Shen LZ.  Continual reassessment method:  a likelihood approach.  
Biometrics 1996 Jun;52(2):673-84.
36.
Piantadosi S, Fisher JD, Grossman S.  Practical implementation of a modified 
continual reassessment method for dose-finding trials.  Cancer Chemother 
Pharmacol 1998;41(6):429-36.
37.
Goodman SN, Zahurak ML, Piantadosi S.  Some practical improvements in the 
continual reassessment method for phase 1 studies.  Stat Med 1995 June 
15;14(11):1149-61.
38.
Coding Guidelines for MedDRA Term Selection, AbbVie Global Pharmaceutical 
Research and Development (GPRD), Global Pharmacovigilance and Clinical 
Project Team.
39.
Oken M, Creech R, Tormey D, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-655.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
139
Appendix A.
List of Abbreviations and Definitions of Terms
Abbreviations
ACD
Acid Citrate Dextrose
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
aPTT
Activated Partial Thromboplastin Time
Bcl
B-Cell Lymphoma
BH
Bcl-2 Homology
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
14C
Carbon-14 (Radiocarbon)
CGH
Comparative Genomic Hybridization
CLL
Chronic Lymphocytic Leukemia
CNS
Central Nervous System
COVID-19
Coronavirus Disease-2019
CR
Complete Remission
CRi
Complete Remission with Incomplete Bone Marrow Recovery
CRM
Continual Reassessment Method
CRF
Case Report Form or Electronic Case Report Form
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP3A
Cytochrome P450 3A
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DTP
Direct To Patient
EC50
50% Effective Concentration
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
140
EDC
Electronic Data Capture
EDTA
Edetic Acid (ethylenediaminetetraacetic acid)
EMEA
European Agency for the Evaluation of Medical Products
ERT
Estrogen Replacement Therapy
FCR
Fludarabine, cyclophosphamide, rituximab
FDA
U.S. Food and Drug Administration
FISH
Fluorescence in situ Hybridization
GCP
Good Clinical Practice
G-CSF
Granulocyte-Colony Stimulating Factor
GM-CSF
Granulocyte Macrophage-Colony Stimulating Factor
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
hr
Hour
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IQR
Interquartile Range
IRB
Institutional Review Board
ITP
Immune Thrombocytopenia Purpura
IWCLL
International Workshop for Chronic Lymphocytic Leukemia
JP
Japanese Pharmacopoeia
K/L
Thousand per Microliter
kg
kilogram
Ki
Inhibition Constant
LDH
Lactate Dehydrogenase
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
mcl
microliter
MCT
Medium Chain Triglyceride
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
g
Microgram
mg
Milligram
min
Minute
mL
Milliliter
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
141
M
Micromolar
MPV
Mean Platelet Volume
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NCI-WG
National Cancer Institute-Working Group
nM
Nanomolar
NOAEL
No Observed Adverse Effect Level
nPR
Nodular Partial Remission
ORR
Objective Response Rate
OS
Overall Survival
PCP
Pneumocystis Pneumonia
PD
Pharmacodynamic or Progressive Disease
PFS
Progression-free Survival
PG
Pharmacogenetic
Ph. Eur.
European Pharmacopoeia
PK
Pharmacokinetic
PLL
Prolymphocytic Leukemia
PR
Partial Remission
PT
Prothrombin Time
QD
Once daily
QTc
QT interval corrected for heart rate
RBC
Red Blood Cell
RPTD
Recommended Phase Two Dose
SAE
Serious Adverse Event
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SSRI
Selective Serotonin Reuptake Inhibitor
STAT
statim (immediately)
TLS
Tumor Lysis Syndrome
TTP
Time-to-Tumor Progression
ULN
Upper Limit of Normal
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
142
US
Ultrasound
USP
United States Pharmacopoeia
WBC
White Blood Cell
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
Cmax
Maximum observed plasma concentration
Cmin
Minimum observed plasma concentration
t1/2
Terminal phase elimination half-life
Tmax
Time to maximum observed plasma concentration
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
143
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Sr. Scientist II
Biomarkers
 
Program Lead II
Clinical Program Development
 
Study Project Manager II
Clinical Program Development
Director
Statistics
 
Executive Medical Director, TA MD 
Clinical Program Development
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
144
Appendix C.
Documents Required Prior to Initiation of the Study
As sponsor of a clinical study, AbbVie has an obligation to ensure that the study will be 
conducted by a qualified investigator with sufficient resources (of time, personnel, and 
physical facilities) to conduct the study and to ensure that the investigator understands and 
agrees to comply with Good Clinical Practices and applicable regulations, policies, and 
procedures.  Prior to the beginning of any clinical study, the investigator will be asked to 
provide the following documentation.
1.
A signed and dated Investigator's agreement page for the study.
2.
A signed and dated Form FDA 1572 certifying the investigator's agreement to 
comply with the appropriate regulations governing the conduct of the study.  A 
signed and dated Investigator Information and Agreement Form certifying the 
investigator's agreement to comply with the appropriate (e.g., ICH GCP) 
regulations governing the conduct of the study.
3.
Current curriculum vitae for the investigator.  If subinvestigators will participate in 
the study, curriculum vitae for each.
4.
Requirements for the Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB).
●
A copy of the signed and dated letter of approval of the IEC/IRB.  The letter 
must specify that both the protocol and informed consent form were approved 
(unless separate documentation that the informed consent was approved is 
provided).
●
A dated list containing the names and affiliations of the members of the 
IEC/IRB, or the institution's General Assurance Number.
●
If the investigator and/or subinvestigator is a member of the IEC/IRB, a letter 
stating that he/she did not participate in the review or approval of the protocol 
or informed consent form.
5.
A specimen copy of the IEC/IRB-approved informed consent document to be used 
in the study.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
145
6.
A list of reference ranges of values for all laboratory tests specified by the protocol 
for all laboratories utilized.
7.
A copy of the laboratory(ies) certification(s) or the authorization number of the 
certification(s), the name of the certifying authority, and the period of certification.
8.
Financial Disclosure Certification forms must be completed by each investigator 
and all subinvestigators identified on the Form FDA 1572 or Investigator 
Information and Agreement Form.  A Financial Disclosure, EU Consent, is 
required to be completed for each investigator and/or subinvestigator who is a 
resident of the European Union.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
146
Appendix D.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol the investigator is 
agreeing to the following:  
1.
Conducting the study in accordance with the relevant, current protocol(s) and only 
make changes in a protocol after notifying AbbVie, except when necessary to 
protect the safety, rights, or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Inform all subjects, or any 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 committees 
[IEC] or institutional review board [IRB]) review and approval of the protocol 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
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.
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 and make 
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.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
147
9.
Reporting promptly all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others to the appropriate individuals, 
coordinating investigator, institutional director and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
148
Appendix E.
Sample List of Excluded and Cautionary Medications
SSRI's (Cautionary)
CYP3A Inhibitors (Excluded)
citralopram (Celexa)
atanazavir
escitalopram (Lexapro)
clarithromycin
fluoxetine (Prozac)
fluconazole
paroxetine (Paxil)
fluvoxamine (Luvox)
sertraline (Zoloft)
indinavir
itraconazole
Anticoagulation Therapy (Excluded)
ketoconazole
coumadin (Warfarin)+
nefazodone
dalteparin (Fragmin)
nelfinavir
enoxaparin (Lovenox)
ritonavir
fondaparinux (Arixtra)
saquinavir
heparin++
telithromycin
melagatran/ximelagatran
voriconazole
tinzaparin (Innohep)
CYP3A Inducers (Cautionary)
Anti-platelet (Excluded)
barbiturates
acetylsalicylic acid (Aspirin)
carbamazepine (Tegretol®)
aspirin/extended-release dipyridamole (Aggrenox)
efavirenz
clopidogrel (Plavix)
nevirapine
dipyridamole (Persantine)
oxcarbazepine
ticlopidine (Ticlid)
phenobarbital
Tirofiban (Aggrastat)
phenytoin (Dilantin®)
rifampin (Rifadin®)
NSAIDS+ (Excluded)
rifapentine
aspirin
St. John's wort
celecoxib
diclofenac
CYP2C9 Substrates (Cautionary)
diflunisal
fluvastatin
etodolac
glipizide
ibuprofen
irbesarten
indomethacin
losartan
ketoprofen
phenytoin
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
149
nabumetone
sulfamethoxazole
naproxen
sulfinpyrazone
oxaprozin
tolbutamide
salsalate
tosomide
sulindac
tolmetin
CYP2C8 Substrates# (Cautionary)
aminodarone
Ethanol (Excluded)**
amodiaquine
cerivastatin
Aldehyde Dehydrogenase Inhibitor (Excluded)**
chloroquine
disulfiram (Antabuse)
lovastatin*
paclitaxel (Taxol)
pioglitazone
repaglinide
rosiglitazone
simvastatin (Zocor)*
troglitazone
+
Warfarin and many NSAIDS are also CYP2C9 substrates.
++
Heparin may be used for patency of a central venous catheter.
*
Significant increase in AUC by co-administration of gemfibrozile, a potent CYP2C8 inhibitor.  However, the 
involvement of CYP2C8 is unclear.
**
This does not apply if the subject is taking Meltrex tablets.
#
Only certain statins qualify as CYP2C8 substrates.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
150
Appendix F.
Simulations Comparing Fixed 3+3 Design Versus CRM-based 
Design
Introduction
Simulations were conducted to compare a fixed 3+3 design to a design based on a specific 
continual reassessment method (CRM).  Designs were compared with respect to total 
sample size required, closeness of the design-determined MTD to the true MTD, and 
number of subjects treated at doses that are potentially 'too high' (e.g., doses with a > 90% 
chance of resulting in a DLT).  Two families of dose-toxicity curves were considered, 
one representing a "steep" dose-toxicity response curve and another representing a 
"shallow" dose-toxicity curve.
The CRM-based method provided essentially uniformly better results than the fixed 
3+3 design.  That is, for each simulated dose-toxicity relationship, the CRM design 
generally required fewer total subjects, resulted in an estimated MTD closer to the true 
MTD, and treated fewer subjects at potentially toxic doses, compared to the fixed 
3+3 design.
The following sections describe the study designs, the simulations, and the performance 
of each design in the simulations.
Methods
Abbreviations
CRM
continual reassessment method
D30
dose with a 30% probability of a DLT
D90
dose with a 90% probability of a DLT
DLT
dose-limiting toxicity
MTD
maximum tolerated dose (defined as D30 for this protocol)
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
151
Fixed 3+3 Design
The following steps describe the dose allocation scheme for the simulated fixed 
3+3 designs.
●
Three simulated subjects treated at the initial dose (10 mg).
●
If no DLTs, double the dose.
●
Proceed similarly until the first DLT is observed.
●
If 1/3 DLT, enroll 3 more subjects at the same dose.
●
If 1/6 DLT, increase dose by 33%.
●
If > 1/6 DLTs decrease dose by 25%.
●
If 2/3 or 3/3 DLTs, decrease dose by 25%.
●
Upon dose decrease:
●
If 0/3 or 1/6 DLTs, this is the MTD
●
If > 1 DLT, dose decrease by 25% and repeat.
●
If 0/3 or 1/6 DLTs, this is the MTD.
●
If > 1 DLT, the MTD is the next highest dose with 0/3 or 1/6 DLTs
CRM Design
Three simulated subjects are treated at a dose of 10 mg.  Data from these 3 subjects (for 
each subject, DLT or no DLT) are combined with 13 imputed values.  Ten values are 
imputed at a very high dose (2000 mg):  9 observations with a DLT and 1 observation 
without a DLT.  These 10 values represent a dose with a probability of a DLT of at least 
90%, and they were assigned a weight of 0.025, so that they collectively represent 
one-fourth of one subject.  Three values are imputed at a dose of 160 mg: 1 observation 
with a DLT and two observations without a DLT.  These 3 values represent data borrowed 
from Study M06-814, in which 1/3 subjects who received a dose of 160 mg experienced a 
DLT.  The 3 imputed values are assigned a weight of 0.083, so that they collectively 
represent one-fourth of one subject.  The use of the imputed data is essential to allow the 
model fit to converge.  Without the imputed data, the logistic regression model fit is 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
152
essentially a step function, which generally does not allow the CRM to converge to the 
MTD.
A 2-parameter logistic regression model is fitted to the data as described above, and the 
next dose is chosen to be at the model-estimated MTD (the dose predicted to result in a 
30% probability of DLT, "D30").  If the predicted dose is more than 100 mg above the 
current dose, the new dose is escalated by 100 mg or less.
When the next predicted D30 value is within 5% of the current dose, the model is 
considered to have converged and the MTD is declared.
Simulation Details
Two families of dose-toxicity relationships were considered:  one with a steep slope 
Figure 1) and one with a shallow slope (Figure 2).  Parameters were chosen so that a total 
of 7 dose-toxicity curves for each family were assessed, spanning the expected dynamic 
range of ABT-263 doses.  Thus, the fixed 3+3 design was compared to the CRM-based 
design in 14 different scenarios.  In each scenario, 1000 simulations of each design were 
conducted and the following characteristics were summarized:
●
Estimated MTD (median, IQR)
●
True DLT probabilities associated with the estimated MTD (median, IQR)
●
Sample size (median, interquartile range [IQR])
●
Subjects dosed above D90 (median)
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
153
Figure 1.
Steep Dose-toxicity Relationships
0%
20%
40%
60%
80%
100%
0
100
200
300
400
500
600
700
800
900
1000
Dose (mg)
Probability of DLT
Intercept:
–5
–10
–15
–20
–25
–30
–35
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
154
Figure 2.
Shallow Dose-toxicity Relationships
Results
Results for simulations of the steep dose-toxicity relationships are summarized in Table 1.  
The CRM design consistently resulted in better estimates of the MTD.  The median 
estimated MTD ranged from D12 to D35, whereas the fixed design consistently 
underestimated the true MTD (median estimated MTD values ranged from < D01 to 
D25).  The CRM design also had an advantage in total number of subjects required, 
especially for dose-toxicity relationships with a lower true MTD.  For higher true MTDs, 
the sample size advantage disappeared due to the restriction on the maximum dose 
increase (100 mg, see Methods).  Finally, the CRM design generally dosed a smaller 
number of subjects above the D90.
0%
20%
40%
60%
80%
100%
0
100
200
300
400
500
600
700
800
900
1000
Dose (mg)
Probability of DLT
Intercept:
–2
–3
–4
–5
–6
–7
–8
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
155
Table 1.
Simulation Results for Steep Dose-toxicity Curves (Slope = 0.04)
Intercept
True 
MTD
(mg)
Design
Estimated MTD
(median, IQR)
True DLT 
probabilities 
assoc. with est. 
MTD
(median, IQR)
Sample size
(median, IQR)
No. 
dosed 
above 
D90
(median)
–5
104
Fixed
90 (80, 90)
.20 (.14, .20)
27 (21, 27)
0
CRM
99 (93, 117)
.26 (.22, .42)
15 (12, 21)
0
–10
229
Fixed
181 (181, 213)
.06 (.06, .19)
30 (30, 30)
3
CRM
234 (212, 240)
.35 (.18, .40)
18 (15, 21)
0
–15
354
Fixed
320 (320, 320)
.10 (.10, .10)
30 (30, 30)
6
CRM
364 (332, 359)
.30 (.15, .35)
21 (18, 24)
0
–20
479
Fixed
362 (362, 481)
.00 (.00, .32)
33 (27, 33)
3
CRM
461 (452, 485)
.17 (.13, .35)
24 (24, 24)
0
–25
604
Fixed
481 (481, 481)
.00 (.00, .00)
27 (27, 30)
0
CRM
592 (574, 628)
.21 (.12, .53)
27 (27, 27)
0
–30
729
Fixed
723 (640, 723)
.25 (.01, .25)
33 (33, 33)
6
CRM
726 (699, 726)
.28 (.12, .28)
30 (30, 30)
0
–35
854
Fixed
723 (723, 723)
.02 (.02, .02)
33 (33, 33)
6
CRM
825 (825, 862)
.12 (.12, .37)
33 (33, 36)
0
Both designs performed better for shallow dose-toxicity curves (Table 2) than they did for 
steep curves, but the CRM design retained advantages over the fixed design, both in the 
accuracy of the estimates (median estimated MTDs ranged from D26 to D30, versus D10 
to D23 for the fixed design) and in total sample size (median of 3 to 11 fewer subjects).
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
156
Table 2.
Simulation Results for Shallow Dose-toxicity Curves (Slope = 0.01)
Intercept
True 
MTD
(mg)
Design
Estimated MTD
(median, IQR)
True DLT 
probabilities 
assoc. with est. 
MTD
(median, IQR)
Sample size
(median, IQR)
No. 
dosed 
above 
D90
(median)
–2
115
Fixed
40 (15, 80)
.17 (.14, .23)
21 (15, 30)
0
CRM
116 (88, 149)
.30 (.24, .38)
18 (15, 24)
0
–3
215
Fixed
159 (90, 199)
.20 (.11, .27)
30 (24, 36)
0
CRM
213 (177, 252)
.30 (.23, .38)
18 (15, 24)
0
–4
315
Fixed
241 (213, 320)
.17 (.13, .31)
33 (27, 36)
0
CRM
314 (262, 346)
.30 (.30, .37)
21 (15, 24)
0
–5
415
Fixed
325 (319, 462)
.15 (.14, .20)
33 (30, 33)
0
CRM
404 (354, 448)
.28 (.19, .37)
21 (18, 24)
0
–6
515
Fixed
481 (362, 481)
.23 (.08, .23)
33 (27, 33)
0
CRM
495 (450, 556)
.26 (.18, .39)
24 (21, 27)
0
–7
615
Fixed
481 (481, 640)
.10 (.10, .35)
30 (30, 33)
0
CRM
596 (556, 660)
.26 (.19, .40)
27 (24, 30)
0
–8
715
Fixed
640 (481, 641)
.17 (.04, .17)
36 (33, 36)
3
CRM
699 (662, 762)
.27 (.20, .41)
27 (27, 33)
0
Example Simulations
Figure 3 and Figure 4 show typical simulation runs for a steep dose-toxicity curve 
(slope = 0.04, intercept = –10) for the fixed 3+3 design and the CRM design, respectively.  
The true MTD for this example is 229 mg.
 










ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
161
Appendix G.
Extension Study - Assessments
Table 1.
Extension Study:  Schedule of Assessments
Procedures
Day 1#
Every 
4 Cycles#
Final Visit#
30 Day 
Safety 
Follow-up 
Visit#
Informed Consent
X
Physical Exam (including weight)
Xa
Xa
X
X
Vital Signs
X
X
X
X
12-lead ECG
X
2D Echocardiogram with Doppler
X
Platelet Countb,#
X
X
X
X
Lymphocyte Enumerationc,#
X
Chemistryd,#
X
X
X
X
Hematologyd,#
X
X
X
X
Urinalysisd,#
X
X
Performance Status (ECOG)#
X
X
Tumor Assessmentse,#
X
Disease Progression Assessment
X
X
X
Adverse Event/Concomitant Medications 
Assessment
X
X
X
Xf
Dispense/Collect ABT-263g
X
X
X
Dispense/Collect Subject Dosing Log
X
X
X
#
Visits and activities may be conducted in the subject's home residence or by phone/virtually.
a.
Symptom directed.
b.
Platelet Counts will be performed and assessed by the investigator or subinvestigator prior to study drug 
administration.  Any platelet count less than 25,000/mm3 should be confirmed the same day by manual reading and 
separate peripheral draw.  Additional platelet counts will be obtained if ABT-263 is held or interrupted.  If a 
platelet count is less than or equal to 50,000/mm3, additional platelet counts will be performed every day at the 
discretion of the investigator.  Platelet counts should be obtained 10 to 60 minutes after the completion of any 
platelet transfusion.  
c.
Perform Lymphocyte Enumeration at the Final Visit and as needed for subjects if deemed necessary by the 
investigator.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
162
Table 1.
Extension Study:  Schedule of Assessments (Continued)
d.
The specific laboratory tests required for chemistry, hematology and urinalysis are listed in Table 7.  Triglycerides, 
amylase and lipase will only be collected at the Final Visit.  For any subjects who are at high risk for tumor lysis 
syndrome (TLS), additional samples for hematology and chemistry may be collected as per the management 
guidelines in Section 6.7.4.  ANC ≥ 500/µL and < 1,000/µL should be monitored at an increased frequency at the 
discretion of the investigator.  Grade 2 chemistry labs should be monitored at an increased frequency at the 
discretion of the investigator.
e.
If additional tumor assessments are collected by the site per standard of care, the data should be recorded on the 
appropriate paper CRF.
f.
Adverse events will be followed until satisfactory clinical resolution of the adverse event is achieved.
g.
A bottle's expiration date and pill count should be taken into account when dispensing 4 cycles of drug.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
163
Appendix H.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.0  Title Page
"Sponsor/Emergency Contact:," "Title" previously read:
Group Medical Director
Has been changed to read:
Executive Medical Director
Section 3.0  Introduction
Subsection ABT-263 Clinical Data
Add:  new fourth paragraph
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Subjects receiving ABT-263 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 
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 CLL, no change to the benefit/risk balance for subjects in this study is 
expected.
Section 5.3.1.1  Study Procedures
Add:  new last paragraph
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. Additional details are provided 
in the subsequent section. Every effort should be made to ensure the safety of subjects 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
164
and site staff, while maintaining the integrity of the study. If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow the updates 
below how to proceed.
Section 5.3.1.1  Study Procedures
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, if it is not possible for all study procedures to be 
performed as specified due to travel restrictions or other reasons, the following 
modifications are allowed:
●
If permitted by local regulations, the IRB/IEC and the subject, the subject 
visits may be conducted in the subject's home residence.
●
Some study visits and/or activities may be performed by phone/virtually.  
These are indicated by a hashtag (#) in the activity table (Appendix G)
○
During a virtual visit, activities that do not need to be performed are 
indicated by a (#) in the activity table (Appendix G).
●
Study visits and/or activities may be performed by a local 
clinic/hospital/laboratory. All procedures performed at local facilities must be 
performed by appropriately qualified personnel.
●
Study Visits and/or activities should be performed as scheduled whenever 
possible. If it is not possible to do so due to the pandemic, perform the activity 
at the earliest feasible opportunity. Laboratory draws must be obtained within 
24 hours from the scheduled visit.
Section 5.3.1.1  Study Procedures
Subsection Informed Consent
Add:  new last paragraph
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 
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
165
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
Section 5.3.1.1  Study Procedures
Subsection Vital Signs
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications 
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, weight, and vital signs measurements may be performed 
by the subject or caregiver as needed.
Section 5.3.1.1  Study Procedures
Subsection Platelet Count
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
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. If laboratory samples cannot be obtained, study drug 
administration may be continued provided the investigator has reviewed all prior 
laboratory results and confirms and discusses with the subject that there is no safety 
concern for the subject to continue use of the study drug in the absence of current labs. 
The subject should be scheduled for laboratory draws as soon as feasible within 14 days 
from the scheduled visit.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
166
Section 5.4.1  Discontinuation of Individual Subjects
Add:  new fourth and fifth paragraph
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.
The investigator should contact the sponsor medical contact before discontinuing a subject 
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
Section 5.5.1  Treatments Administered
Add:  new third and fourth paragraph
During the Study Drug Dosing Period, a subject with confirmed (viral test positive) or 
suspected COVID-19 infection can only be dosed with study drug if the following 
COVID-19 viral clearance criteria are met:
●
Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart 
after at least 10 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 10 days have passed since prior positive result (note:  
subjects who develop symptoms will follow guidance above for symptomatic 
subjects)
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects 
must be discussed with the AbbVie medical contact, along with the possibility of 
premature discontinuation from the study drug dosing period.  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.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
167
Section 5.5.4  Selection and Timing of Dose for Each Subject
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
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 (or subject's caregiver) at home
●
Subject agrees to have the study drug shipped directly to their home
●
Shipments may also include other study supplies (e.g., drug dosing diaries).  
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.  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.
●
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.
Section 6.5  Adverse Event Reporting
"AbbVie Medical Monitor," "Title" previously read:
Group Medical Director
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
168
Has been changed to read:
Executive Medical Director
Section 6.5  Adverse Event Reporting
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
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:
●
COVID-19 Supplemental Signs/symptoms
●
COVID-19 Status Form
Section 7.0  Protocol Deviations
First paragraph previously read:
Protocol deviations should be avoided.  When a deviation from the protocol is deemed 
necessary for an individual subject, the investigator or other physician in attendance must 
contact one of the following AbbVie representatives prior to implementation:
Has been changed to read:
AbbVie does not allow intentional/prospective deviations from the protocol except when 
necessary to eliminate an immediate hazard to study subjects.  The 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), the investigator 
 






ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
171
of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed.
In all cases, these alternative measures must be allowed by local regulations and permitted 
by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures are taken 
to protect the subjects against any immediate hazard.
Section 10.1  Source Documents
Add:  new last paragraph
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.
Appendix A.  List of Abbreviations and Definitions of Terms
Subsection Abbreviations
Add:
COVID-19
Coronavirus Disease-2019
DTP
Direct To Patient
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Sr. Scientist II
Biomarkers
 
Program Lead II
Clinical
 
Study Project Manager II
Clinical
 
Director, Biometrics
Statistics
 
Group Medical Director 
Clinical
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
172
Has been changed to read:
Name
Title
Functional Area
Sr. Scientist II
Biomarkers
 
Program Lead II
Clinical Program Development
 
Study Project Manager II
Clinical Program Development
  
Director
Statistics
 
Executive Medical Director, TA MD 
Clinical Program Development
Appendix G.  Extension Study - Assessments
Table 1.  Extension Study:  Schedule of Assessments
Previously read:
Procedures
Day 1
Every 
4 Cycles
Final Visit
30 Day 
Safety 
Follow-up 
Visit
Informed Consent
X
Physical Exam (including weight)
Xa
Xa
X
X
Vital Signs
X
X
X
X
12-lead ECG
X
2D Echocardiogram with Doppler
X
Platelet Countb
X
X
X
X
Lymphocyte Enumerationc
X
Chemistryd
X
X
X
X
Hematologyd
X
X
X
X
Urinalysisd
X
X
Performance Status (ECOG)
X
X
Tumor Assessmentse
X
Disease Progression Assessment
X
X
X
Adverse Event/Concomitant Medications 
Assessment
X
X
X
Xf
Dispense/Collect ABT-263g
X
X
X
Dispense/Collect Subject Dosing Log
X
X
X
a.
Symptom directed.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
173
b.
Platelet Counts will be performed and assessed by the investigator or subinvestigator prior to study drug 
administration.  Any platelet count less than 25,000/mm3 should be confirmed the same day by manual reading and 
separate peripheral draw.  Additional platelet counts will be obtained if ABT-263 is held or interrupted.  If a 
platelet count is less than or equal to 50,000/mm3, additional platelet counts will be performed every day at the 
discretion of the investigator.  Platelet counts should be obtained 10 to 60 minutes after the completion of any 
platelet transfusion.  
c.
Perform Lymphocyte Enumeration at the Final Visit and as needed for subjects if deemed necessary by the 
investigator.
d.
The specific laboratory tests required for chemistry, hematology and urinalysis are listed in Table 7.  Triglycerides, 
amylase and lipase will only be collected at the Final Visit.  For any subjects who are at high risk for tumor lysis 
syndrome (TLS), additional samples for hematology and chemistry may be collected as per the management 
guidelines in Section 6.7.4.  ANC ≥ 500/µL and < 1,000/µL should be monitored at an increased frequency at the 
discretion of the investigator.  Grade 2 chemistry labs should be monitored at an increased frequency at the 
discretion of the investigator.
e.
If additional tumor assessments are collected by the site per standard of care, the data should be recorded on the 
appropriate paper CRF.
f.
Adverse events will be followed until satisfactory clinical resolution of the adverse event is achieved.
g.
A bottle's expiration date and pill count should be taken into account when dispensing 4 cycles of drug.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
174
Has been changed to read:
Procedures
Day 1#
Every 
4 Cycles#
Final Visit#
30 Day 
Safety 
Follow-up 
Visit#
Informed Consent
X
Physical Exam (including weight)
Xa
Xa
X
X
Vital Signs
X
X
X
X
12-lead ECG
X
2D Echocardiogram with Doppler
X
Platelet Countb,#
X
X
X
X
Lymphocyte Enumerationc,#
X
Chemistryd,#
X
X
X
X
Hematologyd,#
X
X
X
X
Urinalysisd,#
X
X
Performance Status (ECOG)#
X
X
Tumor Assessmentse,#
X
Disease Progression Assessment
X
X
X
Adverse Event/Concomitant Medications 
Assessment
X
X
X
Xf
Dispense/Collect ABT-263g
X
X
X
Dispense/Collect Subject Dosing Log
X
X
X
#
Visits and activities may be conducted in the subject's home residence or by phone/virtually.
a.
Symptom directed.
b.
Platelet Counts will be performed and assessed by the investigator or subinvestigator prior to study drug 
administration.  Any platelet count less than 25,000/mm3 should be confirmed the same day by manual reading and 
separate peripheral draw.  Additional platelet counts will be obtained if ABT-263 is held or interrupted.  If a 
platelet count is less than or equal to 50,000/mm3, additional platelet counts will be performed every day at the 
discretion of the investigator.  Platelet counts should be obtained 10 to 60 minutes after the completion of any 
platelet transfusion.  
c.
Perform Lymphocyte Enumeration at the Final Visit and as needed for subjects if deemed necessary by the 
investigator.
d.
The specific laboratory tests required for chemistry, hematology and urinalysis are listed in Table 7.  Triglycerides, 
amylase and lipase will only be collected at the Final Visit.  For any subjects who are at high risk for tumor lysis 
syndrome (TLS), additional samples for hematology and chemistry may be collected as per the management 
guidelines in Section 6.7.4.  ANC ≥ 500/µL and < 1,000/µL should be monitored at an increased frequency at the 
discretion of the investigator.  Grade 2 chemistry labs should be monitored at an increased frequency at the 
discretion of the investigator.
 


ABT-263
M06-873 Protocol Amendment 14
EudraCT 2007-002143-25
175
e.
If additional tumor assessments are collected by the site per standard of care, the data should be recorded on the 
appropriate paper CRF.
f.
Adverse events will be followed until satisfactory clinical resolution of the adverse event is achieved.
g.
A bottle's expiration date and pill count should be taken into account when dispensing 4 cycles of drug.
 

SAP_001.pdf: 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
2 
Medical History 
Following analysis was provided for each portion of the study.  Medical history data was 
summarized and presented using primary MedDRA system organ classes (SOCs) and 
preferred terms (PTs).  The number and percentage of subjects experiencing events were 
summarized by dose and overall. 
Previous Treatment and Concomitant Medications 
A prior medication was defined as any medication taken prior to the first dose of 
navitoclax.  A concomitant medication was defined as any medication that started prior to 
the first dose of navitoclax and continued to be taken after the first dose of navitoclax or 
any medication that started after the first dose of Navitoclax, but not after the last dose of 
navitoclax.  Following analysis was provided for each portion of the study.  The number 
and percentage of subjects who have taken medications were summarized per subjects and 
by generic drug name for prior medications, concomitant medication.  The number and 
percentage of subjects who have taken 1, 2, 3, 4, 5, 6 and above prior medications and 
concomitant medications were also summarized.   
For summaries of concomitant medications, if an incomplete start date was collected for a 
medication, the medication was assumed to be a concomitant medication unless there was 
evidence that confirms that the medication was not a concomitant medication (e.g., the 
medication end date was prior to the first dose of navitoclax). 
A subject who reports the use of two or more medications was counted only once in the 
summary of "Any Concomitant Medication."  A subject who reports two or more uses of 
the same medication was counted only once in the total for the associated generic drug 
name.  Similar rules apply to prior medications as well. 
Drug Exposure and Compliance 
Following analysis was provided for each portion of the study.  The duration of exposure 
to navitoclax were summarized.  Duration of exposure is defined for each subject as (last 
dose date – first dose date) + 1.  Duration of exposure was summarized using the 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
3 
following statistics:  sample size (N), mean, standard deviation, median, minimum, and 
maximum.  Similar analyses were provided for time on study data.  Time on study is 
defined for each subject as (last visit date – first dose date) + 1.  In addition, the number 
and percentage of subjects exposed to navitoclax were summarized for the following 
categories of exposure duration:  1, 2, 3, 4, 5, and 6 or more cycles. 
The compliance based on investigator opinion for each subject was provided in the data 
listing. 
Pharmacokinetic Analyses 
Tabulations and Summary Statistics 
Plasma concentrations of navitoclax and pharmacokinetic parameter values were tabulated 
for each subject and each dose level, and summary statistics were computed for each 
sampling time and each parameter. 
Model and Tests 
For subjects who participated in the Phase 1, 14/21 day dosing portion of the study, an 
analysis was performed on pharmacokinetic variables for Cycle 1 Day 1 dose to 
simultaneously explore for demographic variables that explained some of the variability in 
pharmacokinetics and to address questions of dose proportionality and linear kinetics.  An 
analysis was performed for dose-normalized Cmax, Tmax, and dose-normalized AUCt 
(AUC0-24).  The model used for the statistical analyses included dose level.  This was done 
by classifying subjects by dose level.  Covariates such as age, body weight, BSA, gender, 
and formulation, as well as others that might have explained some of the variability in the 
population, were considered for inclusion in the model initially.  However, a covariate 
was dropped from the model if the regression coefficient was not significant at level 0.10.  
The natural logarithmic transformation was employed for Cmax and AUCt.  Within the 
framework of the model, tests that had good power for a trend with dose were performed 
on the effect of dose level. 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
4 
A corresponding analysis was also performed on pharmacokinetic variables of the dose on 
Cycle 1 Day 14 for both the Phase 1, 14/21 and 21/21 day dosing schedules.  The 
variables included dose-normalized Cmax, Tmax, and dose normalized AUCt (AUC0-8). 
Exploratory Efficacy 
The following exploratory efficacy analyses were performed for Phase 1 and Phase 2 of 
the study.  Unless specified otherwise all the analyses were presented by dose levels and 
overall; all the response and associated data were evaluated based on NCI WG Criteria 
(1996), and updated IWCLL NCI WG Criteria (2008) for Phase 1, and 2, respectively.  
Progression-Free Survival 
The distribution of PFS was estimated using Kaplan-Meier methodology.  Median time to 
PFS and the corresponding 95% confidence interval were estimated. 
For a given subject, PFS was defined as the number of days from the date the subject 
started study drug to the date the subject experiences an event of disease progression, or to 
the date of death if disease progression was not reached.  All events of disease progression 
were included, regardless of whether the event occurred while the subject was still taking 
study drug or had previously discontinued study drug.  Events of death were included for 
subjects who had not experienced disease progression provided the death occurred within 
2 cycles (42 days) of the date of the last available tumor evaluation.  If a subject had not 
experienced an event of disease progression or death as defined above, then the subject's 
data was censored at the date of the last available evaluation for disease progression.  The 
date of the last available evaluation was the date of the last study visit at which a tumor 
assessment was performed. 
Response Rate 
● Objective Response Rate (ORR) 
○ Phase 1: ORR = CR + PR. 
○ Phase 2: ORR = CR + CRi + PR. 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
5 
● Best Response Rate 
○ Phase 1: Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), Disease Progression (PD), and Incomplete Data (ID) were reported. 
○ Phase 2: Complete Response (CR), Complete Response - incomplete bone 
marrow (CRi), Partial Response (PR), Stable Disease (SD), Disease 
Progression (PD), and Incomplete Data (ID) were reported. 
● Disease Control Rate (DCR) 
○ Phase 1: DCR = CR + PR + SD. 
○ Phase 2: DCR = CR + CRi + PR + SD. 
 
The exact binomial distribution was used to construct this confidence interval for the 
response rates, and the corresponding 95% confidence interval was constructed. 
Time to Tumor Progression 
Time to tumor progression for a given subject was defined as the number of days from the 
date the subject started study drug to the date of the subject's tumor progression.  Time to 
tumor progression was collected up to 2 cycles (42 days) following the date of the last 
available tumor evaluation.  All events of tumor progression were 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 had not progressed, then the data was 
censored at the date of the last study visit at which a tumor assessment was performed. 
The distribution of the time to tumor progression was estimated using Kaplan-Meier 
methodology.  Median time to tumor progression and the corresponding 95% confidence 
interval were estimated. 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
6 
Overall Survival 
Time to death for a given subject was defined as the number of days from the date the 
subject started study drug to the date of the subject's death.  All events of death were 
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 had not died, then the data 
was censored at the date of the last study visit, the last contact date, or the date the subject 
was last known to be alive, whichever was last.  The date of the last study visit was 
determined by selecting the last available date of the following study procedures for a 
subject:  physical examination, vital signs assessment, blood chemistry, hematology, and 
urinalysis collection. 
The distribution of the time to death was estimated using Kaplan-Meier methodology.  
Median survival time and the corresponding 95% confidence interval were estimated. 
Duration of Overall Response 
The duration of overall response for a given subject was defined as the number of days 
from the day the criteria were met for CR, CRi or PR (whichever was recorded first) to 
the date that PD was objectively documented.  The reference for PD was the smallest 
measurement recorded since the treatment started.  If a subject was still responding, then 
the subject's data was censored at the last study visit at which a tumor assessment was 
performed. 
The distribution of the duration of overall response was estimated using Kaplan-Meier 
methodology.  Median duration of overall response and the corresponding 95% 
confidence interval were estimated. 
ECOG Performance Status 
For the ECOG performance scale, descriptive statistics were summarized for each 
assessment.  In addition, a mean change from baseline to each assessment was 
summarized. 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
7 
Safety Analyses 
Safety summaries included all subjects participating in the study unless otherwise 
indicated.  Following analysis was provided for each portion of the study. 
Adverse Events 
Analysis of Treatment-Emergent Adverse Events 
All analyses involving AEs were treatment-emergent adverse events (TEAE) only, unless 
otherwise specified.  TEAE were defined as any event with onset after the first dose of 
navitoclax and no more than 30 days after the last dose of navitoclax.  Events where the 
onset date was the same as the navitoclax start date were assumed to be treatment-
emergent, unless the navitoclax start time and the AE start time were collected and the AE 
start time was prior to the navitoclax start time.  If an incomplete onset date was collected 
for an AE, the AE was assumed to be treatment-emergent unless there was evidence that 
confirms that the AE was not treatment-emergent (e.g., the AE end date was prior to the 
date of the first dose of navitoclax). 
Adverse event data was summarized and presented using primary MedDRA system organ 
classes (SOCs) and preferred terms (PTs) according to the MedDRA 22.0 coding 
dictionary. 
The number and percentage of subjects experiencing treatment-emergent adverse events 
was summarized by phase 1 or 2, day cycle (14/21 or 21/21), navitoclax dose and for the 
whole portion of the study for the following adverse event summaries: 
● Overview of treatment emergent adverse events 
● Any treatment-emergent adverse event by System Organ Class and Preferred 
Term. 
● Subject number associated with treatment-emergent adverse event. 
● Treatment-emergent adverse events by System Organ Class, Preferred Term, 
and maximum NCI toxicity grade (CTCAE V3.0). 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
8 
● Treatment-emergent adverse events broken down by maximum relationship to 
study drug. 
● Any treatment-emergent NCI toxicity (CTCAE V3.0) grade 3 or 4 adverse 
events. 
● Any treatment-emergent NCI toxicity (CTCAE V3.0) grade >=3 adverse 
events. 
● Treatment-emergent adverse events broken down by possibly or probably 
drug-related NCI toxicity grade >=3 adverse events  
● Treatment-emergent adverse events broken down by possibly or probably 
drug-related NCI toxicity grade 3 or 4 adverse events 
● Any treatment-emergent adverse event with possibly or probably drug-related. 
● For treatment-emergent serious adverse events, analyses similar to TEAE were 
provided.  
● Any treatment-emergent adverse event leading to discontinuation of each drug. 
● Any treatment-emergent adverse event leading to each drug interruption. 
● Any treatment-emergent adverse event leading to each drug reduction. 
● Any treatment-emergent adverse event leading to each drug delay. 
● Any treatment-emergent adverse event leading to death. 
● Subject deaths occurring <= 30 days after last dose of study drug. 
● Subject deaths occurring > 30 days after last dose of study drug. 
● Any treatment-emergent DLT adverse events by primary MedDRA system 
organ   class and preferred term. 
 
Selected Adverse Events 
Analysis of adverse events of safety areas of interest were conducted through the 
summary of MedDRA preferred terms identified using standard MedDRA queries 
(SMQs) and custom searches.  Like TEAEs analyses, overview of selected AEs, and 
selected AEs by primary MedDRA system organ class and preferred term were provided.  
The search criteria for each of the safety areas of interest were described below. 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
9 
Identified Risks 
Thrombocytopenia - PTs: 10043554 Thrombocytopenia; 10035528 Platelet count 
decreased 
Neutropenia - PTs: 10001507 Agranulocytosis; 10016288 Febrile neutropenia; 10029354 
Neutropenia; 10059482 Neutropenic infection; 10049151 Neutropenic sepsis; 10029366 
Neutrophil count decreased 
Lymphopenia - PTs: 10025327 Lymphopenia; 10025256 Lymphocyte count decreased 
Potential Risks 
Hemorrhagic Events -  SMQ 20000038 Hemorrhages (Narrow) 
Opportunistic Infections - SMQ 20000235 Opportunistic Infections (Broad) 
Tumor Lysis Syndrome - SMQ 20000219 Tumor Lysis Syndrome (Narrow) 
Hepatotoxicity - SMQ 20000006 Drug Related Hepatic Disorders – Comprehensive 
(Broad); SMQ 20000007 Drug Related Hepatic Disorders – Severe Events Only (Narrow) 
Increased Pancreatic Enzymes - SMQ 20000022 Acute Pancreatitis (Narrow) 
Cardiovascular Events - SMQs: 20000004 Cardiac Failure (Narrow); 20000130 
Pulmonary Hypertension (Narrow) 
Venous Thromboembolic Events - SMQ 20000084 Embolic and Thrombotic Events, 
Venous (Narrow) 
Cerebellar Hypoplasia - PT 10008033 Cerebellar Hypoplasia 
Decreased Spermatogenesis - SMQ 20000210 Fertility Disorders (Narrow; males only) 
Skin Cancer or Second Malignancies - SMQs: 20000173 Skin Neoplasms, Malignant and 
Unspecified (Broad); 20000090 Malignancies (Broad) 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
10 
Allergic Reactions - SMQ 20000021 Anaphylactic Reaction (Broad) 
Drug Interactions - HLT 10022528 Interactions 
Analysis of Laboratory and Vital Signs Data 
The value for baseline used in laboratory and vital sign analyses is defined in the 
Definition of Baseline section.  All laboratory and vital signs were summarized by dose 
and the study portion as a whole. 
Analysis of Mean Changes from Baseline in Clinical Laboratory Data 
Changes from baseline were analyzed for each scheduled post-baseline visit and for the 
final visit for lymphocyte enumeration, urinalysis, blood chemistry and hematology 
parameters, as well as vital sign parameters. 
Laboratory tests to be summarized are included in Table 1. 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
11 
Table 1. 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red Blood Cell (RBC) count 
White Blood Cell (WBC) 
count 
Neutrophils 
Bands 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
Platelet count 
Reticulocyte count 
Prothrombin time (PT) 
Activated partial 
thromboplastin time (aPTT) 
Mean corpuscular volume 
(MCV) 
MPV 
MCH 
MCHC 
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 phosphate 
Uric acid 
Cholesterol  
Total protein 
Glucose 
Triglycerides  
Albumin 
Lactate dehydrogenase (LDH) 
Magnesium 
Chloride 
Bicarbonate 
Lipase 
Urine PH 
Urine specific gravity 
Lymphocyte Enumeration 
B-Lymphocytes total 
Natural killer cells total 
T-Helper cells total 
T-Lymphocytes total 
T-Suppressor cells total 
 
Mean changes from baseline at each scheduled post-baseline visit and Final Visit was 
summarized with the baseline mean, visit mean, change from baseline mean, standard 
deviation, and minimum/maximum values. 
Analyses of Shift from Baseline in Clinical Laboratory Data 
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse 
Events (NCI CTCAE), baseline and post-baseline laboratory observations were 
categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 according to NCI CTCAE 
grade version 3.0. 
The baseline and final grades were defined respectively as the grade of the last 
measurement collected prior to the first dose of navitoclax, and as the last post-baseline 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
12 
measurement collected no more than 30 days after the last dose of navitoclax.  The 
maximum NCI toxicity grade value was the value with highest NCI toxicity grade 
collected after the first dose of navitoclax and within 30 days following the last dose of 
navitoclax.  In cases where multiple values are collected on the same day, the maximum 
grade value was selected as the value for that day. 
For each variable, shift tables were generated that cross tabulate the number of subjects 
with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 versus final 
observations of grade 0, grade 1, grade 2, grade 3, or grade 4. 
Additionally, for each variable, the number and percentage of subjects that have a baseline 
observation that was categorized as a grade 0, grade 1, or grade 2 and that also have a 
grade 3 or 4 final observation was presented.  In addition to final observation, a similar set 
of summaries were produced for the maximum post-baseline laboratory observations. 
For urinalysis, cross tabulated the number of subjects with baseline and maximum 
dipstick results.  Similar cross tabulations were provided for baseline and final dipstick 
results. 
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values were provided.  Listings were also provided for 
urinalysis values with dipstick results of 2+ or higher.  All measurements collected, 
regardless of the number of days after the last dose of navitoclax, were included in these 
listings. 
The NCI CTCAE grade 3 criteria are given in Table 2 and Table 3 below. 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
13 
Table 2. 
Criteria for Potentially Clinically Significant Laboratory Values – 
Chemistry Variables 
Chemistry Variables 
Units 
Definition of Potentially Clinically Significant 
Current (Version 3) Grade 3 
Low 
High 
Total bilirubin 
mcmol/L 
 
> 3.0 × ULN 
Albumin 
g/L 
< 20 
 
Aspartate amino transaminase 
(AST/SGOT) 
U/L 
 
> 5.0 × ULN 
Alanine amino transferase 
(ALT/SGPT) 
U/L 
 
> 5.0 × ULN 
Alkaline phosphatase 
U/L 
 
> 5.0 × ULN 
Creatinine 
mcmol/L 
 
> 3.0 × ULN 
Sodium 
mmol/L 
< 130 
> 155 
Potassium 
mmol/L 
< 3.0 
> 6.0 
Total calcium 
mmol/L 
< 1.75 
> 3.1 
Glucose 
mmol/L 
< 2.2 
> 13.9 
Inorganic Phosphate 
mmol/L 
< 0.6 
 
Bicarbonate 
mmol/L 
< 11 
 
Cholesterol 
mmol/L 
 
> 10.34 
Triglycerides 
mmol/L 
 
> 5.0 × ULN 
Magnesium 
mmol/L 
< 0.4 
> 1.23 
 
Table 3. 
Criteria for Potentially Clinically Significant Laboratory Values – 
Hematology Variables 
Hematology Variables 
Units 
Definition of Potentially Clinically Significant 
Current (Version 3) Grade 3 
Hemoglobin 
g/L 
< 80 
White blood cell count 
109/L 
< 2 
Neutrophils 
109/L 
< 1 
Lymphocytes 
109/L 
< 0.5 
Platelets 
109/L 
< 50 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
14 
Assessment of Mean Changes from Baseline in Vital Signs Variables 
Analyses of mean change from baseline in continuous vital signs variables which are 
measured longitudinally were performed (systolic blood pressure, diastolic blood 
pressure, heart rate, weight, and temperature).  For each change from baseline analysis, 
the following summary statistics were presented:  sample size, baseline mean, visit mean, 
and the mean, standard deviation, and minimum/maximum of the changes from baseline.  
The baseline and visit means were calculated for each visit for subjects who have both a 
baseline and visit value. 
Assessment of Potentially Clinically Significant Vital Signs Values 
For selected vital signs variables, a listing of all observations collected was 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 was provided for each variable. 
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 4 below based on CTCAE criteria: 
Table 4. 
Criteria for Potentially Clinically Significant Laboratory Values – 
Vital Signs Variables 
Vital Signs Variables 
Criterion 
Definition of Potentially Clinically Significant 
Systolic blood pressure 
High 
Value > 150 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 
 


 
Navitoclax 
M06-873 Clinical Study Report – Second Interim 
R&D/20/1074 
 
 
15 
Analysis Conventions 
Definition of Baseline 
The baseline value was defined as the last non-missing measurement collected before the 
first dose of navitoclax. 
Definition of Final Observation 
The final observation (Final Visit) was defined as the last non-missing observation 
collected within 30 days following the last dose of navitoclax. 
Definition of Rx Days (Days Relative to the First Dose of navitoclax) 
Rx Days were calculated for each time point relative to the first dose date of navitoclax.  
They were defined as the number of days between the day of the first dose of navitoclax 
and the specific time point.  Rx days were negative values when the time point of interest 
was prior to the first navitoclax dose day.  Rx days were positive values when the time 
point of interest was after the first navitoclax dose day.  The day of the first dose of 
navitoclax was defined as Rx Day 1, while the day prior to the first navitoclax dose was 
defined as Rx Day –1 (there is no Rx Day 0).