Clinical trial NCT03873493
Conditions: Leukemia T-cell Prolymphocytic Leukemia (T-PLL) Cancer
Keywords: T-cell Prolymphocytic Leukemia (T-PLL) Cancer Venetoclax Venclexta Venclyxto Ibrutinib Imbruvica Relapsed or Refractory T-lymphoid malignancy
Sponsor: AbbVie
Start date: 2020-01-14; Completion date: 2021-11-04
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective of this study is to evaluate the efficacy of the combination of venetoclax plus ibrutinib for treating adults with T-cell prolymphocytic leukemia (T-PLL).

Detailed description:
This study is planned as an adaptive 2-stage design as follows:

Stage 1: Enroll 14 participants with relapsed or refractory (R/R) T-PLL and move to Stage 2 if 4 or more participants meet protocol-specified response criteria. Response assessment will be performed on a continued basis until all 14 participants have enrolled into Stage 1 and have completed the Week 24 disease assessment.

Stage 2: Enroll up to an additional 23 participants.

The study was stopped after Stage 1. Stage 2 was not conducted.

Arms: arm 1: Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission.
Interventions: intervention 1: Venetoclax intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Venetoclax tablets taken orally once a day (QD). Initially, venetoclax was administered utilizing a 5-step dose ramp-up over 5 days. Subjects were hospitalized and closely monitored for 7 days. The venetoclax ramp-up was administered in a daily manner: 20 mg on Week 1 Day 1, 50 mg on Week 1 Day 2, 100 mg on Week 1 Day 3, 200 mg on Week 1 Day 4, and 400 mg on Week 1 Day 5 and thereafter, once daily, until the end-of-treatment. The dose of venetoclax may have been increased to 600 mg QD at Week 8 or thereafter. intervention 2: Ibrutinib capsules taken orally once a day, 420 mg/day until the end-of-treatment.

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
9
3
STUDY OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES
10
3.2
PRIMARY ENDPOINT
10
3.3
SECONDARY ENDPOINTS
10
3.4
SAFETY ENDPOINTS
11
3.5
PHARMACOKINETIC ENDPOINTS
11
3.6
BIOMARKER AND EXPLORATORY RESEARCH ENDPOINTS
11
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION RECOMMENDATIONS
18
5.3
PROHIBITED MEDICATIONS AND THERAPY
20
5.4
PRIOR AND CONCOMITANT THERAPY
20
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
21
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
23
5.7
STUDY DRUG
23
5.8
RANDOMIZATION/DRUG ASSIGNMENT
24
5.9
PROTOCOL DEVIATIONS
24
6
SAFETY CONSIDERATIONS
24
6.1
COMPLAINTS AND ADVERSE EVENTS
24
6.2
TOXICITY MANAGEMENT
28
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
34
7.1
STATISTICAL AND ANALYTICAL PLANS
34
7.2
DETERMINATION OF SAMPLE SIZE
34
7.3
DEFINITION FOR ANALYSIS POPULATIONS
35
7.4
STATISTICAL ANALYSES FOR EFFICACY
35
7.5
STATISTICAL ANALYSES FOR SAFETY
36
7.6
INTERIM ANALYSIS
36
8
ETHICS
36
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
36
8.2
ETHICAL CONDUCT OF THE STUDY
36
8.3
SUBJECT CONFIDENTIALITY
37
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
37
10 DATA QUALITY ASSURANCE
37
11 COMPLETION OF THE STUDY
37
12 REFERENCES
38
LIST OF TABLES
TABLE 1.
DOSE MODIFICATIONS FOR VENETOCLAX AND IBRUTINIB:  MODERATE AND STRONG CYP3A 
INHIBITOR USE
21
TABLE 2.
STUDY DRUG INFORMATION
24
TABLE 3.
TUMOR BURDEN CATEGORIES
29
TABLE 4.
DOSE MODIFICATION FOR TOXICITY DURING VENETOCLAX TREATMENT
33
TABLE 5.
IBRUTINIB DOSE REDUCTION LEVELS
34
TABLE 6.
SAMPLE SIZE USING OPTIMAL ADAPTIVE 2-STAGE DESIGN
35
LIST OF FIGURES
FIGURE 1.
DOSING SCHEMATIC
13
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LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
39
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
41
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
42
APPENDIX D.
DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS SYNDROME
43
APPENDIX E.
RECOMMENDATIONS FOR INITIAL MANAGEMENT OF ELECTROLYTE ABNORMALITIES AND 
PREVENTION OF TUMOR LYSIS SYNDROME
44
APPENDIX F.
RECOMMENDED DOSE REDUCTIONS RELATED TO DRUG TOXICITIES
47
APPENDIX G.
ACTIVITY SCHEDULE
49
APPENDIX H.
PROTOCOL AMENDMENT SUMMARY OF CHANGES
53
APPENDIX I.
OPERATIONS MANUAL
61
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy characterized by 
proliferation of post-thymic prolymphocytes, usually refractory to current treatment strategies or 
complicated by relapse and associated with short overall survival.  Patients with T-PLL typically 
experience elevated and exponentially rising lymphocyte counts along with splenomegaly, 
hepatomegaly, lymphadenopathy, and effusions.  Responses to alkylating agents, purine analogs, and 
polychemotherapy are poor, ranging from 20% to 53% in mostly previously untreated patients with 
short survival durations.  There is very scarce clinical data for the overall response rate (ORR) in the 
relapsed or refractory (R/R) patient population and the ORR is not expected to be greater than 20%.  
Therefore, in pretreated patients, responses to non-alemtuzumab therapy are estimated to achieve an 
ORR of 20%.1,2,3
The use of the monoclonal anti-CD52 antibody alemtuzumab has improved response rates of 50% to 
75% or even higher (up to 90%) when applied in the first-line setting.4,5  Based on data available, benefit 
(if any) from a combination of alemtuzumab with purine analogs or polychemotherapy compared to 
alemtuzumab alone is unclear.  Thus far, alemtuzumab remains the most effective treatment option in 
patients with T-PLL; however, despite relatively high response rates (50% to 90%), all patients eventually 
relapse with a median progression-free survival (PFS) of less than 12 months.  Allogeneic stem cell 
transplantation is considered a treatment goal for eligible patients since long survival durations have 
been observed.
In 2 recent ex vivo drug screening studies, consistent activities of B-cell lymphoma (BCL)-2 inhibition in 
T-PLL were observed.6,7  Venetoclax is a potent, selective, and orally bioavailable small molecule 
inhibitor of BCL-2 that binds with > 1,000-fold higher affinity for BCL-2 (inhibition rate constant 
[Ki] < 0.010 nM) than for B-cell lymphoma – extra large (BCL-XL; Ki = 48 nm) or myeloid cell leukemia 
(MCL)-1 (Ki > 444 nM).  Venetoclax (also referred to as ABT-199, A-1195425.0, GDC-0199, RO5537382, 
Venclexta®, and Venclyxto®) is currently being evaluated for the treatment of patients with chronic 
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), acute myeloid leukemia (AML), multiple 
myeloma, and non-Hodgkin's lymphoma (NHL).
Venetoclax is currently approved in the United States (US) for the treatment of patients with CLL or SLL 
with or without 17p deletion and who have received at least 1 prior therapy.  In addition, venetoclax 
was granted a conditional marketing authorization from the European commission for the following 
indication:  Venclyxto monotherapy is indicated for the treatment of CLL in the presence of 17p deletion 
or tumor protein p53 (TP53) mutation in adult patients who are unsuitable for or have failed a B-cell 
receptor inhibitor (BCRi) or in the absence of 17p deletion or TP53 mutation in adult patients who have 
failed both chemoimmunotherapy and a BCRi.  As of July 2018, marketing authorizations have been 
granted in the US, European Union, Canada, and more than 20 additional countries worldwide.
As proof of principle, the first-in-human treatment using venetoclax in 2 late-stage subjects with T-PLL 
was reported.7  Responses were positive; however, potential mechanisms of resistance may develop 
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through BCL-2 and BCL-XL induction.  Therefore, studies testing venetoclax with appropriate 
combination partners in subjects with T-PLL are warranted.  Ex vivo drug combination studies in primary 
T-PLL subject samples demonstrated that T-PLL cell-specific synergism of venetoclax was highest with 
ibrutinib.8  Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton's tyrosine kinase (BTK) which was co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC for the treatment of patients with B-cell malignancies.  Ibrutinib has been 
approved in many regions globally including the US and European Union for adult patients in one or 
more of the following indications:  CLL/SLL including CLL/SLL with a 17p deletion; mantle cell lymphoma 
in patients who have received at least 1 prior therapy; Waldenström's macroglobulinemia; marginal 
zone lymphoma who require systemic therapy and who have received at least 1 prior anti-CD20-based 
therapy; and chronic graft versus host disease following the failure of 1 or more lines of systemic 
therapy.  For further details, please refer to the IMBRUVICA® (ibrutinib) Investigator's Brochure.9
Preliminary clinical response from 1 subject treated with venetoclax in combination with ibrutinib was 
recently reported at the 23rd Congress of the European Hematology Association;8 clinical response was 
demonstrated by significant clinical improvement, significant decrease in spleen size, and improvement 
in disease-related laboratory values such as leukocytosis, lactate dehydrogenase, and β2 microglobulin 
(B2M).
Clinical Hypothesis
The combination of venetoclax with ibrutinib can be safely administered and will result in a greater 
percentage of subjects who achieve a best ORR (complete remission [CR]/CR with incomplete bone 
marrow recovery [CRi] + partial response [PR]).
In subjects with R/R T-PLL, the treatment with venetoclax plus ibrutinib will be considered promising if 
the combination yields a best ORR of 40% or greater.  A poor rate is defined a best ORR of 20% or less 
based on the previously available data.
2.2 Benefits and Risks to Subjects
Effective treatment options remain dismal for patients with R/R T-PLL as well as for treatment-naïve 
patients who have no access or are ineligible to treatment with alemtuzumab.  While clinical trials are 
the recommended treatment option for both treatment-naïve and R/R patients by treatment guidelines 
(e.g., National Comprehensive Cancer Network [NCCN] guidelines), as of August 2018 there are currently 
no ongoing interventional clinical studies specific to this rare disease.
The recently reported ex vivo data and very limited subject data provide rationale for a clinical study 
with the combination of venetoclax and ibrutinib.  Clinical data from this same combination target dose 
regimen has also recently been presented for a different indication (i.e., CLL [CAPTIVATE study]).  Early 
data from 163 subjects show a spectrum of adverse events (AEs) consistent with the historic safety 
profile of single-agent ibrutinib and single-agent venetoclax with no new safety signals and promising 
activity (77% undetectable minimal residual disease [MRD] in peripheral blood after 6 months of 
therapy).8
For further details, please see findings from completed studies including safety data in the venetoclax 
Investigator's Brochure10 and the ibrutinib Investigator's Brochure.9
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Considering the coronavirus disease – 2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Based on the limited information to date, no 
additional risk to study participants is anticipated with the use of venetoclax plus ibrutinib.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary

To demonstrate the efficacy in subjects with R/R T-PLL treated with venetoclax plus ibrutinib.
Secondary

To assess safety and tolerability in subjects with T-PLL treated with venetoclax plus ibrutinib.

To assess the ability of the subset of transplant-naïve subjects to proceed to further 
autologous/allogeneic stem cell transplantation (assessed by number of eligible subjects 
reaching transplant).

To evaluate the PFS, duration of response, time-to-progression, event-free survival, disease 
control rate, and overall survival.
Exploratory

To identify biomarker/genetically-defined subgroups regarding response and survival.
3.2 Primary Endpoint
The primary endpoint is the ORR which is defined as the proportion of subjects achieving CR, CRi, or PR 
as their best overall response (per investigator assessment) in R/R T-PLL subjects based on the T-PLL 
consensus criteria 2019 (refer to the Operations Manual Section 3.14).1,11
3.3 Secondary Endpoints
Key secondary endpoints are as follows:

PFS, defined as the time from the date of first dose of any study drug to the date of earliest 
disease progression or death

duration of response, defined for subjects who achieve a best overall response of CR, CRi, or PR, 
as the time from the date of first response (CR, CRi, or PR) to the earliest date of disease 
progression or death

time-to-progression, defined as the time from the date of first dose of any study drug to the 
date of earliest disease progression
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
event-free survival, defined as the time from the date of first dose of any study drug to the date 
of earliest disease progression, death, or start of a new anti-T-PLL therapy

disease control rate, defined as the proportion of subjects achieving CR, CRi, PR, or stable 
disease as best overall response

overall survival, defined as the time from the date of first dose of any study drug to death from 
any cause

number of eligible subjects reaching autologous or allogeneic transplantation; eligible subjects 
are the transplant-naïve subjects who have achieved CR
All secondary endpoints will be assessed per investigator assessment in R/R T-PLL subjects based on the 
T-PLL consensus criteria 2019.11
3.4 Safety Endpoints
Safety evaluations include AE monitoring, physical examinations, vital sign measurements, 
electrocardiogram (ECG) variables (if clinically indicated), and clinical laboratory testing (hematology and 
chemistry) as measures of safety and tolerability for the entire study duration.
3.5 Pharmacokinetic Endpoints
Plasma samples for venetoclax and ibrutinib will be collected to determine trough concentrations 
(Ctrough).  A nonlinear mixed-effects modeling approach may be used to estimate the population central 
values and the individual values of venetoclax parameters such as clearance.
Additional parameters may be estimated if useful in the interpretation of the data.
3.6 Biomarker and Exploratory Research Endpoints
Biospecimens (blood and bone marrow aspirates and/or biopsy) may be collected at specified time 
points throughout the study for a side study for exploratory analyses of known and/or novel disease-
related or drug-related biomarkers.  Types of biomarkers may include nucleic acids, proteins, lipids, or 
metabolites.  These biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  The analyses may include but are not limited to:  
molecular profiling of T-PLL cells, ex-vivo sensitivity, and MRD assessments.
The analyses are exploratory in nature, may be conducted in non-Good Laboratory Practice (GLP) 
laboratories, and the results from these correlative studies may not be included with the clinical study 
report.  The collection of these biospecimens will be optional and subjects will be asked to sign a 
separate informed consent form.  Further details regarding the biomarker research rationale and 
collection times are located in the Operations Manual Section 3.17.
The samples may also be used to develop new therapies, research methods, or technologies.  In 
addition, samples from this study may be stored for future use.  Samples may then be used to validate 
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putative biomarker signatures obtained from a prospective study, leading to the development of 
diagnostic tests.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This study is an open-label, single-arm, Phase 2, multicenter study evaluating the efficacy of venetoclax 
plus ibrutinib with an optimal adaptive 2-stage design as follows:

Stage 1:  Enroll 14 subjects with R/R T-PLL and move to Stage 2 if 4 or more responders as 
follows:

response assessment for Stage 1 will be performed on a continued basis until all 14 subjects 
have enrolled into Stage 1 and have completed the Week 24 disease assessment

Stage 2:  Enroll up to an additional 23 subjects in Stage 2 (up to a total of 37 subjects for Stage 1 
and Stage 2).
If a pretreatment bone marrow assessment was performed per standard-of-care prior to the first dose 
of study drug, the results should be recorded in the electronic case report form (eCRF).
Safety will be continuously assessed and dose adjustments will be considered for both venetoclax and 
ibrutinib, in accordance with product-specific guidelines (refer to Section 6.2).
Interim analysis will occur after Stage 1.  The study will stop for futility if the number of responders at 
Stage 1 is ≤ 3.  If 4 or more subjects respond prior to enrolling all 14 subjects in Stage 1, enrollment will 
not pause between stages.  The maximal sample size will be 37 subjects.  If there are 7 or more 
responders out of 14 subjects in Stage 1, 17 subjects with R/R T-PLL will be enrolled in Stage 2.  Details 
of the adaptive 2-stage design will be provided in the Statistical Analysis Plan (SAP) and Table 6.
Subjects who are treatment-naïve (i.e., unsuitable for alemtuzumab or alemtuzumab treatment is 
unavailable) may be enrolled during Stage 2 of the study.  The number of treatment-naïve subjects to be 
enrolled will depend on the required sample size for the R/R subjects in Stage 2 which is based on the 
number of responders from Stage 1 and considering the maximum of 37 subjects in total to be enrolled 
in the study.
Ibrutinib 420 mg will be dosed orally (PO), once daily (QD) starting on Day –1.  Venetoclax will be 
initiated on Week 1, Day 1 with an initial 5-day dose ramp-up for venetoclax (Figure 1).  Venetoclax 
400 mg (target dose) will be dosed PO, QD; an option to increase the dose of venetoclax to 600 mg QD 
will be available at Week 8 or thereafter if there is evidence of incomplete response and/or if the dose 
of ibrutinib has been decreased to 280 mg/day or 140 mg/day due to toxicity management.  The dose of 
venetoclax should not be increased to 600 mg/day in subjects with significant venetoclax toxicity.  The 
maximum dose allowed for venetoclax is 600 mg/day.
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Treatment duration of combination treatment will be as follows:

eligible subjects will proceed to stem cell transplantation after reaching CR (combination 
therapy will be discontinued but subjects will be followed for disease progression)

up to 2 years, will be given to subjects who are ineligible for stem cell transplantation unless 
treatment is intolerable or the subject develops progressive disease
For subjects who continue to derive clinical benefit after 2 years of treatment, AbbVie will work with the 
investigator to consider the potential continuation of therapy, as per local regulations.
See Section 5 for information regarding eligibility criteria.
The dosing schematic is shown in Figure 1.  To mitigate the risk of tumor lysis syndrome (TLS) (see 
Section 6.2) with venetoclax, a 5-step dose ramp-up with hospitalization for close monitoring and 
prophylaxis has been developed.  Due to the aggressive nature of T-PLL, the venetoclax ramp-up will be 
administered in a daily manner, starting with 20 mg on Week 1, Day 1 and reaching the target dose of 
400 mg on Week 1, Day 5.  Refer to Section 6.2 for details for TLS management.
Further information regarding study procedures is located in the Operations Manual Section 3.
Figure 1.
Dosing Schematic
CR = complete remission; D = day; W = week
Note:
Venetoclax 5-step dose ramp-up in 5 days to target dose of 400 mg daily with an option to increase the dose to 
600 mg QD at Week 8 or thereafter if there is evidence of incomplete response and/or if the dose of ibrutinib has 
been decreased to 280 mg/day or 140 mg/day due to toxicity management.
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4.2 Discussion of Study Design
Choice of Control Group
Not applicable.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with T-PLL.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Subjects with T-PLL have poor survival rates with currently available therapy.  Venetoclax (ABT-199) is a 
potent, selective, and orally bioavailable small molecule inhibitor of BCL-2 and can be safely combined 
with ibrutinib, a BTK inhibitor.  Treatment with this combination may result in potentially meaningful 
clinical efficacy in this patient population.
Selection of Doses in the Study
The maximum-tolerated dose for venetoclax monotherapy has not been reached, but daily doses up to 
800 mg were well tolerated in CLL/SLL and doses up to 1200 mg were tolerated in NHL (Study M12-175).  
A 400-mg dose of venetoclax was selected as the target dose since this is the approved dose in CLL as 
monotherapy and was the dose evaluated in combination with ibrutinib at 420 mg in CLL 
(i.e., CAPTIVATE) and MCL (i.e., AIM) clinical studies which there are supportive efficacy and safety data 
for this combination.  Additionally, a 420-mg dose of ibrutinib was selected as the evaluated dose since 
this is the approved dose for CLL/SLL, Waldenström's macroglobulinemia, and chronic graft versus host 
disease.  Venetoclax dosing will be introduced at an initial dose of 20 mg and escalated (if no TLS occurs) 
to the 400-mg target dose over a 5-day dose ramp-up period that occurs during the initial 
hospitalization.
Ongoing combination trials of venetoclax with either low-dose cytarabine (Studies M14-387 and 
M16-043) or azacitidine (Studies M14-358 and M15-656) initiated venetoclax at a 100-mg dose and 
ramp-up over 3 to 4 days to the target dose level.  To date, this strategy has been effective at minimizing 
the risk of clinical TLS with a rate across the AML program of < 1%.  The proposed ramp-up period for 
T-PLL is a more conservative approach to minimize the TLS risk in this indication.  If the effective dose is 
not established in T-PLL at 400 mg, additional escalation of venetoclax dose to 600 mg may be 
investigated to establish whether escalating doses and exposures improve the subject's clinical 
response.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
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Consent
1. Subjects or their legally authorized representative(if permitted per local regulations) 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.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old, suitable for oral administration of study drugs.
3. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of study drug:

alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 × the upper limit of 
normal (ULN);

adequate liver function as indicated by a total bilirubin ≤ 1.5 × ULN (subjects with 
documented Gilbert's syndrome may have bilirubin > 1.5 × ULN)

absolute neutrophil count (ANC) > 1000/µL (growth factor support is allowed to achieve 
eligibility criteria);

platelet count > 50,000/µL (platelet transfusion is allowed if the cytopenia is due to 
infiltration of the leukemia in the bone marrow);

creatinine clearance (CrCL) ≥ 50 mL/minute (calculated according to the modified formula of 
Cockcroft and Gault [Men:  ([140 – age (years)] × bodyweight [kg])/(72 × creatinine [mg/dL]); 
Women:  (modified Cockcroft and Gault formula) for men × 0.85] or directly measured with 
a 24-hour urine collection);

hemoglobin > 8 g/dL (red blood cell transfusion is allowed if the cytopenia is due to 
infiltration of the leukemia in the bone marrow).
4. Willingness or ability to comply with procedures required in this protocol.
Disease Activity
5. Diagnosis of T-PLL that requires treatment because of disease-related constitutional 
symptoms, symptomatic bone marrow failure, rapidly enlarging lymph nodes, spleen, and liver, 
increasing lymphocytosis, or extra-nodal involvement.
6. Subject meets an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
Subject History
7. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months.
8. No history of or current decompensated cirrhosis including Child-Pugh class B or C, ascites, 
hepatic encephalopathy, or variceal bleeding.
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9. No malignancies other than T-PLL that:

currently requires systemic therapies;

was not previously treated with curative intention (unless the malignant disease is in a 
stable remission due to the discretion of the treating physician); or

has developed signs of progression after curative treatment.
10. Negative for human T-cell lymphotropic virus, type 1 (testing only required in endemic 
countries).
11. No prior allogeneic stem cell transplant within 6 months of study drug administration and no 
requirement for graft versus host therapy.
12. No life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator's opinion, could compromise the subject's safety, interfere with the absorption or 
metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
13. No history of stroke or intracranial hemorrhage within 6 months prior to enrollment.
14. No major surgery within 4 weeks of first dose of study drug.
15. No known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
16. No currently active, clinically significant cardiovascular disease such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association 
Functional Classification or a history of myocardial infarction, unstable angina, or acute coronary 
syndrome within 6 months prior to enrollment.
17. No active infection with human immunodeficiency virus (HIV) (i.e., positive for anti-HIV 
antibody).
18. No active infection with hepatitis B virus.  Subjects testing positive for hepatitis B surface 
antigen or hepatitis B core antibody but having undetected viral load (i.e., hepatitis B virus DNA 
testing negative) at screening may be enrolled.
19. No active infection with hepatitis C virus.  Subjects testing positive for hepatitis C antibody 
may only be enrolled if completed curative therapy and polymerase chain reaction are negative 
for hepatitis C virus RNA at screening.
20. No uncontrolled or active infection including severe acute respiratory syndrome (SARS)-
coronavirus (CoV)-2 which is confirmed by a local, medically acceptable testing method.
21. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug.
22. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.
23. No clinically relevant or significant ECG abnormalities.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Contraception
24. A negative serum pregnancy test for all women of childbearing potential at the screening 
visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
25. If female, subject must be either postmenopausal OR permanently surgically sterile OR, for 
women of childbearing potential, practicing at least 1 protocol-specified method of birth control 
that is effective from study Day 1 through at least 30 days after the last dose of venetoclax or 
3 months after the last dose of ibrutinib, whichever is later.
26. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or for approximately 30 days after the last dose of venetoclax or 3 months after the last 
dose of ibrutinib, whichever is later.
27. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through 30 days after the last dose of venetoclax and 90 days 
after the last dose of ibrutinib, to practice the protocol-specified contraception.
28. Male who is not considering fathering a child or donating sperm during the study or for 
approximately 30 days after the last dose of venetoclax and 90 days after the last dose of 
ibrutinib.
Concomitant Medications
29. Subject must have received prior alemtuzumab (unless unsuitable or unavailable).
30. Subject must not have been previously treated with a BCL-2 inhibitor.
31. Subject must not have been treated with any of the following within 14 days or 5 half-lives 
of the drug (whichever is shortest) prior to the first dose of ibrutinib or venetoclax and through 
the last dose of study drug, or has not recovered to < Grade 2 clinically significant adverse 
effect(s)/toxicity(s) of the previous therapy:

any anticancer therapy including chemotherapy or radiotherapy

investigational therapy, including targeted small molecule agents
32. Subject must not have received the following within 7 days prior to the first dose of ibrutinib 
or venetoclax through the last dose of any study drug:

steroid therapy for antineoplastic treatment

other chronic immunosuppressants (e.g., for immune thrombocytopenia or autoimmune 
hemolytic anemia)

warfarin or other vitamin K antagonists
33. Subject must not have received biologic agents (e.g., monoclonal antibodies) for 
antineoplastic treatment within 30 days prior to first dose of ibrutinib or venetoclax and through 
the last dose of study drug.
34. Subject must not have systemically used known moderate or strong cytochrome P450 
(CYP)3A inhibitors or inducers within 7 days prior to the first dose of ibrutinib or venetoclax.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
35. Subject must not have received any live or attenuated live vaccine within 28 days prior to 
the first dose of ibrutinib or venetoclax.  Seasonal flu vaccines that do not contain a live virus are 
permitted.
36. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or starfruit within 3 days before the first dose of study 
drug administration and through the last dose of study drug.
37. Subject must not anticipate the use of prohibited medications or foods during study 
participation (see Section 5.3 for additional prohibited medications or foods).
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Nonchildbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of nonchildbearing potential due to meeting any of the following criteria:

postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause;

postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone level > 40 IU/L; or

permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Females, Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drugs and for at least 
30 days after the last dose of venetoclax or 3 months after the last dose of ibrutinib, whichever 
is later.  Females must commit to one of the following methods of birth control:

combined (estrogen- and progestogen-containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days 
prior to study baseline (Day 1).  Also, a barrier method must be used during this study from 
initial study drug administration to 30 days after the last dose of venetoclax or 3 months 
after the last dose of ibrutinib, whichever is later, as drug-drug interaction with venetoclax 
or ibrutinib upon the hormonal contraception is unknown;

progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study baseline (Day 1).  Also, a 
barrier method must be used during this study from initial study drug administration to 
30 days after the last dose of venetoclax or 3 months after the last dose of ibrutinib, 
whichever is later, as drug-drug interaction with venetoclax or ibrutinib upon the hormonal 
contraception is unknown;
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure);

intrauterine device;

intrauterine hormone-releasing system;

vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject); or

true abstinence, defined as refraining from heterosexual intercourse when this is in line with 
the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, 
ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable).
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.  If required per local practices, one of the following should be used in addition to one of 
the birth control methods listed above (excluding true abstinence):

progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, initiated at least 30 days prior to Study Day 1;

male or female condom with or without spermicide;

cap, diaphragm, or sponge with spermicide; or

a combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier method).
Contraception Requirements for Males
Male subjects who are sexually active with a woman of childbearing potential must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at 
least 30 days after the last dose of venetoclax and at least 90 days after the last dose of ibrutinib.  His 
female partner(s) must also use at least one of the following methods of birth control:

combined (estrogen- and progestogen-containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days prior to 
study Day 1

progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Day 1

bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure)

intrauterine device

intrauterine hormone-releasing system
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.3 Prohibited Medications and Therapy
In addition to the medications and therapy listed in the eligibility criteria (concomitant medications 
section), the following medications are prohibited throughout the study:

warfarin and coumarin derivatives
The following are prohibited during ibrutinib initiation and venetoclax dose ramp-up (refer to the 
Operations Manual Section 3.6):

strong CYP3A inhibitors
Live vaccination is prohibited during study participation.  Live vaccination can only be administered at 
least 4 weeks after the last dose of study drug and only after B-cell or absolute lymphocyte count (ALC) 
recovery.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the study 
must be recorded through the post-treatment visit (30-day follow-up visit) (refer to the Operations 
Manual Section 3.6).
Short courses (≤ 14 days) of steroid treatment for noncancer-related medical reasons (e.g., joint 
inflammation, asthma exacerbation, rash, antiemetic use, and infusion reactions) at doses that are 
clinically indicated are permitted.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.
The following medications are allowed to use with caution after completion of the venetoclax dose 
ramp-up if no appropriate therapeutic alternative exists (additional guidance noted):

strong CYP3A inhibitors (dose reductions for both venetoclax and ibrutinib)
The following cautionary medications include (if necessary, additional guidance noted):

moderate CYP3A inhibitors (requires venetoclax and ibrutinib dose reductions)

strong and moderate CYP3A inducers (avoid)

P-glycoprotein (P-gp) substrates

breast cancer resistance protein substrates/inhibitors

organic anion-transporting polypeptide (OATP)1B1/1B3 substrates

P-gp inhibitors
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

supplements such as fish oil and vitamin E

other anticoagulants or medications that inhibit platelet function (warfarin and coumarin 
derivatives prohibited)
Co-administration of a strong or moderate CYP3A inhibitor requires a specified venetoclax and ibrutinib 
dose adjustment as presented in Table 1.  After discussion with the investigator and AbbVie Therapeutic 
Area Medical Director (TA MD), co-administration of a strong CYP3A inhibitor with ibrutinib may be 
allowed.
Table 1.
Dose Modifications for Venetoclax and Ibrutinib:  Moderate and Strong CYP3A 
Inhibitor Use
Drug
Dose if No Moderate or 
Strong CYP3A Inhibitor
Dose if Co-Administered with 
a Moderate CYP3A Inhibitor
Dose if Co-Administered with a 
Strong CYP3A Inhibitora
Venetoclax
20 mg
10 mg
--b
50 mg
20 mg
--b
100 mg
50 mg
--b
200 mg
100 mg
--b
400 mg
200 mg
100 mg
600 mg
300 mg
150 mg
Ibrutinib
420 mg
140 mg
Withhold for duration of inhibitor 
use or reduce to 140 mg
CYP = cytochrome P450
a.
Further dose reductions may be required.
b.
Strong CYP3A inhibitors are prohibited during initial ramp-up.
Note:
Refer to Section 4.1 for venetoclax ramp-up and target doses.
Moderate and strong CYP3A inhibitors and inducers should only be used when no appropriate 
therapeutic alternative exists.
Consult the Operations Manual Appendix B for specific examples of prohibited and cautionary 
medications that fall into these categories.  Additional information regarding prohibited and cautionary 
medications is summarized in the Operations Manual Section 3.6.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study and/or study drug at any time for 
reasons including, but not limited to, the following:

clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie TA MD;

investigator's opinion that discontinuation is in the best interest of the subject;
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

subject requests withdrawal from the study;

eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk;

introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk;

subject becomes pregnant while on study drug;

subject's response to therapy is unsatisfactory as evidenced by progression of disease while on 
study drug;

subject requires radiotherapy, cancer-related surgery as a result of tumor progression, or 
alternate antineoplastic agents during the study period;

subject is significantly noncompliant with study procedures which would put the subject at risk 
for continued participation in the trial.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix I.
The investigator should contact the sponsor TA MD before discontinuing a subject from the study for a 
reason other than "planned per protocol" to ensure all acceptable mitigation steps have been explored.
Refer to the Operations Manual in Appendix I for details on how to handle study activities/procedures.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
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)
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie TA MD along with the possibility of premature discontinuation from the study drug 
dosing period.  Follow subsequent protocol Section 5.6 for subjects who discontinued study drug.  
Frequency or timing of COVID-19 testing and intervals between testing for the above viral clearance 
criteria may be adjusted to account for epidemiologic trends, updated information regarding infectivity, 
and local/institutional guidelines.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits unless subjects 
have decided to discontinue the study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the final visit should be completed as soon as possible, preferably within 
2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after the last dose of study drug 
may be completed to ensure all treatment-emergent AEs/serious adverse events (SAEs) have been 
resolved.
5.7 Study Drug
Venetoclax manufactured by AbbVie will be administered PO, QD beginning on Week 1, Day 1 and 
should be taken at approximately the same time each day.  Subjects will be trained to self-administer 
venetoclax (refer to Operations Manual Section 6.1).
Ibrutinib 420 mg will be administered PO, QD starting on Day –1 and should be taken around the same 
time each day.  Subjects will be trained to self-administer ibrutinib (refer to Operations Manual 
Section 6.1).
Venetoclax and ibrutinib should be taken approximately at the same time with a meal and water, within 
30 minutes after the completion of breakfast or the subject's first meal of the day.
If vomiting occurs after taking venetoclax or ibrutinib, no additional dose should be taken that day.  In 
cases where a dose of venetoclax or ibrutinib is missed or forgotten, the subject should take the 
forgotten dose as soon as possible, provided that the dose is taken within 8 hours of the missed dose 
and is taken with 240 mL of water and food.  Otherwise, the missed dose should not be taken and the 
subject should take the next dose at the next scheduled dosing time.
Subject dosing will be recorded in a subject dosing diary.  The subject will be instructed to return all drug 
containers (even if empty) to the study site personnel at each study visit.  The study site personnel will 
document compliance.
AbbVie will supply drug for venetoclax and ibrutinib.  Study drug provided by AbbVie should not be 
substituted or alternately sourced unless otherwise directed by AbbVie.  Noninvestigational medicinal 
product (standard-of-care) must be obtained commercially. If a subject is unable to come to the study 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
site to pick up their study drug due to COVID-19, a direct-to-patient (DTP) study drug shipment can be 
made from the study site to the subject if allowed by local regulations.  AbbVie will submit any required 
notifications to the regulatory authority as applicable.  Refer to the Operations Manual in Appendix I for 
details on DTP shipment of study drug.
Study drug information is presented in Table 2.
Table 2.
Study Drug Information
Investigational Product
Mode of Administration
Dosage Form
Strength
Venetoclax
Oral
Film-coated tablet
100, 50, and 10 mg
Ibrutinib
Oral
Hard capsule
140 mg
Venetoclax will be packaged in blisters or bottles with quantities sufficient to accommodate study 
design.  Ibrutinib will be packaged in bottles with quantities sufficient to accommodate study design.  
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  Site staff will complete all blank spaces on the label before dispensing to subjects.  Study 
drug will only be used for the conduct of this study.
5.8 Randomization/Drug Assignment
This is an open-label, single-arm study.  There is no randomization for this study.  All subjects will be 
assigned a unique identification number by the IRT at the screening visit (refer to the Operations Manual 
Section 6.3).
5.9 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  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 IEC/IRB regulatory authorities (as applicable) and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product, this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including 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 
"special situations," such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meets protocol-specific criteria (see 
Section 6.2 regarding toxicity management), and/or if the investigator considers them to be AEs.
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
preplanned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or contract research organization (as appropriate) as an 
SAE within 24 hours of the site being made aware of the SAE (refer to the Operations Manual Section 4.3 
for reporting details and contact information):
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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).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, protocol-related SAEs and protocol-related nonserious AEs will be collected from the time the 
subject signs the study-specific informed consent.
The following definitions will be used for a Serious Adverse Reaction (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
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SAR
Defined as all noxious and unintended responses to an Investigational Medicinal 
Product (IMP) related to any dose administered that result in an SAE as defined 
above.
SUSAR
A suspected SAR:  refers to individual SAE case reports from clinical trials where a 
causal relationship between the SAE and the IMP was suspected by either the 
sponsor or the investigator, is not listed in the applicable Reference Safety 
Information, and meets one of the above serious criteria.  All individually reported 
SARs are considered suspected.
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements.
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study:

TLS

major hemorrhage

neutropenia
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.  If a reported AE increases in 
severity, the initial AE should be given an outcome date and a new AE must be reported on a different 
onset date than the end date of the previous AE to reflect the change in severity.  The dates on the AEs 
cannot overlap.  For all reported SAEs that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity.
For AEs not captured by the NCI CTCAE, the following should be used:
Grade 1
The AE is transient and easily tolerated by the subject (mild).
Grade 2
The AE causes the subject discomfort and interrupts the subject's usual activities 
(moderate).
Grade 3
The AE causes considerable interference with the subject's usual activities and may 
be incapacitating (moderate to severe).
Grade 4
The AE is life-threatening and requires urgent intervention (severe).
Grade 5
The AE resulted in death of the subject (severe).
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The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day after 
the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners will be collected from the 
date of the first dose through 30 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Toxicity Management
The management of specific AEs and laboratory parameters is described below.  This includes AEs of 
TLS, major hemorrhage, and neutropenia for venetoclax and known potential risks associated with 
ibrutinib.
Tumor lysis syndrome:  There is a potential for TLS in subjects affected by hematologic malignancies.  
Depending on the specific tumor type, risk factors may include one or more of the following:  bulky 
disease or high tumor burden, renal insufficiency, splenomegaly, elevated pretreatment lactate 
dehydrogenase levels, elevated leukocyte count, and dehydration.
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS.  Changes in electrolytes 
consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the 
first dose of venetoclax (Appendix E).  Potassium increases can be life-threatening and should be treated 
as an emergency.  Definitions of laboratory TLS and clinical TLS are provided in the Appendix D (Howard 
grading classification).  Due to the short dose ramp-up used in this study, all subjects will be managed as 
high risk for TLS.  If a subject experiences blood chemistry changes suggestive of TLS, the dose of 
venetoclax should be withheld and reductions may be required (Appendix F).
Major hemorrhage:  Fatal bleeding events have occurred in patients treated with ibrutinib.  A major 
hemorrhage is any hemorrhagic AE of Grade 3 or higher; any SAE of bleeding of any grade; or any 
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central nervous system hemorrhage/hematoma of any grade.  All hemorrhagic AEs requiring a 
transfusion of red blood cells should be reported as a Grade 3 or higher per NCI-CTCAE.  Ibrutinib may 
be withheld and/or reductions may be required.
Neutropenia:  Venetoclax may cause neutropenia.  Subjects with a history of neutropenia who have 
received multiple prior therapies and/or have significant bone marrow involvement may be at a 
particularly high risk.  Grade 3 or 4 neutropenia has been reported in subjects treated with venetoclax.  
Subjects will be managed for neutropenia as detailed below.
Known potential risks associated with ibrutinib are listed below, and treatment may be discontinued or 
adjusted in response to occurrence of these events, as appropriate.  Please refer to the ibrutinib 
Investigator's Brochure9 for additional information on potential risks for ibrutinib.

hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary 
malignancies, and TLS
Subjects will be monitored for these events throughout the study and treatment may be discontinued or 
adjusted as appropriate.
Prophylaxis and Management of Tumor Lysis Syndrome
The risk of TLS is a continuum based on multiple factors including tumor burden, CrCL, and other 
comorbidities.  Subjects with high tumor burden (e.g., any lymph node with a diameter > 5 cm or 
ALC > 25 × 109/L) are at greater risk of TLS when initiating venetoclax.  Reduced renal function 
(CrCL < 80 mL/min) further increases the risk.  The risk may decrease as tumor burden decreases with 
venetoclax treatment.  Tumor burden categories are provided in Table 3.
Prior to initiating venetoclax, tumor burden assessment, including radiographic evaluation (e.g., CT 
scan), should be performed for all subjects during screening.  In addition, blood chemistry (potassium, 
calcium, phosphorus, uric acid, and creatinine) assessments should be performed in all subjects at 
screening with correction of pre-existing abnormalities.
Table 3.
Tumor Burden Categories
Tumor Burden 
Category
Criteria
Low

All measurable lymph nodes with the largest diameter < 5 cm AND ALC < 25 × 109/L
Medium

Any measurable lymph node with the largest diameter ≥ 5 cm and < 10 cm OR 
ALC ≥25 × 109/L
High

Any measurable lymph node with the largest diameter ≥ 10 cm OR ALC ≥ 25 × 109/L 
AND any measurable lymph node with the largest diameter ≥ 5 cm but < 10 cm
ALC = absolute lymphocyte count
All subjects will be hospitalized for close monitoring and prophylaxis during the venetoclax dose ramp-
up, starting 1 day prior to venetoclax initiation until 1 day after reaching target dose of venetoclax 
(400 mg QD).
All TLS prophylaxis measures should be appropriately recorded in the eCRF.
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Hydration:  All subjects, regardless of risk for TLS, should be adequately hydrated before starting 
treatment with venetoclax and during the dose ramp-up phase.  The recommended volume is 1.5 to 
2.0 L (approximately 6 to 8 glasses) of water each day.  Subjects should be instructed to drink water at 
least 48 hours before and on the day of the first dose.  Intravenous (IV) fluids should be administered 
(i.e., 150 – 200 mL/hour) daily, as tolerated, during the hospitalization period.
Antihyperuricemic agents:  Oral uric acid-reducing agent (allopurinol except if contraindicated) should 
be administered 72 hours before first venetoclax dose to all subjects; rasburicase should be considered 
prophylactically if the subject's baseline uric acid is elevated, unless contraindicated.
Blood chemistry monitoring:  Chemistry and hematology laboratory tests are to be performed upon 
admission the night before the first dose of venetoclax.  The investigator's decision to proceed with 
venetoclax treatment initiation will be based on these laboratory values.  Laboratory monitoring for TLS 
is to occur at time 0 (predose, within 4 hours before venetoclax administration) and 4, 8, 12, and 
24 hours after each dose escalation (including the optional increase to 600 mg at Week 8 or thereafter) 
on real time (turnaround < 2 hours).  A dose increase must not be allowed until the subject's 24-hour 
laboratory test results have been reviewed by investigator.  Results from time 0 (predose) laboratory 
values will be collected and used as baseline to assess potential electrolyte abnormalities occurring after 
venetoclax administration.  Results from time 0 (predose) on Day 1 are not required to be available prior 
to initiating venetoclax treatment.
Nephrology consultation:  Nephrology (or other acute dialysis service) consultation should be 
considered upon admission per institutional standards at the investigators' discretion to ensure 
emergency dialysis is available and the appropriate staff is aware and prepared to handle any necessary 
intervention for TLS.  Telemetry should also be considered.
In case of evidence of TLS, dosing with venetoclax should be interrupted and/or reduced (refer to 
Appendix F).  Drug interruption for up to 72 hours following transient (i.e., lasting < 48 hours) chemical 
changes and laboratory TLS will not require a dose reduction.  If the TLS has not resolved within 
72 hours, then a dose reduction should be considered.  The subject may be allowed to re-escalate to the 
final dose based on a risk assessment (including tumor burden status) after discussion between the 
investigator and the TA MD.  If active correction of electrolytes was performed, the first dose of 
venetoclax should only be given when electrolytes have been stable without additional treatment for at 
least 24 hours.  For subjects who have had a dosing interruption lasting more than 1 week during the 
ramp-up or more than 2 weeks when subjects are receiving the daily dose of 400/600 mg, TLS risk 
should be reassessed to determine if restarting at a reduced dose is necessary (e.g., all or some levels of 
the dose titration).
Management of Treatment-Related Neutropenia
Complete blood counts should be monitored throughout the treatment period.  Dose interruptions are 
required and dose reductions might be needed for subjects with severe neutropenia.  Supportive 
measures including antimicrobials for any signs of infection and prophylactic use of growth factors 
(e.g., granulocyte-colony stimulating factor [G-CSF]) should be considered (refer to Appendix F).
Prophylaxis for Infection
Anti-infective prophylaxis for viral (e.g., acyclovir, zelitrex, or similar agent) and/or bacterial 
(e.g., trimethoprim-sulfamethoxazole and either levofloxacin or amoxicillin-clavulanate or similar agents 
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and pneumococcal vaccination) infections is required for all subjects with ANC of < 500/μL at any time 
point.  Institutional infectious organisms and their drug resistance patterns should primarily be 
considered and the choice of these agents should be based on regional guidelines or institutional 
standards.  The investigator should confirm that the prophylaxis agent(s) can be safely administered 
with study drugs.  Some medications may require dose adjustments due to the potential for drug-drug 
interactions.  Refer to Table 4 and Table 5 for implementing dose modifications for 
venetoclax + ibrutinib as necessary.
Management of Infection
Management of treatment-emergent infections is the responsibility of the investigator.  Institutional 
infectious organisms and their drug resistance patterns should primarily be considered and the choice of 
agents to treat these infections should be based on regional guidelines or institutional standards.  The 
investigator should confirm that a concomitant medication/supplement can be safely administered with 
study drugs.  Some medications may require dose adjustments due to the potential for drug-drug 
interactions.  Refer to Table 4 and Table 5 for implementing dose modifications for 
venetoclax + ibrutinib as necessary.
Management of Major Hemorrhage
Fatal bleeding events have occurred in subjects treated with ibrutinib.  For all hemorrhagic AEs, a 
transfusion of red blood cells may be required and ibrutinib may be withheld and/or reductions may be 
required.
Guidelines for Management with Antiplatelet Agents and Anticoagulants
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Supplements such as fish oil and vitamin E preparations should be avoided.  Use ibrutinib with caution in 
subjects requiring other anticoagulants or medications that inhibit platelet function.  Subjects with 
congenital bleeding diathesis have not been studied.  Subjects requiring the initiation of therapeutic 
anticoagulation therapy (e.g., atrial fibrillation) should consider the risks and benefits of continuing 
ibrutinib treatment.  If therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should 
be held and not be restarted until the subject is clinically stable and has no signs of bleeding.  Subjects 
should be observed closely for signs and symptoms of bleeding.  No dose reduction is required when 
study drug is restarted.
In a drug-drug interaction study in healthy subjects, administration of a single dose of venetoclax with 
warfarin resulted in an 18% to 28% increase in observed maximum concentration (Cmax) and area under 
the concentration versus time curve from time 0 to infinite time (AUC0-inf) of R-warfarin and S-warfarin.  
Because venetoclax was not dosed to steady state, the international normalized ratio is recommended 
to be monitored closely in subjects receiving warfarin.
Guidelines for Ibrutinib Management with Surgeries or Procedures
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following guidance 
should be applied to the use of ibrutinib in the perioperative period for subjects who require surgical 
intervention or an invasive procedure while receiving ibrutinib:
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
Minor Surgical Procedures:  For minor procedures (such as a central line placement, needle 
biopsy, lumbar puncture [other than shunt reservoir access], thoracentesis, or paracentesis) 
ibrutinib should be held for at least 3 days prior to the procedure and should not be restarted 
for at least 3 days after the procedure.  For bone marrow biopsies that are performed while the 
subject is on ibrutinib, it is not necessary to hold ibrutinib.

Major Surgical Procedures:  For any surgery or invasive procedure requiring sutures or staples 
for closure, ibrutinib should be held at least 7 days prior to the intervention and should be held 
at least 7 days after the procedure and restarted at the discretion of the investigator when the 
surgical site is reasonably healed without serosanguineous drainage or the need for drainage 
tubes.

Emergency Procedures:  For emergency procedures, ibrutinib should be held as soon as possible 
and until the surgical site is reasonably healed or for at least 7 days after the urgent surgical 
procedure, whichever is longer.
Management of Treatment-Related Hematologic Toxicities Other Than Neutropenia or 
Lymphopenia
Treatment should be withheld for any Grade 4 hematologic toxicity.  Once the toxicity has resolved to 
Grade 1 or baseline level (recovery), treatment may be restarted (Appendix F).  If the toxicity recurs, the 
dose reduction guidelines outlined in Table 4 should be followed when resuming study treatment 
following resolution.  Additional dose reductions may occur at the discretion of the investigator.
Management of Treatment-Related Nonhematologic Toxicity
Treatment should be withheld for any clinically relevant ≥ Grade 3 nonhematologic toxicity.  Once the 
toxicity has resolved to Grade 1 or baseline level (recovery), treatment may be restarted (Appendix F).  If 
the toxicity recurs, the dose reduction guidelines outlined in Table 4 should be followed when resuming 
study treatment following resolution.  Additional dose reductions may occur at the discretion of the 
investigator.
Management of Decrease in Spermatogenesis
Venetoclax may cause a decrease in spermatogenesis.  Male subjects considering preservation of 
fertility should bank sperm before initiating treatment with venetoclax.
Dose Modifications Based on Toxicities
Subjects who discontinue 1 study drug because of study drug-related toxicities may continue to receive 
the other study drug per the discretion of the investigator.
Dose Interruptions and Modifications for Venetoclax
See Appendix F for dose modifications for toxicities related to venetoclax and Table 4 for 
recommendations for re-initiating venetoclax treatment after interruption.  If venetoclax dose 
interruption is > 4 weeks, the TA MD should be consulted.
Dose modifications for possible drug-drug interactions are provided in Section 5.4.
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Table 4.
Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption (mg/day)
Restart Dose (mg/day)a
600
400
400
300
300
200
200
100
100
50
50
20
20
10
a.
If patient is not hospitalized for close monitoring, continue the reduced dose for 1 week before increasing the dose.
Dose Interruptions and Modifications for Ibrutinib
Treatment with ibrutinib should be temporarily stopped for unmanageable, potentially ibrutinib-related 
toxicity that is Grade ≥3 in severity. Ibrutinib may be temporarily stopped for a maximum of 
28 consecutive days. Ibrutinib should be discontinued permanently in the event of a toxicity lasting 
more than 28 days unless continued treatment is approved by the sponsor.
The dose of ibrutinib must be modified according to the dose modification guidance in Table 5 and 
Appendix F if any of the following potentially drug-related toxicities occur:

Grade 3 or higher neutropenia with infection or fever

ANC < 500/µL

platelets < 50,000/µL in the presence of clinically significant bleeding (Grade ≥ 2)

platelets < 25,000/µL

Grade 3 nausea or Grade 3 or 4 vomiting or diarrhea if persistent despite optimal antiemetic or 
antidiarrheal therapy

any other Grade 4 or unmanageable Grade 3 toxicity
If the dose of ibrutinib is reduced, the dose of ibrutinib may be re-escalated at the investigator's 
discretion in the absence of a recurrence of the toxicity that led to the reduction. No dose escalation of 
ibrutinib above 420 mg is allowed in this study. Dose changes must be recorded in the dose 
administration eCRF.
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Table 5.
Ibrutinib Dose Reduction Levels
Starting Dose Level
420 mg
Dose reduction Level 1
280 mg
Dose reduction Level 2
140 mg
Dose reduction Level 3
Discontinue
For dose modification during concomitant treatment with CYP3A inhibitors, refer to Table 1.
During combination dosing with venetoclax, the decision to dose modify a study drug due to a toxicity 
will be based on the investigator attribution of relatedness to a given drug. For example, if an AE occurs 
and is considered related to venetoclax but not ibrutinib, the dose of venetoclax should be modified 
while ibrutinib should remain the same. If the AE is considered potentially related to both drugs, 
adjusting the dose of venetoclax before ibrutinib is the recommended first action, taking into 
consideration the possibility of higher systemic exposure of venetoclax when administered in 
combination with ibrutinib. For cases where the investigator is uncertain of what action to take, the 
TA MD may be contacted for further discussion.
If ibrutinib is discontinued for toxicity, then treatment with venetoclax may be continued.
Please consult the ibrutinib Investigator's Brochure9 for more details regarding management of known 
risks of the drug and/or discontinuation (permanent or temporary).
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
SAP.  The statistical analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA) 
under the UNIX operation system.
An interim efficacy analysis will be performed when Stage 1 subjects have completed the Week 24 
disease assessments in R/R T-PLL subjects.
The primary efficacy analysis will be performed for Stage 1 and Stage 2 subjects after their completion of 
the Week 24 disease assessments in R/R T-PLL subjects.
The final analysis will be performed when all subjects have discontinued the study or have completed 
protocol defined follow-up time, whichever is later.
7.2 Determination of Sample Size
Approximately 37 subjects will be enrolled based on the optimal adaptive 2-stage design.12  The adaptive 
2-stage design is presented in the Table 6 below and details will be provided in the SAP.
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Table 6.
Sample Size Using Optimal Adaptive 2-Stage Design
H0:  p ≤ 20% versus H1:  p ≥ 40%
1-β = 80%, 1-sided test, significance level = 0.05
Comments
n1 = 14
S
n2(S)
n(S)
r(S)
≤ 3
0
14
0
Stop for futility after Stage 1
4
23
37
11
R/R versus treatment-naïve 
Stage 2 sample size distribution 
will vary depending on the 
number of responses from Stage 1
5
20
34
10
6
20
34
10
≥ 7a
17
31
9
CR = complete remission; CRi = CR with incomplete bone marrow recovery; PR = partial response; R/R = relapsed or refractory
p:  probability of achieving a response (CR, CRi, or PR).
Power:  1-β = 80%.
Significance level:  10% (2-sided).
n1:  Sample size for Stage 1.
S:  Number of responses from Stage 1.
n2(S):  R/R sample size for Stage 2.
n(S):  Total R/R sample size of Stage 1 and Stage2.
r(S):  Critical value of total number of responses from Stage 1 and Stage 2 to demonstrate efficacy.  "Critical value" is the 
threshold beyond which the null hypothesis is rejected (i.e., claiming efficacy).  For example, the test is statistically 
significant if the number of responders is at least 12 with a sample size of 37 subjects.
a.
The Stage 2 portion will still be conducted to evaluate efficacy in additional subjects even if the Stage 1 portion shows 
significant efficacy.
7.3 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all R/R T-PLL subjects who received at least 1 dose of study drug.  The 
FAS will be used for all safety, pharmacokinetic, efficacy and baseline analyses.  The analyses for the 
treatment-naïve subjects will be included in the SAP.
7.4 Statistical Analyses for Efficacy
The primary efficacy endpoint will be the ORR, defined as the proportion of subjects achieving CR, CRi, 
or PR as their best overall response in R/R T-PLL subjects as per investigator based on the T-PLL 
consensus criteria 2019.11  The best overall response of CR/CRi/PR will be defined as achieving CR, CRi, 
and PR at any point during the study (CR/CRi will need confirmation assessment based on the T-PLL 
consensus criteria 2019).11  The estimate and 90% confidence interval for ORR based on binomial 
distribution will be constructed.  Subjects who have not achieved any component of ORR will be 
considered as nonresponders in the calculation of ORR at the time of analysis.
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The secondary efficacy analysis will be based on the following endpoints:  PFS, duration of response, 
time-to-progression, event-free survival, disease control rate, overall survival, and number of eligible 
subjects reaching autologous or allogeneic transplantation. All secondary endpoints will be assessed per 
investigator assessment in R/R T-PLL subjects based on the T-PLL consensus criteria 2019.11
Time-to-event endpoints will be analyzed using Kaplan-Meier methodology. Median time-to-event and 
the corresponding 95% CI will be provided.  Binary endpoints will be analyzed using binomial distribution 
and estimate of proportion along with 95% confidence interval will be provided.
Details on the primary and other efficacy analyses are provided in the SAP.
7.5 Statistical Analyses for Safety
The safety and tolerability will be assessed by evaluation of study drug exposure, AEs, SAEs, and deaths 
as well as changes in laboratory measurements, physical examinations, and vital sign parameters.
Statistical analyses for safety are described and fully documented in the SAP.
7.6 Interim Analysis
An interim analysis for efficacy and safety will be conducted after all subjects enrolled in Stage 1 have 
completed the Week 24 disease assessment for the purpose of submission.  The study will stop for 
futility if the numbers of responses at Stage 1 is ≤ 3.
Details pertaining to the interim analyses can be found in the SAP.
A Steering Committee composed of a group of investigators who are participating in this study and who 
are experts in the management of T-PLL and an internal specialist in infectious diseases who is not 
currently involved in the conduct or oversight of Study M18-803 will review efficacy, safety, and 
exploratory research throughout the study.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
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conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local laboratory instead of a central laboratory), 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.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits to ensure human subject protection and reliability of study results.  Data will be 
generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or date of the last follow-up 
contact, whichever is later.
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12
REFERENCES
1.
Gandhi V, Tam C, O'Brien S, et al.  Phase I trial of nelarabine in indolent leukemias.  J Clin Oncol.  
2008;26(7):1098-105.
2.
Jain P, Aoki E, Keating M, et al.  Characteristics, outcomes, prognostic factors and treatment of 
patients with T-cell prolymphocytic leukemia (T-PLL).  Annals Oncol.  2017;28(7):1554-9.
3.
Herbaux C, Genet P, Bouabdallah K, et al.  Bendamustine is effective in T-cell prolymphocytic 
leukaemia.  British J Haematol.  2015;168(6):902-19.
4.
Dearden CE, Khot A, Else M, et al.  Alemtuzumab therapy in T-cell prolymphocytic leukemia:  
comparing efficacy in a series treated intravenously and a study piloting the subcutaneous 
route.  Blood.  2011;118(22):5799-802.
5.
Dearden C.  Management of prolymphocytic leukemia.  Hematology Am Soc Hematol Educ 
Program.  2015;2015(1):361-7.
6.
Andersson EI, Pützer S, Yadav B, et al.  Discovery of novel drug sensitivities in T-PLL by high-
throughput ex vivo drug testing and mutation profiling.  Leukemia.  2018;32(3):774-87.
7.
Boidol B, Kornauth C, van der Kouwe E, et al.  First-in-human response of BCL-2 inhibitor 
venetoclax in T-cell prolymphocytic leukemia.  Blood.  2017;130(23):2499-503.
8.
Kornauth C, Boidol B, Koller J, et al.  Efficacy of venetoclax as a single agent and in combination 
with ibrutinib in refractory or relapsed T-cell prolymphocytic leukemia.  Oral Presentation 
EHA23, abstract S829, June 16, 2018.  EHA Learning Center.
9.
Pharmacyclics.  Imbruvica (ibrutinib) Investigator's Brochure.  Current version.
10. AbbVie.  Venetoclax (ABT-199) Investigator's Brochure.  Current version.
11. Staber PB, Herling M, Bellido M, et al.  Consensus criteria for diagnosis, staging, and treatment 
response assessment of T-cell prolymphocytic leukemia.  Blood.  2019;134(14):1132-43.
12. Shan G, Wilding GE, Hutson AD, Gerstenberger S.  Optimal adaptive two-stage designs for early 
phase II clinical trials.  Statistics in Medicine.  2016;35(8):1257-66.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC0-inf
area under the concentration versus time curve from time 0 to infinite time
B2M
β2 microglobulin
BCL
B-cell lymphoma
BCL-XL
B-cell lymphoma – extra large
BCRi
B-cell receptor inhibitor
BTK
Bruton's tyrosine kinase
CLL
chronic lymphocytic leukemia
Cmax
observed maximum concentration
CoV
coronavirus
COVID-19
coronavirus disease – 2019
CR
complete remission
CrCL
creatinine clearance
CRi
complete remission with incomplete bone marrow recovery
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentrations
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DTP
direct-to-patient
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FAS
Full Analysis Set
GCP
Good Clinical Practice
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G-CSF
granulocyte-colony stimulating factor
GLP
Good Laboratory Practice
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
Ki
inhibition rate constant
MCL
myeloid cell leukemia
MRD
minimal residual disease
NCI
National Cancer Institute
NCI
National Cancer Institute
NHL
non-Hodgkin's lymphoma
OATP
organic anion-transporting polypeptide
ORR
overall response rate
PFS
progression-free survival
P-gp
P-glycoprotein
PO
oral
PR
partial response
QD
once daily
RNA
ribonucleic acid
R/R
relapsed or refractory
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS
severe acute respiratory syndrome
SLL
small lymphocytic lymphoma
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TLS
tumor lysis syndrome
TP53
tumor protein p53
T-PLL
T-cell prolymphocytic leukemia
ULN
upper limit of normal
US
United States
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M18-803:  A Prospective, Open-Label, Single-Arm, Phase 2, Multicenter Study Evaluating the 
Efficacy of Venetoclax Plus Ibrutinib in Subjects with T-Cell Prolymphocytic Leukemia
Protocol Date:  11 November 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager 
Clinical Program Development
Senior Manager
Medical Writing
Assistant Medical Director
Global Medical Affairs
Head of Statistics, Oncology
Statistical Science
Director
Clinical Pharmacology and Pharmacometrics
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APPENDIX D. DEFINITIONS OF LABORATORY AND CLINICAL 
TUMOR LYSIS SYNDROME
Metabolic Abnormality
Criteria for Classification of Laboratory 
Tumor Lysis Syndrome
Criteria for Classification of Clinical 
Tumor Lysis Syndrome
Hyperuricemia
Uric acid > 8.0 mg/dL (475.8 μmol/L) in 
adults or above the upper limit of the 
normal range for age in children
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/L) in 
adults or > 6.5 mg/dL (2.1 mmol/L) in 
children
Hyperkalemia
Potassium > 6.0 mmol/liter
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/L) or ionized calcium 
< 1.12 mg/dL (0.3 mmol/L)a
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle twitching, 
carpopedal spasm, Trousseau's sign, 
Chvostek's sign, laryngospasm, or 
bronchospasm), hypotension, or heart 
failure probably or definitely caused by 
hypocalcemia
Acute kidney injuryb
Not applicable
Increase in the serum creatinine level of 
0.3 mg/dL (26.5 µmol/L) (or a single 
value > 1.5 × the upper limit of the age-
appropriate normal range if no baseline
creatinine measurement is available) or 
the presence of oliguria, defined as an 
average urine output < 0.5 mL/kg/hr for 
6 hrs
a.
The corrected calcium level in mg/dL = measured calcium level in mg/dL + 0.8 × (4-albumin in g/dL).
b.
Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg/dL (26.5 μmol/L) or a period of 
oliguria lasting 6 hours or more.  By definition, if acute kidney injury is present, the subject has clinical tumor lysis 
syndrome.
Note:
In laboratory tumor lysis syndrome, 2 or more metabolic abnormalities must be present during the same 24-hour 
period within 3 days before the start of therapy or up to 7 afterward.  Clinical tumor lysis syndrome requires the 
presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or 
death.
Source:  Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54.
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APPENDIX E. RECOMMENDATIONS FOR INITIAL 
MANAGEMENT OF ELECTROLYTE 
ABNORMALITIES AND PREVENTION OF TUMOR 
LYSIS SYNDROME
Abnormality
Management Recommendations
Hyperkalemia (Including Rapidly Rising Potassium)
Potassium ≥ 0.5 mmol/L increase from 
prior value (even if potassium within 
normal limits [WNL])

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.  If further ≥ 0.2 mmol/L increase 
in potassium, but still < upper limit of normal (ULN), manage 
as per potassium ≥ ULN.  Otherwise recheck in 1 hour.

Resume per protocol testing if change in potassium is 
< 0.2 mmol/L, and potassium < ULN, and no other evidence 
of tumor lysis.

At the discretion of the investigator, may recheck prior to 
hospitalization.  If stable or decreased, and still WNL, 
hospitalization is at the discretion of the investigator.  
Potassium, phosphorus, uric acid, calcium and creatinine 
must be rechecked within 24 hours.
Potassium > upper limit of normal

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) notification with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if 
there is ECG/telemetry evidence of life-threatening 
arrhythmias.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.

If potassium < ULN 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 1, 2 and 
4 hours, if no other evidence of tumor lysis.
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Abnormality
Management Recommendations
Potassium ≥ 6.0 mmol/L (6.0 mEq/L) and/or 
symptomatic (e.g., muscle cramps, 
weakness, paresthesias, nausea, vomiting, 
diarrhea)

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) assessment with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.

Administer sodium bicarbonate 1 to 2 mEq IV push.

If sodium bicarbonate is used, rasburicase should not be 
used as this may exacerbate calcium phosphate 
precipitation.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if 
there is ECG/telemetry evidence of life-threatening 
arrhythmias.  Do not administer in same IV line as sodium 
bicarbonate.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine every hour STAT.
Hyperuricemia
Uric acid ≥ 8.0 mg/dL (476 µmol/L)

Consider rasburicase (dose based on local guidelines and/or 
institutional standards).

If rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate 
precipitation.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.
Uric acid ≥ 10 mg/dL (595 µmol/L)
OR 
Uric acid ≥ 8.0 mg/dL (476 µmol/L) with 
25% increase and creatinine increase 
≥0.3 mg/dL (≥ 0.027 mmol/L) from predose 
level

Administer rasburicase (dose based on local guidelines 
and/or institutional standards).

When rasburicase is used, sodium bicarbonate should 
not be used as this may exacerbate calcium phosphate 
precipitation.

Notify nephrology (or other acute dialysis service).

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.

If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hours, 
later, if no other evidence of tumor lysis.
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Abnormality
Management Recommendations
Calcium ≤ 7.0 mg/dL (1.75 mmol/L) AND 
Subject symptomatic (e.g., muscle cramps, 
hypotension, tetany, cardiac arrhythmias)

Administer calcium gluconate 50 to 100 mg/kg IV slowly 
with ECG monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.

If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 
4 hours, later, if no other evidence of tumor lysis.

Calculate corrected calcium and check ionized calcium if 
albumin low.
Hyperphosphatemia
Phosphorus ≥ 5.0 mg/dL (1.615 mmol/L) 
with ≥ 0.5 mg/dL (0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate).

Nephrology (or other acute dialysis service) notification 
(dialysis required for phosphorus ≥ 10 mg/dL).

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.

If phosphorus < 5.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hours, later, if no other evidence of 
tumor lysis.
Creatinine
Increase ≥ 25% from baseline

Start or increase rate of IV fluids.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 to 2 hours STAT.
ECG = electrocardiogram; IV = intravenous
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APPENDIX F. RECOMMENDED DOSE REDUCTIONS RELATED 
TO DRUG TOXICITIES
Recommended Venetoclax Dose Modifications for Toxicities
Event
Occurrence
Action
Tumor Lysis Syndrome
Blood chemistry changes or 
symptoms suggestive of TLS
Any
Withhold the next day's dose.  If resolved within 24 to 
48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 
48 hours to resolve, resume at a reduced dose (see Table 4).
For any events of clinical TLS, resume at a reduced dose 
following resolution (see Table 4).
Dose reduction or interruption of companion study drug 
may occur at the discretion of the investigator.
Non-Hematologic Toxicities
Grade 3 or 4 non-
hematologic toxicities
1st occurrence
Interrupt venetoclax.  Once the toxicity has resolved to 
Grade 1 or baseline level, venetoclax therapy may be 
resumed at the same dose.  No dose modification is 
required.
2nd and 
subsequent 
occurrences
Interrupt venetoclax.  Follow dose reduction guidelines in 
Table 4 when resuming treatment with venetoclax after 
resolution.  A greater dose reduction may occur at the 
discretion of the investigator.
Hematologic Toxicities
Grade 3 or 4 neutropenia 
with infection or fever; or 
Grade 4 hematologic 
toxicities (except 
lymphopenia)
1st occurrence
Interrupt venetoclax.  To reduce the infection risks 
associated with neutropenia, G-CSF may be administered 
with venetoclax if clinically indicated.  Once the toxicity has 
resolved to Grade 1 or baseline level, venetoclax therapy 
may be resumed at the same dose.
2nd and 
subsequent 
occurrence
Interrupt venetoclax.  Consider using G-CSF as clinically 
indicated.  Follow dose reduction guidelines in Table 4 when 
resuming treatment with venetoclax after resolution.  
Additional dose reductions may occur at the discretion of 
the physician.
Consider discontinuing venetoclax for subjects who require dose reductions to less than 100 mg for more than 
2 weeks.
G-CSF = granulocyte-colony stimulating factor; TLS = tumor lysis syndrome
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Recommended Ibrutinib Dose Modifications for Toxicities
Event
Occurrence
Action
Any of the following 
potentially drug-related 
toxicities (refer to 
Section 6.2):

Grade 3 or higher 
neutropenia with 
infection or fever

ANC < 500/µL

platelets < 50,000/µL in 
the presence of clinically 
significant bleeding 
(Grade ≥ 2)

platelets < 25,000/µL

Grade 3 nausea or 
Grade 3 or 4 vomiting or 
diarrhea if persistent 
despite optimal 
antiemetic or 
antidiarrheal therapy

any other Grade 4 or 
unmanageable Grade 3 
toxicity
1st occurrence
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; 
may restart at original dose level.
2nd occurrence
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; 
may restart at 1 dose level lower (i.e., dose reduction 
Level 1).  Follow dose reduction guidelines in Table 5.
3rd occurrence
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; 
may restart at 1 dose level lower (i.e., dose reduction 
Level 2).  Follow dose reduction guidelines in Table 5.
4th occurrence
Discontinue study drug (i.e., dose reduction Level 3).  Follow 
dose reduction guidelines in Table 5.
Note:  For hematologic toxicities, restart of ibrutinib may be considered once the toxicity has resolved to study 
entry criteria level or better.
ANC = absolute neutrophil count
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APPENDIX G. ACTIVITY SCHEDULE
The following table shows the required activities.  The individual activities are described in detail in the 
Operations Manual Section 3.  Allowed modifications due to COVID-19 are detailed within the 
Operations Manual.
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APPENDIX H. PROTOCOL AMENDMENT SUMMARY OF 
CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
01 October 2018
Version 2.0
02 May 2019
Version 2.1 (United Kingdom Only)
10 September 2019
Version 2.2 (Italy Only)
02 October 2019
Version 2.3 (France Only)
08 November 2019
Version 2.4 (Germany Only)
17 January 2020
Version 2.4.1 (Germany Only)
15 July 2020
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol, 
incorporate necessary protocol modifications due to the COVID-19 pandemic, and the following:

Rationale:  To list only 1 TA MD for this protocol and update the address for 
.

Updated 
 address on the Protocol cover page and in the Operations 
Manual, Appendix I (Section 1 and Section 4.3).

Removed 
 as an additional TA MD for this protocol on the Protocol cover page 
and in the Operations Manual, Appendix I (Section 1).

Rationale:  To refer to the T-PLL consensus criteria 2019 for the primary endpoint.

Added a reference to the T-PLL consensus criteria 2019 for clarification of the primary 
endpoint in the Protocol, Section 3.2.

Rationale:  To align secondary objectives with secondary endpoints.

Added a secondary objective in the Protocol, Section 1 and Section 3.1 as follows:  To 
evaluate the PFS, duration of response, time-to-progression, event-free survival, disease 
control rate, and overall survival.

Added disease control rate to the secondary endpoints in the Protocol, Section 1 and 
Section 3.3.

Added brief definitions for the secondary endpoints in Section 3.3.

Added a reference to the T-PLL consensus criteria 2019 for clarification of assessment of the 
secondary endpoints in Section 3.3.

Rationale:  To add instruction for recording bone marrow assessment data if a pretreatment 
bone marrow sample was provided.

Added the following statement in the Protocol, Section 4.1 and the Operations Manual, 
Appendix I (Section 2): " If a pretreatment bone marrow assessment was performed per 
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standard-of-care prior to the first dose of study drug, the results should be recorded in the 
electronic case report form (eCRF)."

Rationale:  To clarify that once the clinical trial treatment has been completed, the potential 
continuation of therapy will be as per local regulations and to extend the post-treatment follow-
up visits period in the Protocol, Section 1 and Section 4.1.

Added that AbbVie will work with the investigator to consider the potential continuation of 
therapy as per local regulations.

Removed requirement for subjects to be followed for disease progression for "up to 2 years" 
after eligible subjects proceed to stem cell transplantation.

Rationale:  To update eligibility criteria (Section 5.1) for signing the informed consent because a 
legally authorized representative is not allowed to sign according to German Drug Act.

Added that subjects or their legally authorized representative (if permitted per local 
regulations) must voluntarily sign and date an informed consent to Criterion #1.

Rationale:  To update eligibility criteria (Section 1 and Section 5.1) for creatinine clearance 
because limited safety data exists for venetoclax administered among subjects with renal 
function between 30 and 50 mL/minute.

Changed the creatinine clearance requirement from ≥ 30 mL/minute to ≥ 50 mL/minute in 
Criterion #3.

Rationale:  To clarify that subjects should not receive any live or attenuated live vaccine during 
study participation from 28 days prior to the first dose of study drug, to include only those 
criteria applicable for entry into the study, and to allow seasonal flu vaccines.

Modified eligibility Criterion #35 in the Protocol, Section 5.1 to state "Subjects must not 
have received any live or attenuated live vaccine within 28 days prior to the first dose of 
ibrutinib or venetoclax.  Seasonal flu vaccines that do not contain a live virus are permitted."

Rationale:  To clarify the contraception recommendations for male subjects relative to the 
first dose of venetoclax or ibrutinib to match the package insert.

Updated eligibility Criterion #27 (Section 5.1) to include the following:  "If male, and subject 
is sexually active with female partner(s) of childbearing potential, he must agree, from Study 
Day 1 through 30 days after the last dose of venetoclax and 90 days after the last dose of 
ibrutinib, to practice the protocol-specified contraception."

Updated eligibility Criterion #28 (Section 5.1) to include the following:  "Male who is not 
considering fathering a child or donating sperm during the study or for approximately 
30 days after the last dose of venetoclax and 90 days after the last dose of ibrutinib."

Updated male contraception recommendation (Section 5.2) to include the following:  "Male 
subjects who are sexually active with a woman of childbearing potential must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 
through at least 30 days after the last dose of venetoclax and at least 90 days after the last 
dose of ibrutinib."

Rationale:  To add live vaccines to the list prohibited medications and therapy in Section 5.3.
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
Updated the list of prohibited medications and therapy to include live vaccinations during
study participation and until at least 4 weeks after the last dose of study drug and only after 
B-cell or absolute lymphocyte count (ALC) recovery.

Rationale:  To update the required safety text in the Protocol Section 6.1.

Updated the guidance on the "special situations" that may cause an AE.

Added additional guidance to define an AE for the following situations:  worsening of a 
pre-existing condition, worsening in severity of a reported AE, or laboratory abnormalities 
and changes in vital signs.

Added definitions for a Serious Adverse Reaction (SAR) and Suspected Unexpected Serious 
Adverse Reaction (SUSAR).

Rationale:  To fix a discrepancy in the timing of recording adverse events (AEs) as stated in the 
Protocol, Section 6.1 versus the Operations Manual, Appendix I (Section 4.1).

Added language in Section 6.1 to clarify that all AEs reported from the time of study drug 
administration until 30 days after discontinuation of study drug administration will be 
collected.

Rationale:  To remove reporting guidance for AEs associated with the underlying disease under 
investigation in the Protocol, Section 6.1 because this is no longer valid protocol language.

Deleted all language related to the following:  disease progression and the underlying 
disease under investigation including symptoms that the investigator assesses as specific to 
disease progression should not be reported as an AE unless it results in a serious outcome.

Rationale:  To include laboratory monitoring for TLS for any increase in venetoclax dose.

Updated Section 6.2 to include TLS laboratory monitoring for the optional increase of 
venetoclax to 600 mg at Week 8 or thereafter.

Rationale:  To clarify and standardize the recommendations for the management of treatment-
emergent infections and anti-infective prophylaxis requirements.

Updated Section 6.2 to include guidelines for the management of infections and to require 
anti-infective prophylaxis for all subjects with absolute neutrophil count (ANC) of < 500/μL.

Rationale:  To clarify the dose interruption and modification language for venetoclax and 
ibrutinib in Section 6.2.

Updated Section 6.2 to include that the TA MD should be consulted if venetoclax dose 
interruption is > 4 weeks.

Updated Section 6.2 to align ibrutinib dose modification guidelines with Appendix F.

Rationale:  To add when the interim, primary, and final analyses will take place in the Protocol, 
Section 7.1.

Added an interim efficacy analysis that will be performed when Stage 1 subjects have 
completed the Week 24 disease assessments.

Added a primary efficacy analysis that will be performed for Stage 1 and Stage 2 subjects 
after their completion of the Week 24 disease assessments.
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
Added a final analysis will be performed when all subjects have discontinued the study or 
have completed protocol defined follow-up time.

Rationale:  To define terms used in Table 6, Section 7.2.

Added the following definition to the footnotes for critical value:  "Critical value" is the 
threshold beyond which the null hypothesis is rejected (i.e., claiming efficacy).

Added the following definition to the footnotes for p:  probability of achieving a response 
(CR, CRi, or PR).

Added the following definition to the footnotes for power:  1-β = 80%.

Added the following definition to the footnotes for significance level:  10% (2-sided).

Rationale:  To add further description of the statistical analyses for efficacy and safety in
Section 7.4 and Section 7.5.

Added clarification to the primary efficacy endpoint (Section 7.4).

Added the endpoints to be analyzed for the secondary efficacy analysis (Section 7.4) and the 
safety analysis (Section 7.5).

Added a description of the time-to-event endpoints that will be analyzed using Kaplan-Meier 
methodology (Section 7.4).

Removed the interim and final efficacy analyses which is now presented in the Protocol, 
Section 7.1.

Rationale:  To update the steering committee membership to include an internal specialist in 
infectious diseases and remove "optional" from the heading in Section 7.6.

Updated to include an internal specialist in infectious diseases who is not currently involved 
in the conduct or oversight of Study M18-803 as a member of the Steering Committee.

Rationale:  To update the required text for the ethical conduct of the study in the Protocol 
Section 8.2.

Updated the guidance for study procedures in the event a significant disaster/crisis occurs.

Rationale:  To update the protocol signatory list in  Appendix C.

Changed the statistical sciences signatory from 
 (Director) to 
 (Head 
of Statistics).

Rationale:  To update Appendix F to include any Grade 3 non-hematologic toxicities for 
venetoclax dose modifications and to include additional criteria for ibrutinib dose modifications.

Updated Appendix F to include Grade 3 or 4 non-hematologic toxicities for recommended 
venetoclax dose modifications.

Added "Grade 3 or higher neutropenia with infection or fever" to the list of potentially drug-
related toxicities that would result in a recommended dose modification of ibrutinib.

Removed the time criteria of "after 7 days" for the potentially drug-related toxicity of 
ANC < 500/µL that would result in a recommended dose modification of ibrutinib.
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Rationale:  To add monthly pregnancy testing during the treatment period and until the end of 
the relevant systemic exposure.

Updated the Protocol, Appendix G (Schedule of Activities) to include monthly urine 
pregnancy tests during the treatment period until the 30-day follow-up visit.

Updated the Operation Manual, Appendix I (Section 2) to reflect the changes made in the 
Protocol, Schedule of Activities.

Updated the Operation Manual, Appendix I (Section 3.12) to update the urine pregnancy 
language as follows:  "A urine pregnancy test will be performed for all female subjects of 
childbearing potential on Day –1 and every 4 weeks until 30 days after the last dose of 
venetoclax or 90 days after the last dose of ibrutinib, whichever the latest, as indicated in 
Section 2.1."

Updated the Operations Manual, Appendix I (Section 3.12, Table 1, footnote [b]) to align 
with the additional pregnancy tests required post-screening:  "Performed at screening and 
as indicated in Section 2.1."

Rationale:  To add lymph node and spleen measurements during the physical examination and 
an optional pretreatment bone marrow assessment.

Updated the Protocol, Appendix G (Schedule of Activities) to include physical examination 
(or ultrasound) procedure for lymph node and spleen measurements.

Updated the Protocol, Appendix G (Schedule of Activities) to include an optional 
pretreatment bone marrow assessment per standard-of-care prior to the first dose of study 
drug.

Updated the Operation Manual, Appendix I (Section 2) to reflect the changes made in the 
Protocol, Schedule of Activities.

Updated the Operation Manual, Appendix I (Section 3.7) to include that spleen and lymph 
node measurements will be performed during the physical examination or via ultrasound as 
part of the clinical response assessment.

Rationale:  To add TLS monitoring for all venetoclax dose-escalation.

Updated the Protocol, Appendix G (Schedule of Activities) to include TLS monitoring if
escalation of venetoclax to 600 mg at Week 8 or thereafter occurs.

Updated the Operation Manual, Appendix I (Section 2) to reflect the changes made in the 
Protocol, Schedule of Activities.

Rationale:  To add post-treatment follow-up visits for any subject who has not experienced PD 
at the time of permanent discontinuation of venetoclax and ibrutinib and to add and unlimited 
survival calls.

Updated the Protocol, Appendix G (Schedule of Activities) to include post-treatment 
follow-up visits.

Updated the Protocol, Appendix G (Schedule of Activities) to remove the time restriction of 
2 years for survival follow-up calls.
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Updated the Operation Manual, Appendix I (Section 2) to reflect the changes made in the 
Protocol, Schedule of Activities.

Updated the Operation Manual, Appendix I (Section 2) to clarify the criteria for subjects who 
may be contacted for survival every 6 months by telephone.

Updated the Operation Manual, Appendix I (Section 3.11) to include a description and 
timing of the post-treatment follow-up visits and removed the 2-year time limit for survival 
follow-up telephone calls.

Updated the Operation Manual, Appendix I (Section 3.17 [Table 5]) to include post-
treatment follow-up visits.

Rationale:  To clarify the visit days in the Schedule of Activities and to modify the visit windows.

Added Day 1 to the Weeks ≥4 visits in the Protocol, Appendix G (Schedule of Activities).

Removed the visit windows on Weeks 4 and 8, Day 1.

Changed the visit window from –7 days to ± 3 days for Weeks ≥ 12, Day 1.

Added a ± 7-day window for the CT scan and bone marrow biopsy sample.

Updated the Operation Manual, Appendix I (Section 2) to reflect the changes made in the 
Protocol, Schedule of Activities.

Rationale:  To delete any mention of end-of-study at the Final visit to avoid confusion.

Updated the Protocol, Appendix G (Schedule of Activities) to remove end-of-study from the 
Final visit.

Updated the Operation Manual, Appendix I (Section 2 and Section 3.17 [Table 5]) to clarify 
that the final visit will occur at the end of study treatment.

Rationale:  To delete the blood sample for clinical response because clinical response laboratory 
tests are already included in the standard hematology tests.

Deleted the row for "blood sample for clinical response" in the Protocol, Appendix G
(Schedule of Activities).

Updated the Operation Manual, Appendix I (Section 2) to reflect the changes made in the 
Protocol, Schedule of Activities.

Rationale:  To update the timing of the dispensing of study drug in the Operations Manual, 
Appendix I (Section 2).

Changed the timing of the dispensing of venetoclax and ibrutinib from "Day –3, Day –2, or 
Day –1" to "within 3 days of the first dose of study drug (Day –1)."

Rationale:  To clarify the timing of the TLS laboratory samples in the Operations Manual, 
Appendix I (Section 2 and Section 3.12).

Updated the timing of the of the TLS laboratory samples during ramp-up of venetoclax as 
follows:  "TLS monitoring will occur predose (full chemistry panel is required) and at 4, 8, 12, 
and 24 hours postdose (TLS chemistry panel is required) after each dose escalation of 
venetoclax (including escalation to 600 mg at Week 8 or thereafter).  For the 24-hour 
sample, a window of –1 hour is allowed.  If the predose sample coincides with the 24-hour 
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
postdose sample, then the predose sample may be used for both the predose and 24-hour 
analyses."

Rationale:  To update the criteria for signing the informed consent in the Operations Manual 
(Appendix I) because a legally authorized representative is not allowed to sign according to 
German Drug Act.

Updated Section 3.1 to add that the informed consent statement will be reviewed, signed, 
and dated by the subject or their legally authorized representative (if permitted per local 
regulations).

Rationale:  To update the Operations Manual (Appendix I) to include SARS-CoV-2 testing.

Updated Section 3.12, Table 1 to add SARS-CoV-2 testing at screening to the list of clinical 
laboratory tests (other tests).

Rationale:  To clarify that subjects who have a positive hepatitis B serology should be monitored 
and managed following local medical standards to reduce risk of hepatitis B reactivation.

Added the following text to the Operation Manual, Appendix I (Section 3.12):  "All subjects 
enrolled will be followed with clinical laboratory testing at scheduled time points 
throughout the study.  If a subject experiences a sign or symptom that may be suggestive of 
hepatitis B reactivation and/or a laboratory abnormality suggestive of potential hepatitis B 
reactivation (e.g., elevated aminotransferases), the investigator should pursue further work-
up per clinical practice guidelines/standards.  If a subject has positive hepatitis B serology, 
the subject should be monitored and managed following local medical standard to reduce 
risk of hepatitis B reactivation."

Rationale:  To delete baseline criteria for subjects who receive intravenous hydration prior to 
first dose of study drug and to clarify that tumor burden is only defined by 2 factors in the 
Operations Manual (Appendix I).

Deleted the following criteria from Section 3.12:  "The baseline value will be the last 
laboratory value before the subject receives intravenous hydration for TLS prophylaxis 
within 72 hours."

Updated Section 3.12 to clarify that tumor burden will be determined by CT scans and ALC 
levels.

Rationale:  To update the disease assessment criteria using the response evaluation criteria in 
lymphoma (RECIL)-based T-PLL consensus criteria and to clarify that disease assessment will 
continue after last dose of study drug in Appendix I.

Updated Section 3.13 to indicate that disease assessment will be performed using the RECIL-
based T-PLL consensus criteria assessment schedule.

Updated Table 2 and Table 3 to add additional information and criteria for the clinical 
response and the confirmatory response, respectively, using the RECIL-based T-PLL 
consensus criteria (Section 3.14).

Updated Section 3.14 to clarify that "clinical response will be assessed by laboratory tests 
and physical examination (or ultrasound) using the T-PLL consensus criteria."
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Updated Section 3.14 the instruction for any subject who has not experienced PD at time of 
discontinuation of study drug as follows:  "Disease assessment will continue to be 
performed after the last dose of study drug until disease progression for any subject who 
has not experienced progressive disease (PD) at the time of permanent discontinuation of 
venetoclax and ibrutinib."

Updated Reference 1 with RECIL-based T-PLL consensus criteria for disease assessment.

Rationale:  To clarify the method for taking blood draws for pharmacokinetic (PK) samples in the 
Operations Manual, Appendix I (Section 3.16).

Added that PK blood draws will be collected "by venipuncture."

Rationale:  To include information on COVID-19-related re-evaluation of the benefit and risk to 
subjects participating in the study.

Added information on the re-evaluation of the benefit and risk to subjects in Section 2.2.

Rationale:  To add eligibility criteria to exclude subjects who tested positive for SARS-CoV-2 
infection from participating in the study.

Updated eligibility criteria (Criterion #20) in Section 5.1 to exclude subjects positive for 
SARS-CoV-2 infection.

Rationale:  To add instructions for necessary protocol modifications in the event of a COVID-19-
related temporary study drug interruption.

Added instructions to refer to the Operations Manual for acceptable protocol deviations in 
Section 5.5.

Rationale:  To include instructions on COVID-19-related study drug pickup and DTP shipment.

Added instructions to refer to the Operations Manual for DTP shipment in the event that 
subjects are unable to pick up study drug onsite due to COVID-19 in Section 5.7.

Rationale:  To include a statement that AbbVie will modify the study protocol as needed due to 
a COVID-19-related state of emergency.

Added a statement in Section 8.2 noting that AbbVie will modify the study protocol as 
necessary due to the pandemic, referring to the Operations Manual in Appendix I for 
additional details.

Rationale:  To note that remote monitoring of subjects may be employed as needed during a 
COVID-19-related state of emergency.

Added a statement in Section 9 that remote monitoring may be employed as needed.

Rationale:  To include information on COVID-19-related allowed protocol modifications.

Added a reference to the Operations Manual for allowed modifications in Appendix I.

Rationale:  To provide details on completing study activities/procedures in a COVID-19-related 
state of emergency.

Updated Appendix I – Operations Manual updated to include details on how to perform 
specific activities/procedures that may be impacted by a COVID-19 state-of-emergency.
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STUDY M18-803  |  Version 3.0  |  EudraCT 2018-002179-17
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX I.
OPERATIONS MANUAL
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p. 2 of 41
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical Contact
, MD
Assistant Medical Director
AbbVie
Alte Steinhausenstrasse 14
CH-6330 Cham, Switzerland
EMERGENCY 24-hour Number:  
+1 (973) 784-6402
Mobile:
Email:
Safety Concerns
Oncology Safety Team
AbbVie
Dept. R48S, Bldg. AP30
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 (847) 935-2609
Email:
SafetyManagement_Oncology@abbvie.com
SAE Reporting 
outside of RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 938-0660
Protocol 
Deviations
Study Project Manager I
AbbVie
10 rue d'Arcueil
94528 Rungis, France
OR
Study Management Associate II
AbbVie
1 North Waukegan Road, 
North Chicago, IL 60064
Phone:
Email:
OR
Phone:
Email:
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
15
3
STUDY PROCEDURES
18
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
18
3.2
MEDICAL HISTORY
18
3.3
DRUG AND ALCOHOL SCREEN
19
3.4
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS
19
3.5
ADVERSE EVENT ASSESSMENT
19
3.6
CONCOMITANT MEDICATION
19
3.7
PHYSICAL EXAMINATION AND ULTRASOUND
20
3.8
HEIGHT AND WEIGHT
20
3.9
VITAL SIGNS
20
3.10
12-LEAD ELECTROCARDIOGRAM
21
3.11
POST-TREATMENT FOLLOW-UP AND SURVIVAL VISITS
21
3.12
CLINICAL LABORATORY TESTS
22
3.13
COMPUTED TOMOGRAPHY SCAN
25
3.14
DISEASE ASSESSMENT
26
3.15
BONE MARROW ASPIRATE AND BIOPSY
29
3.16
PHARMACOKINETIC SAMPLING
29
3.17
OPTIONAL BIOMARKER AND EXPLORATORY RESEARCH SAMPLING
30
3.18
DISPENSE STUDY DRUG
32
3.19
SUBJECT WITHDRAWAL FROM STUDY
34
4
SAFETY MANUAL
34
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
34
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
35
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
35
5
COUNTRY-SPECIFIC REQUIREMENTS
37
5.1
SUSAR REPORTING
37
6
STUDY DRUG
37
6.1
TREATMENTS ADMINISTERED
37
6.2
PACKAGING AND LABELING
37
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
38
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
38
7
REFERENCES
38
LIST OF TABLES
TABLE 1.
CLINICAL LABORATORY TESTS
23
TABLE 2.
CLINICAL RESPONSE CRITERIA (BASED ON PHYSICAL EXAMINATION/ULTRASOUND AND 
LABORATORY TESTS)
27
TABLE 3.
CONFIRMATORY RESPONSE CRITERIA (BASED ON CT AND BONE MARROW ASSESSMENTS)
28
TABLE 4.
PHARMACOKINETIC SAMPLING TIMES
30
TABLE 5.
SAMPLING TIMES FOR OPTIONAL BIOMARKERS
32
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
39
APPENDIX B.
SAMPLE LIST OF PROHIBITED AND CAUTIONARY MEDICATIONS
41
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to the coronavirus disease – 2019 (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 on how to proceed.
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall treatment period activity schedule.
Activities are grouped by category (interview, examination, etc.).  Further information about each 
activity is provided in Section 3.
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 for the Weeks ≥4 
visits:

The Weeks ≥4 visits and/or activities may be performed by phone/virtually.

During a virtual visit, if the clinical response assessment is suggestive of a CR/CRi, the 
computed tomography (CT) scan and/or bone marrow biopsy will need to be done onsite as 
soon as possible to confirm the clinical response.

If an activity is missed during a virtual visit, perform the activity at the earliest feasible 
opportunity.

Laboratory draws must be obtained within 24 hours or as soon as possible from the 
scheduled visit and may be performed by a local clinic/hospital/laboratory.  All procedures 
performed at local facilities must be performed by appropriately qualified personnel.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3 STUDY PROCEDURES
3.1 Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject and answer 
all questions regarding this study.  Prior to any study-related screening procedures being performed on 
the subject or any medications being discontinued by the subject in order to participate in this study, 
the informed consent statement will be reviewed, signed, and dated by the subject or their legally 
authorized representative (if permitted per local regulations), the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of the signed 
informed consent will be given to the subject and the original will be placed in the subject's medical 
record.  An entry must also be made in the subject's dated source documents to confirm that informed 
consent was obtained before any study-related procedures and that the subject received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
Samples for optional biomarker analyses will only be collected if the subject has voluntarily signed and 
dated a separate written consent form for biomarker testing that has been approved by an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) after the nature of the testing has been 
explained and the subject has had an opportunity to ask questions.  The separate written consent may 
be part of the main consent form.  If the subject does not consent to the biomarker testing, the subject's 
participation in the study will not be impacted.
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.
3.2 Medical History
A complete medical history including demographics, history of tobacco, alcohol, and drug use will be 
taken at screening.  The subject's medical history will be updated before the first dose of study drug 
(Day –1).  This updated medical history will serve as the baseline for clinical assessment.  A detailed 
oncology history will also be collected including:  histology, date of diagnosis of T-cell prolymphocytic 
leukemia (T-PLL), any surgical procedures, and treatments administered (including dates and type of 
modality).
On Day –1, any additional medical history observed after signing of the informed consent but before 
initial study drug administration and not considered related to study-required procedures will be 
recorded in the subject's medical history.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.3 Drug and Alcohol Screen
Subjects should have no history of clinically significant (per investigator's judgment) drug or alcohol 
abuse within the last 6 months.
3.4 Eastern Cooperative Oncology Group Performance Status
For all subjects, the Eastern Cooperative Oncology Group (ECOG) performance status will be performed 
as outlined in Section 2.
ECOG performance status will be assessed as follows:
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead
3.5 Adverse Event Assessment
Please refer to Section 4.
3.6 Concomitant Medication
If a subject reports taking any over-the-counter or prescription medications, vitamins, and/or herbal 
supplements or if administration of any medication becomes necessary beginning with the screening 
visit through 30 days after last dose of study drug, the name of the medication, dosage information 
including dose, route, and frequency, dates of administration including start and end dates, and reason 
for use must be recorded on the appropriate electronic Case Report Form (eCRF).
Subjects should receive full supportive care during study participation, including transfusion of blood 
products, fluid and electrolyte replacement, and antibiotics when appropriate.  Subjects who use oral 
contraceptives, hormone-replacement therapy, or other maintenance therapy should continue their 
use.
General guidelines regarding prohibited and cautionary concomitant medications and dietary 
restrictions are provided in Protocol Section 5.1, Section 5.3, and Section 5.4.  Co-administration of 
venetoclax and ibrutinib with a strong cytochrome P450 (CYP)3A inhibitor is prohibited during ibrutinib 
initiation and venetoclax dose ramp-up (refer to the Protocol Section 5.3).  Although cautionary, use of a 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
strong CYP3A inhibitor (after dose ramp-up), moderate CYP3A inhibitors, and strong or moderate CYP3A 
inducers are allowed if no appropriate therapeutic alternative exists (refer to the Protocol Section 5.4).  
Dose reductions of venetoclax and ibrutinib are required with concomitant administration of a strong or 
moderate CYP3A inhibitor (refer to the Protocol Section 5.4).  Alternative treatments with less CYP3A 
induction or inhibition should be considered.
A sample list of prohibited medications and cautionary medications that may interact with study drug is 
provided in Appendix B.  It is not possible to produce a complete list of medications that fall into these 
categories; if in question, please refer to the appropriate product label.
For guidance regarding medications for management of TLS and neutropenia, refer to the Protocol 
Section 6.2.
The AbbVie Therapeutic Area Medical Director (TA MD) identified in Section 1 should be contacted if 
there are any questions regarding concomitant or prior therapy(ies).
3.7 Physical Examination and Ultrasound
A complete physical examination will be performed at screening and a sign- and symptom-directed 
physical examination for all other scheduled visits as specified in Section 2.  The physical examination 
performed at screening will serve as the baseline physical examination for the entire study.  Any 
significant physical examination findings after the first dose will be recorded as adverse events (AEs).  All 
findings, whether related to an AE or part of each subject's medical history, will be captured on the 
appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
Additionally, spleen and lymph node measurements will be performed during the physical examination 
or via ultrasound as part of the clinical response assessment at screening and for the scheduled visits as 
specified in Section 2.
3.8 Height and Weight
Height will be measured at the screening visit only.  Body weight will be measured at scheduled visits as 
specified in Section 2.1.  The subject should wear lightweight clothing and no shoes during weighing.
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, height and weight measurements may be performed by the subject or caregiver as 
needed.
3.9 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at visits as specified in Section 2.1.  In addition, vital signs will be measured as clinically 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
indicated.  Blood pressure and pulse rate should be measured after the subject has been sitting for at 
least 3 minutes.
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, vital signs may be obtained by the subject or caregiver as needed.
3.10 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at screening and if clinically indicated.  The ECG 
should be performed prior to blood collection.
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:

Normal ECG

Abnormal ECG – not clinically significant

Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event this may not be performed due to study modifications related to the COVID-19 pandemic, 
perform the 12-lead ECG at the next earliest feasible visit or arrange to have an alternative acceptable 
local facility perform the ECG for the subject.
3.11 Post-Treatment Follow-Up and Survival Visits
Subjects who discontinue study drug but have not experienced progressive disease (PD) will return for 
post-treatment follow-up visits.  The post-treatment follow-up visits will follow the same schedule as the 
visit schedule (i.e., Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, and every 12 weeks 
thereafter).  Subjects will return for post-treatment follow-up visits until study completion starting from 
study drug discontinuation until documented PD or other post-treatment therapies (including stem cell 
transplantation) are received.  Follow-up hematology and disease response assessment data will be 
collected.
Survival information (i.e., the date and cause of death) will be collected via telephone calls at 6-month 
intervals or as needed to allow for more frequent survival analyses.
All subjects will be followed for survival information (i.e., date and cause of death, all poststudy
anticancer treatment including stem cell transplantation, reasons for poststudy anticancer treatment,
regimens, dates of initiation and completion, etc.) unless the subject requests to be withdrawn from the 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
study survival follow-up; this request must be documented in the subject's medical record and signed by 
the investigator.  If the subject withdraws from study follow-up, the study staff may use a public 
information source (such as county records) to obtain information about survival status only, as 
appropriate per local regulations.
3.12 Clinical Laboratory Tests
The blood samples for serum chemistry tests will be collected as specified in Section 2.  The baseline 
laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.  Required tests are 
listed in Table 1.
Local laboratories will be utilized to process and provide results for clinical laboratory tests allowing for 
immediate subject medical management.  The principal investigator or subinvestigator will review, 
initial, and date all laboratory results after receipt from the local laboratory.  Local laboratory values will 
be entered by the site directly onto the appropriate eCRF and laboratory normal ranges and certification 
for the laboratory that is used will be provided to the AbbVie clinical team if the result is clinically 
significant (i.e., necessitating an immediate treatment or treatment modification).
For chemistry laboratory tests performed for TLS prophylaxis and monitoring, refer to Table 1.
The baseline laboratory tests will be reviewed for eligibility before study drug administration as specified 
in Section 2.1.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:

repeat the test to verify the out-of-range value;

follow the out-of-range value to a satisfactory clinical resolution; or

discontinue the subject from the study or require the subject to receive treatment.
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Table 1.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit
Hemoglobin
Red blood cell count
White blood cell count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Blood urea nitrogen
Creatinine
Total bilirubin
Albumin
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acida
Total protein
Glucose
Bicarbonate
Creatinine clearance (Cockcroft-
Gault calculation)
Lactate dehydrogenase
Serum β2 microglobulin
Urine and serumb qualitative 
pregnancy testing
human chorionic 
gonadotropinc,d
Follicle-stimulating hormoneb,c,e
Anti-HIV antibodyb
Viral serologiesb,f
hepatitis B surface antigen or 
hepatitis B core antibody
HCV antibody (and RNA if HCV 
antibody is positive)
T-cell lymphotropic virus, type 1g
SARS-CoV-2b
Coagulation Panelb
TLS Chemistry Panel
Prothrombin time (PT)
AND/OR
International normalized ratio 
(INR)
AND/OR
Activated partial thromboplastin 
time (aPTT)
Creatinine
Potassium
Calcium
Inorganic phosphorus
Lactate dehydrogenase
Uric acida
CoV = coronavirus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; RNA = ribonucleic acid; SARS = severe acute 
respiratory syndrome; TLS = tumor lysis syndrome
a.
At room temperature, rasburicase causes enzymatic degradation of the uric acid in blood/plasma/serum samples 
potentially resulting in spuriously low plasma uric acid assay readings.  The following special sample handling procedure 
must be followed to avoid ex vivo uric acid degradation.  Uric acid must be analyzed in plasma.  Blood must be collected 
into prechilled tubes containing heparin anticoagulant.  Immediately immerse plasma samples for uric acid measurement 
in an ice water bath.  Plasma samples must be prepared by centrifugation in a precooled centrifuge (4°C).  Finally, the 
plasma must be maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
b.
Performed at screening and as clinically indicated in Section 2.1.
c.
Females only.
d.
Pregnancy testing is not required for females of nonchildbearing potential.
e.
If needed to determine postmenopausal status.
f.
Monitoring for hepatitis reactivation should be performed per local clinical standards.
g.
Performed at screening in endemic countries only.
Serum Pregnancy Test
A pregnant or breastfeeding female will not be eligible for participation or continuation in this study.
Pregnancy testing should not be performed for postmenopausal women.  Determination of 
postmenopausal status will be made during the screening period based on the subject's history.
A qualitative serum pregnancy test will be performed at screening for all women of childbearing 
potential.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
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The serum pregnancy test will be sent to and performed by the local laboratory.  If the serum pregnancy 
test is positive the subject is considered a screen failure.  If the serum pregnancy test is borderline, it 
should be repeated ≥ 3 days later to determine eligibility.
If the repeat serum pregnancy test is:

positive, the subject is considered a screen failure;

negative, the subject can be enrolled into the trial;

still borderline will be considered documentation of continued lack of a positive result, the 
subject can be enrolled into the study (unless prohibited per local requirements) in the absence 
of clinical suspicion of pregnancy and other pathological causes of borderline results.
Urine Pregnancy Test
A urine pregnancy test will be performed for all female subjects of childbearing potential on Day –1 and 
every 4 weeks until 30 days after the last dose of venetoclax or 90 days after the last dose of ibrutinib, 
whichever the latest, as indicated in Section 2.1.  Unless a woman is suspected to have become 
pregnant, additional pregnancy testing during the clinical trial is not necessary; however, additional 
urine pregnancy tests can be done at any visit, as needed.
If the urine pregnancy test (which is performed at the site) is negative, begin or continue dosing.  If urine 
pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects 
must discontinue from the study.
Viral Serology
Samples will be collected to identify hepatitis B virus (hepatitis B surface antigen or hepatitis B core 
antibody) and hepatitis C virus (HCV) (HCV antibody and ribonucleic acid [RNA] if HCV antibody is 
positive) as listed in Table 1.
All subjects enrolled will be followed with clinical laboratory testing at scheduled time points throughout 
the study.  If a subject experiences a sign or symptom that may be suggestive of hepatitis B reactivation 
and/or a laboratory abnormality suggestive of potential hepatitis B reactivation (e.g., elevated 
aminotransferases), the investigator should pursue further work-up per clinical practice 
guidelines/standards.  If a subject has positive hepatitis B serology, the subject should be monitored and 
managed following local medical standard to reduce risk of hepatitis B reactivation.
Viral serology samples are to be collected and sent to the local laboratory for testing.
Human Immunodeficiency Virus
Samples will be collected to identify human immunodeficiency virus (HIV) (anti-HIV antibody) at 
screening, unless prohibited by local regulations, as listed in Table 1.  The investigator must discuss any 
local reporting requirements to local health agencies with the subject.  The site will report confirmed 
positive results to their health agency per local regulations, if necessary.
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Coagulation
Prothrombin time (PT) and activated partial thromboplastin time (aPTT)/international normalized ratio 
(INR) samples will be collected at screening and on study when clinically indicated.
TLS Risk Assessment and Monitoring
TLS risk assessment will occur at screening as indicated in Section 2.1.
TLS risk assessment will be defined by tumor burden, renal function, and other factors (refer to the 
Protocol Section 6.2).  Tumor burden will be determined by computed tomography (CT) scans and 
absolute lymphocyte count (ALC) levels.
Laboratory monitoring for TLS will occur during the ramp-up period and once reaching the designated 
dose during Week 1 as indicated in Section 2.1; TLS monitoring will occur predose (full chemistry panel is 
required) and at 4, 8, 12, and 24 hours postdose (TLS chemistry panel is required) after each dose 
escalation of venetoclax (including escalation to 600 mg at Week 8 or thereafter).  For the 24-hour 
sample, a window of –1 hour is allowed.  If the predose sample coincides with the 24-hour postdose 
sample, then the predose sample may be used for both the predose and 24-hour analyses.
Laboratory monitoring for TLS will occur during the ramp-up period and once reaching the designated 
dose during Week 1 as indicated in Section 2.1; TLS monitoring will occur 4, 8, 12, and 24 hours after 
each dose escalation.  For chemistry laboratory tests performed for TLS monitoring, refer to Table 1.
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 laboratory, hospital, or other facility.  Local laboratory results 
should be obtained along with reference ranges and kept within the subjects' source documentation.  
Local laboratory 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 
laboratory results.  The subject should be scheduled for laboratory draws as soon as feasible within 
3 days from the scheduled visit.
3.13 Computed Tomography Scan
A CT scan with contrast (or magnetic resonance imaging [MRI]) will be performed at screening, at 
Week 24 visit, and at any time during the study as listed in Section 2.1 to confirm a clinical response 
(complete remission [CR]/complete remission with incomplete blood count recovery [CRi]).  A CT scan 
will be accepted for screening purposes if previously performed within 35 days before the first dose of 
study drug.  Otherwise, a CT scan must be performed within the screening window (28 days) for all 
subjects.
Contrast-enhanced CT scans including neck, chest, abdomen, and pelvis will be performed for disease 
assessment using the response evaluation criteria in lymphoma (RECIL)-based T-PLL consensus criteria 
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assessment schedule1 (as outlined in Table 3) as reported by a local radiologist.  A contrast-enhanced 
MRI of the neck, chest, abdomen and pelvis with a noncontrast CT scan of the chest may be used for 
subjects with whom a contrast CT is medically contraindicated (i.e., subjects with a severe allergy to CT 
contrast agents or subjects with impaired renal clearance).  Whichever method is used at screening, this 
method should be consistently used throughout the duration of the study.
Any CT scan (or MRI) done throughout the study should be captured on the appropriate eCRF.
3.14 Disease Assessment
All measurable disease must be documented at screening (baseline) before the first dose of study drug 
for all subjects based on the analysis of clinical laboratory tests (hematology), physical examination, and 
contrast-enhanced CT scan of involved neck, chest, abdomen, and pelvis (or MRI, if CT scan is medically 
contraindicated).
For all subjects, clinical response (laboratory and physical examination assessments) will be assessed by 
the investigator during Weeks 4, 8, 12, 16, 24, 36 and every 12 weeks thereafter, and at the final visit.  
Note:  disease assessments may be performed approximately 7 days before the scheduled visit.  The 
clinical response will be assessed by laboratory tests and physical examination (or ultrasound) using the 
T-PLL consensus criteria1 (as outlined in Table 2).
If clinical response is suggestive of a CR/CRi, a CT scan with contrast (or MRI) should be done for a 
confirmatory assessment as outlined in Section 3.13.
If a CT scan indicates a CR/CRi, a bone marrow aspirate and biopsy will be required as soon as possible 
to confirm the clinical response.  For subjects who opt-in for correlative biomarker analyses, a portion of 
the bone marrow aspirate should be split for the optional biomarker collections listed in Section 3.17.
To meet the CR criteria, the CT scan and bone marrow are both required to be negative.  Some subjects 
fulfill all the criteria for a CR but have a persistent anemia, thrombocytopenia, or neutropenia 
apparently unrelated to T-PLL, but related to drug toxicity.  These subjects will be assessed with a 
response of CRi.
Disease assessment will continue to be performed after the last dose of study drug until disease 
progression for any subject who has not experienced PD at the time of permanent discontinuation of 
venetoclax and ibrutinib.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
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factors influencing response to treatment, scientific questions related to T-PLL, and/or in the 
development of new therapies and diagnostic tests.  The analyses are exploratory in nature, may be 
conducted in non-Good Laboratory Practice (GLP) laboratories, and the results from correlative studies 
may not be included with the clinical study report.
Cells isolated from the peripheral blood/bone marrow may be analyzed to assess specific genetic 
mutations and/or to track the tumor cells to determine the presence of minimal residual disease (MRD).  
Additionally, the expression levels (RNA or protein) of molecules may be assessed (e.g., molecules 
involved in the apoptosis machinery) and evaluated for correlations with efficacy.
All biomarker samples should be labeled and shipped as outlined in the study-specific laboratory 
manual.  AbbVie (or people or companies working with AbbVie) will store these samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be retained while 
research on venetoclax or drugs of this class, or this disease and related conditions continues, but for no 
longer than 20 years after study completion or per local requirement.
Biomarker Collections
Peripheral blood samples will be collected at screening (Day –28 through Day –2), Week 1 (Days –1, 1, 
and 6), Weeks 4, 8, 12, 16, 24, 36, and every 12 weeks thereafter, and at the final visit (see Table 5).
A cheek swab will be collected at screening (refer to Table 5).
Specific instructions for preparation and storage of biomarker specimens will be provided by AbbVie or 
its designee.
Biomarker sampling times are listed in Table 5.
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Table 5.
Sampling Times for Optional Biomarkers
Parameter
Samplea,b
(volume)
Day –28 
through 
Day –2
Week 1 
(Day –1, 
Day 1, Day 6)
Weeks 4, 8, 
12, 16, and 24
Week 36 and 
Every 12 Weeks 
Thereafter
Final 
Visitc
and 
PTFUd
MRD 
(molecular)
Peripheral 
blood (6 mL)
X
X
X
X
Tumor profiling
Peripheral 
blood (8 mL)
X
Tumor ex vivo 
sensitivity
Peripheral 
blood (8 mL)
X
Xe
MRD 
(molecular)
Bone marrow 
(2 mL)
Any time during the study (i.e., confirmation 
of a clinical response).
Tumor profiling
Bone marrow 
(1 mL)
Any time during the study (i.e., confirmation 
of a clinical response).
Tumor ex vivo 
sensitivity
Bone marrow 
(3 mL)
Any time during the study (i.e., confirmation 
of a clinical response).
Germline 
control for 
tumor profiling
Cheek swab
X
MRD = minimal residual disease; PTFU = post-treatment follow-up
a.
Peripheral blood for biomarker assessment will be taken at indicated time points and any other time during the study with 
a bone marrow sample for confirmation of a clinical response.
b.
If a computed tomography scan indicates a CR/CRi, a bone marrow sample will be taken during the study to confirm the 
clinical response; the sample will be split for analyses of disease and biomarker assessments provided informed consent 
was given for correlative studies.
c.
The final visit will occur at the end of the study or the end of study treatment.
d.
Post-treatment follow-up visits will be conducted until documented progressive disease or other post-treatment therapies 
(including stem cell transplantation) are received.  The post-treatment follow-up visits will follow the same schedule as the 
visit schedule (i.e., Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, and every 12 weeks thereafter).
e.
Predose and 6 hours post-venetoclax dose.
Note:
Participation in the biomarker/correlative studies is optional.  If informed consent is provided, then peripheral blood 
and/or bone marrow biospecimens will be collected at the indicated time points.
3.18 Dispense Study Drug
Study drug will be dispensed to subjects as specified in Section 2.1.  The first dose of study drug will be 
administered after all other baseline (Day –1) procedures are completed.  At the visits specified in 
Section 2.1, the site personnel will review and retain a copy of the dosing diary, review returned study 
drug kits, and empty study drug packaging to verify compliance.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M18-803 Version 3.0
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Dosing Instructions and Dosing Card
Subjects will be provided with self-administration dosing instructions and a study drug dosing diary at 
visits noted in Section 2.1.  Subjects will be instructed to record the exact date, time (to the nearest 
minute), and number of tablets and capsules of the last 2 doses of venetoclax and ibrutinib, respectively, 
taken prior to each scheduled PK sample collection as noted in Section 2.1.  Subjects should be 
instructed to complete the dosing diary at the time the doses are taken.  Site personnel will collect the 
completed dosing diaries from all subjects at the visits indicated in Section 2.1.  The information from 
the study drug dosing diary will be recorded in the eCRF.  In the event that the dosing diary is not 
available, the site may obtain dosing information via subject interview and record this information in the 
eCRF and the subject's source documents.
To facilitate proper dosing of study drug before PK blood samples are taken, the following procedures 
should be performed:

Site personnel will contact the subject approximately 2 days prior to the scheduled visit date to 
review the importance of properly documenting dosing information (specifically, the date and 
time of the last 2 doses prior to the visit where the PK sample is drawn) onto the dosing diary 
and remind the subject to bring the completed dosing diary to the scheduled study visit.  The 
date and time of the contact will be recorded in the subject's source documents.

The completed dosing diary will be collected by site personnel on the day of the visit and kept as 
a source record of dosage administration times documented in the eCRF.
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.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.
3.19 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition.  Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether or not the subject decides to continue 
participation in the study.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All protocol-related serious adverse events (SAEs) as well as protocol-related nonserious AEs 
(e.g., infection at liver biopsy site done during screening) will be collected from the time the subject 
signed the study-specific informed consent until study drug administration.  From the time of study drug 
administration until 30 days after discontinuation of study treatment, all AEs and SAEs will be collected 
whether solicited or spontaneously reported by the subject.  After 30 days following completion of study 
treatment and throughout the post-treatment period, all spontaneously reported SAEs will be collected 
(nonserious AEs will not be collected).  All AEs should be followed until resolution, return to baseline, or 
determined to be stable per the investigator.
AE = adverse event; SAE = serious adverse event
a.
30 Days after the last dose of venetoclax or ibrutinib.
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If a subject has a confirmed or suspected COVID-19 infection and study drug was interrupted, the 
investigator should contact the sponsor emergency medical contact (TA MD) listed above before 
reintroducing study drug.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the investigational medicinal product in accordance 
with global and local guidelines.  Appendix A of the venetoclax Investigator Brochure2 and Section 6 of 
the ibrutinib Investigator Brochure3 will serve as the Reference Safety Information (RSI).  The RSI in 
effect at the start of a DSUR reporting period serves as the RSI during the reporting period.  For follow-
up reports, the RSI in place at the time of occurrence of the 'suspected' serious adverse reaction will be 
used to assess expectedness.
6 STUDY DRUG
6.1 Treatments Administered
Venetoclax will be dispensed in the form of 10-, 50- and 100-mg film-coated tablets (refer to the 
Protocol Section 5.7) at the visits listed in Section 2.1.  Each dose of venetoclax will be taken with 
approximately 240 mL of water.  Subjects will be trained to self-administer venetoclax orally once daily 
(QD) within 30 minutes after the completion of breakfast or the subject's first meal of the day.  On 
days the subject is given ibrutinib, venetoclax and ibrutinib should be administered approximately at the 
same time.
Ibrutinib will be self-administered orally QD in the form of 140-mg hard capsules (refer to the Protocol 
Section 5.7) at the visits listed in Section 2.1.  The capsules should be swallowed whole with water and 
should not be opened, broken, or chewed.  On Day -1, ibrutinib should be taken with 240 mL of water 
and within 30 minutes after the completion of breakfast or the subject's first meal of the day.
Study drug must not be dispensed without contacting the interactive response technology (IRT) system.  
Study drug may only be dispensed to subjects enrolled in the study through the IRT system.  At the end 
of the treatment period or at the final visit, the site will contact the IRT system to provide visit date 
information and study drug return information for each kit.
For additional details on dispensing study drug, especially in the event DTP is necessary, see 
Section 3.18.
6.2 Packaging and Labeling
Ibrutinib will be supplied in bottles and venetoclax will be supplied in bottles or blister cards to 
accommodate the study design.  Each kit will be labeled as required per country requirements.  The 
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labels must remain affixed to the kits.  All blank spaces should be completed by site staff prior to 
dispensing to subject.
Storage and Disposition of Study Drug
Venetoclax and ibrutinib must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  The 
investigational products are for investigational use only and are to be used only within the context of 
this study.  The study drugs supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use, destroyed on site, or 
returned to AbbVie, as appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This is a nonrandomized, open-label, single arm study.  All eligible subjects will receive the venetoclax 
400 mg (target dose) QD and ibrutinib 420 mg QD for up to 2 years.
At the screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.  For subjects who rescreen, the screening number 
assigned by the IRT at the initial screening visit should be used.
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system (refer to the 
Protocol Section 5.8).
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in the study protocol, Section 4.2.
All tablets of venetoclax will be dosed together QD.  All capsules of ibrutinib will be dosed together QD.  
All subjects should take all doses of study drugs as detailed in Section 6.1.
Venetoclax and ibrutinib will be administered at the designated study visits as specified in Section 2.1.
7 REFERENCES
1.
Staber PB, Herling M, Bellido M, et al.  Consensus criteria for diagnosis, staging, and treatment 
response assessment of T-cell prolymphocytic leukemia.  Blood.  2019;134(14):1132-43.
2.
AbbVie.  Venetoclax (ABT-199) Investigator's Brochure.  Current version.
3.
Amgen.  Imbruvica (ibrutinib) Investigator's Brochure.  Current version.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
ALC
absolute lymphocyte count
aPTT
activated partial thromboplastin time
CLL
chronic lymphocytic leukemia
COVID-19
coronavirus disease – 2019
CR
complete remission
CRi
complete remission with incomplete bone marrow recovery
CT
computed tomography
CYP
cytochrome P450
DTP
direct-to-patient
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
GLP
Good Laboratory Practice
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MRI
magnetic resonance imaging
OATP
organic anion-transporting polypeptide
PD
progressive disease
PK
pharmacokinetic(s)
P-gp
P-glycoprotein
PT
prothrombin time
QD
once daily
RECIST
response evaluation criteria in solid tumors
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RNA
ribonucleic acid
SAE
serious adverse event
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TLS
tumor lysis syndrome
T-PLL
T-cell prolymphocytic leukemia
Page 101 of 104
 



SAP_001.pdf: 
Venetoclax (ABT-199)
M18-803 – Statistical Analysis Plan
Version 2.0 – 18 Jul 2019
1
1.0
Title page
Statistical Analysis Plan
Study M18-803
A Prospective, Open-Label, Single-Arm, Phase 2, 
Multicenter Study Evaluating the Efficacy of 
Venetoclax Plus Ibrutinib in Subjects with T-Cell 
Prolymphocytic Leukemia
Date:  18 Jul 2019
Version 2.0
 
NCT03873493


Venetoclax (ABT-199)
M18-803 – Statistical Analysis Plan
Version 2.0 – 18 Jul 2019
2
2.0
Table of Contents
1.0
Title page ..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................4
4.0
Study Background...................................................................4
4.1
Objective....................................................................................................4
4.2
Study Design..............................................................................................5
4.2.1
Study Design and Design Diagram............................................................5
4.2.2
Variables Used for Stratification at Randomization ..................................6
4.3
Endpoint.....................................................................................................6
4.3.1
Primary Efficacy Endpoint ........................................................................6
4.3.2
Secondary Efficacy Endpoints...................................................................7
4.3.3
Safety Endpoint..........................................................................................7
4.3.4
Pharmacological Endpoint.........................................................................7
4.4
Sample Size Justification ...........................................................................7
4.5
Interim Analysis.........................................................................................8
4.6
Multiplicity Testing Procedures for Type-I Error Control ........................8
4.7
Missing Data Imputation............................................................................9
5.0
Analysis Populations and Important Subgroups .................9
5.1
Analysis Population ...................................................................................9
5.2
Subgroup....................................................................................................9
6.0
Efficacy Analyses.....................................................................9
6.1
General Considerations..............................................................................9
6.2
Primary Efficacy Analysis .......................................................................10
6.3
Secondary Efficacy Analysis ...................................................................10
6.4
Sensitivity Analysis: ................................................................................12
6.5
Efficacy Subgroup Analyses....................................................................12
7.0
Safety Analyses ......................................................................13
7.1
General Considerations............................................................................13
7.2
Analysis of Adverse Events.....................................................................13
7.3
Analysis of Laboratory Data....................................................................15
7.4
Analysis of Vital Signs ............................................................................17
 


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7.5
Analysis of ECG Parameters....................................................................18
8.0
Summary of Changes ............................................................19
8.1
Summary of Changes Between the Previous Version and the 
Current Version........................................................................................19
8.2
Summary of Changes in Previous Version ..............................................19
9.0
Appendix.................................................................................20
10.0
References...............................................................................21
List of Tables
Table 1.
Sample Size Using Optimal Adaptive 2-Stage Design..............................8
Table 2.
Selected Adverse Events..........................................................................15
Table 3.
Laboratory Criteria for TLS.....................................................................16
Table 4.
Criteria for Potentially Clinically Significant Vital Signs – Vital 
Signs Variables ........................................................................................18
 


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3.0
Introduction
This statistical analysis plan (SAP) describes the full (safety and efficacy) statistical 
analyses for venetoclax (ABT-199) Protocol M18-803 dated May 02, 2019.  It will 
provide details of statistical methods to be followed for the study.  More details in terms 
of analysis conventions to guide the statistical programming work will be provided in SPP 
(Statistical Programming Plan).
Unless noted otherwise, all analyses will be performed using SAS® version 9.3 or later 
(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.
SAP will not be updated in case of future administrative or minor amendments to the 
protocol unless the changes have any impact on the analysis of the study data. 
4.0
Study Background 
4.1
Objective
Primary Objective:
The primary objective of this study is to evaluate the efficacy of venetoclax in 
combination with ibrutinib in subjects with relapsed or refractory (R/R) T-cell 
prolymphocytic leukemia (T-PLL).  Efficacy will be measured by overall response rate 
(ORR) in R/R subjects.
Secondary Objectives:
●
Secondary efficacy analyses will be performed by the following endpoints:
○
Progression-free survival (PFS)
○
Duration of response (DoR)
○
Time-to-progression (TTP)
○
Event-free survival (EFS)
○
Overall survival (OS)
 


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●
To assess safety and tolerability in subjects with T-PLL treated with 
venetoclax in combination with ibrutinib.  Safety will be assessed by
○
Adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram variables and clinical laboratory testing.
●
To assess the ability of the subset of transplant-naïve subjects to proceed to 
further autologous/allogeneic stem cell transplantation, will be measured by
○
Total number of eligible subjects reaching autologous or allogeneic 
transplantation.
Exploratory Objective:
The exploratory objective is to identify biomarker/genetically-defined subgroups 
regarding response and survival.  Types of biomarkers may include nucleic acids, 
proteins, lipids, or metabolites.  These biomarker assessments may be used to assess and 
generate prognostic, predictive, pharmacodynamics, or surrogate biomarker signatures.  
Analyses of biomarkers may be done as an external study report and will not be a part of 
the clinical study report.
4.2
Study Design 
This is a Phase 2, open-label, single-arm, multicenter study designed to evaluate the 
efficacy and safety of venetoclax when administered with ibrutinib, in subjects with R/R 
T-PLL.
4.2.1
Study Design and Design Diagram
Approximately 37 subjects with T-PLL will be enrolled based on the optimal adaptive 
2-stage design.1
●
Stage 1:  Enroll 14 subjects with R/R T-PLL and move to Stage 2 if 4 or more 
responders as follows:
○
response assessment for Stage 1 will be performed on a continued basis 
until all 14 subjects have enrolled into Stage 1 and have completed the 
Week 24 disease assessment.
 


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●
Stage 2:  Enroll up to an additional 23 subjects with T-PLL in Stage 2 (up to a 
total of 37 subjects for Stage 1 and Stage 2) depending on the number of R/R 
T-PLL responders at Stage 1.
Interim analysis will occur after all 14 R/R T-PLL subjects enrolled in Stage 1 of the 
study have completed their Week 24 disease assessments.  The study will stop for futility 
if the number of responders at Stage 1 is ≤ 3.  If 4 or more subjects respond prior to 
enrolling all 14 subjects in Stage 1, enrollment will not pause between stages.  The 
maximal sample size will be 37 subjects if number of responders at Stage 1 is 4.  If there 
are 7 or more responders out of 14 subjects in Stage 1, 17 R/R subjects will be enrolled in 
Stage 2 (see Section 4.4 for details).
Subjects who are treatment-naïve (i.e., unsuitable for alemtuzumab or alemtuzumab 
treatment is unavailable) may be enrolled during Stage 2 of the study.  The number of 
treatment-naïve subjects to be enrolled will depend on the required sample size for the 
R/R subjects in Stage 2 which is based on the number of responders from Stage 1 and 
considering the maximum of 37 subjects in total to be enrolled in the study.
It is to be noted that the opening of Stage 2 will be determined based on R/R T-PLL 
subjects, enrolled in Stage 1.
Safety will be continuously assessed and dose adjustment or tumor lysis syndrome (TLS) 
risk management will be considered for both venetoclax and ibrutinib.
4.2.2
Variables Used for Stratification at Randomization
This is an open-label, single-arm study.  There is no randomization for this study.  All 
subjects will be assigned a unique identification number by the IRT at the screening visit.
4.3
Endpoint
4.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint in this study is ORR in R/R T-PLL subjects.
 


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4.3.2
Secondary Efficacy Endpoints
The following are the secondary efficacy endpoints in the study:  PFS, DoR, TTP, EFS, 
OS, total number of eligible subjects (transplant-naïve subjects who have achieved CR) 
reaching autologous or allogeneic transplantation.
4.3.3
Safety Endpoint
Safety data of the study will be assessed through adverse events reporting, including 
adverse event (AE) monitoring, laboratory values, physical examinations, vital signs, and 
ECG assessment.  Other protocol-specified tests that are deemed critical to the safety will 
also be analyzed.  (See Section 7.0 for analysis details).
4.3.4
Pharmacological Endpoint
Plasma samples for venetoclax and ibrutinib will be collected to determine trough 
concentrations (Ctrough).  A nonlinear mixed effects modeling approach may be used to 
estimate the population central values and the individual values of venetoclax parameters 
such as clearance.
4.4
Sample Size Justification
Approximately 37 subjects with T-PLL will be enrolled based on the optimal adaptive 
2-stage design.  In Stage 1, 14 subjects with R/R T-PLL will be enrolled and the number 
of responders in Stage 1 will be used to determine the number of subjects to be enrolled 
for Stage 2.
Sample size calculation is done based on clinical hypothesis (using optimal adaptive 
2-Stage design considering 1-sided significance level of 0.05 and power of 80%):  In 
subjects with R/R T-PLL, the treatment with venetoclax plus ibrutinib will be considered
promising if the combination yields a best ORR of 40% or greater, which is the alternative 
hypothesis.  A poor rate is defined as best ORR of 20% or less, which is the null 
hypothesis. 
 


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The details of the design are presented in the Table 1 below:
Table 1.
Sample Size Using Optimal Adaptive 2-Stage Design
H0:  p ≤ 20% versus H1:  p ≥ 40%
1-β = 80%, 1-sided test, significance level = 0.05
Comments
n1 = 14
S
n2(S)
n(S)
r(S)
≤ 3
0
14
0
Stop for futility after Stage 1
4
23
37
11
R/R versus treatment-naïve
Stage 2 sample size distribution
will vary depending on the
number of responses from Stage 1
5
20
34
10
6
20
34
10
≥ 7a
17
31
9
n1:  Sample size for Stage 1.
S:  Number of responses from Stage 1.
n2(S):  Sample size for Stage 2.
n(S):  Total sample size of Stage 1 and Stage 2.
r(S):  Critical value of total number of responses from Stage 1 and Stage 2 to demonstrate efficacy.
a.
The Stage 2 portion will still be conducted to evaluate efficacy in additional subjects even if the Stage 1 portion 
shows significant efficacy.
4.5
Interim Analysis
A planned interim analysis for efficacy will be conducted after 14 subjects with R/R 
T-PLL enrolled in Stage 1 have completed their Week 24 disease assessments.  The study 
will stop for futility if the number of responders at Stage 1 is ≤ 3.  If 4 or more subjects 
respond prior to enrolling all 14 subjects in Stage 1, enrollment will not pause between 
stages.  The maximal sample size will be 37 subjects if number of responders at Stage 1 is 
4.  If there are 7 or more responders out of 14 subjects in Stage 1, 17 R/R subjects will be 
enrolled in Stage 2.
4.6
Multiplicity Testing Procedures for Type-I Error Control
This is a Phase II hypothesis generating study; therefore, no multiplicity adjustment will 
be applied for the statistical analysis.
 


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4.7
Missing Data Imputation
The missing data imputation will not be performed for this study.  For time-to-event 
endpoints, censoring will be defined for missing data.
5.0
Analysis Populations and Important Subgroups
5.1
Analysis Population 
The Full Analysis Set (FAS) includes all R/R subjects who received at least 1 dose of 
study drug (either venetoclax or ibrutinib).  The FAS will be used for all safety, 
pharmacokinetic, efficacy and baseline analyses.
The analyses for the treatment naïve subjects may be conducted for similar efficacy and 
safety endpoints, if needed, otherwise data will be listed.
5.2
Subgroup
Subgroups will be based on demographic and baseline characteristics (age, gender, race, 
and high risk T-PLL factors such as tumor burden at screening; and other genetical 
abnormalities.).  Full details will be provided in the SPP.
6.0
Efficacy Analyses
6.1
General Considerations
Efficacy will be evaluated based on clinical response criteria adapted from the response 
assessment criteria proposed by the international T-PLL study group. Confirmation of 
responses CR and CRi will be performed based on modified RECIL 2017, which is based 
on CT imaging (or MRI).
After the data collection is completed and reviewed for completeness and all data 
management quality assurance (QA) and quality control (QC) procedures are performed, 
the clinical database data will be extracted for documentation and statistical analyses of 
 


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the efficacy and safety data for the pre-specified cutoff date.  Other considerations will be 
detailed in the SPP, if needed.
6.2
Primary Efficacy Analysis 
Overall Response Rate (ORR) (CR + CRi + PR) will be defined as the proportion of 
subjects who achieved best response of confirmed complete remission (CR), confirmed 
complete remission with incomplete marrow recovery (CRi), or partial remission (PR) 
based on the clinical response criteria proposed by the international T-PLL study group as 
assessed by investigator up through the Week 24 disease assessment (including early 
study termination).  The corresponding 95% confidence interval for the proportion using 
Binomial distribution will be constructed.  Subjects who have not achieved any 
component of ORR will be considered as nonresponders in the calculation of ORR at the 
time of analysis.  An interim efficacy analysis will be performed when 14 subjects in 
Stage 1 have completed the Week 24 disease assessments.  The final primary efficacy 
analysis will be performed for Stage 1 and Stage 2 subjects after their completion of at 
least Week 24 disease assessments.
6.3
Secondary Efficacy Analysis 
The secondary efficacy analysis will be performed for the following endpoints:
Progression-Free Survival (PFS) will be defined as the number of days from the date of 
first dose of study drug to the date of earliest disease progression or death.  All events of 
disease progression will be included regardless whether the event occurred while the 
subject was taking the study drug or had previously discontinued the study drug.  If the 
subject has not experienced disease progression or death, the subject's data will be 
censored at the date of last disease assessment.  Data for subjects who receive non-
protocol specified T-PLL therapy (i.e., excluding stem cell transplantation for eligible CR 
subjects) prior to disease progression will be censored at the last disease assessment prior 
to receiving non-protocol therapy.  Data for subjects without any disease assessments 
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will be analyzed by Kaplan-Meier methodology.  Median PFS will be calculated and 
95% confidence interval for median PFS will be presented.
Duration of Response (DoR) will be defined as the number of days from the date of first 
response (CR, CRi, or PR) to the earliest date that progressive disease (PD) or death.  For 
subjects who have a PR before CR, or CRi, in subsequent visits, the DoR is computed 
from the earliest PR.  If the subject has not experienced disease progression or death, the 
subject's data will be censored at the date of last disease assessment.  For subjects who do 
not have subsequent disease assessment after their first response, the subject data will be 
censored at the first response.  For subjects who never experience response, the subject's 
data will not be included in the analysis.  DoR will be analyzed by Kaplan-Meier 
methodology.  Median DoR will be calculated and the corresponding 95% confidence 
interval will be presented.
Time- to- Progression (TTP) will be defined as the number of days from the date of first 
dose of study drug to the date of earliest disease progression.  All events of disease 
progression will be included regardless whether the event occurred while the subject was 
taking the study drug or had previously discontinued the study drug.  If the subject has not 
experienced disease progression, the subject's data will be censored at the date of last 
disease assessment.  Data for subjects who receive non-protocol specified T-PLL therapy 
(i.e., excluding stem cell transplantation for eligible CR subjects) prior to disease 
progression will be censored at the last disease assessment prior to receiving non-protocol 
therapy.  Data for subjects without any disease assessments performed after the baseline 
visit will be censored at the time of dosing plus 1 day.  TTP will be analyzed by Kaplan-
Meier methodology.  Median TTP will be calculated and 95% confidence interval for 
median TTP will be presented.
Event-free survival (EFS) will be defined as the number of days from the date of first dose 
of study drug to the date of earliest disease progression, death, or start of a new anti-T-
PLL therapy.  If the specified event (disease progression, death, start of a new anti-T-PLL 
treatment) does not occur, patients will be censored at the date of last disease assessment 
or date of stem cell transplantation.  Data for subjects without any disease assessments 
 


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performed after the baseline visit will be censored at the date of first dose plus 1 day.  EFS 
will be analyzed by Kaplan-Meier methodology.  EFS will be calculated and 
95% confidence interval for median EFS will be presented.
Overall Survival (OS) will be defined as the number of days from the date of first dose of 
study drug to the date of death due to any cause.  All events of death will be included, 
regardless of whether the event occurred while the subject was still taking any study drug, 
or after the subject discontinued study drug.  For subjects who did not die, their data will 
be censored at the date of last study visit or the last known date to be alive, whichever is 
later.  OS will be analyzed by Kaplan-Meier methodology.  Median OS will be calculated 
and 95% confidence interval for median OS will be presented.  Data from subjects that are 
alive at the time of analysis will be censored at the date of last study visit or the last 
known date the subject was alive, whichever is later.
6.4
Sensitivity Analysis:
For all the time-to-event endpoints (PFS, TTP, DoR, EFS and OS) a sensitivity analysis 
may be performed for the CR subjects who have undergone stem-cell transplantation by 
censoring them at their last disease assessment prior to the transplant.
Transplant-naïve subjects to proceed to further autologous/allogeneic stem cell 
transplantation will be measured by the - proportion of eligible subjects reaching 
autologous or allogeneic transplantation.  The eligible subjects are defined as the 
transplant-naïve subjects who have achieved CR and then proceed to further 
autologous/allogeneic stem cell transplantation.
6.5
Efficacy Subgroup Analyses
The subgroup analyses will be performed for ORR (overall response rate) for the full 
analysis set defined in Section 5.2.  Subgroup analyses will be detailed in the SPP.
 


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7.0
Safety Analyses
7.1
General Considerations
A safety analysis will be performed for all subjects who take at least one dose of study 
drug (venetoclax or ibrutinib).  Safety evaluations include but are not limited to capturing 
adverse events (AEs), clinical laboratory testing (hematology and chemistry), vital sign 
measurements, electrocardiogram (ECG) testing (as clinically indicated), as a measure of
safety and tolerability for the entire study duration.  Throughout the study, AEs will be 
evaluated by the NCI-CTCAE v. 5.0 and summarized.  Laboratory test results, vital signs 
and ECG assessments will be analyzed as appropriate. 
7.2
Analysis of Adverse Events
All summaries/analyses involving AEs will include treatment-emergent adverse events 
(TEAE) only, unless otherwise specified.  TEAE are defined as any event with onset after 
the first dose of study drug and no more than 30 days after the last dose of study drug.  
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the AE start time are collected 
and the AE start time is prior to the study drug start time.  If an incomplete onset date was 
collected for an AE, the AE will be assumed to be treatment-emergent unless there is 
evidence that confirms that the AE was not treatment-emergent (e.g., the AE end date was 
prior to the date of the first dose of study drug).
For summaries of AEs related (reasonable possibility) to study drug, at each level of 
summation (overall, SOC, and PT) each subject is counted only once.  If a subject has an 
AE with unknown relationship, then the subject will be counted in the relationship 
category of "unknown," even if the subject has another occurrence of the same event with 
a relationship of "no reasonable possibility" present.  The only exception is if the subject 
has another occurrence of the same AE with the relationship of "reasonable possibility."  
In this case, the subject will be counted under the reasonable possibility category.
 


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Adverse event data will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) according to the MedDRA coding 
dictionary version 21.0 or higher.
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following adverse event summaries:
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE version 5.0) 
grade 3, 4, or 5 adverse events.
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE version 5.0) 
grade 3 or 4 adverse event.
●
Adverse events broken down by NCI toxicity grade (Severity).
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event leading to discontinuation of 
venetoclax.
●
Any treatment-emergent adverse event leading to venetoclax interruption.
●
Any treatment-emergent adverse event leading to venetoclax reduction.
●
Any treatment-emergent adverse event that is rated at least possibly related to 
venetoclax by the investigator (Reasonable Possibility Related)
●
Any treatment-emergent adverse event leading to discontinuation of ibrutinib.
●
Any treatment-emergent adverse event leading to ibrutinib interruption.
●
Any treatment-emergent adverse event leading to ibrutinib reduction.
●
Any treatment-emergent adverse event that is rated at least possibly related to 
ibrutinib by the investigator (Reasonable Possibility Related)
●
Any treatment-emergent adverse event leading to death.
In addition, selected adverse events will be summarized.  The list of such events is shown 
in Table 2.
 


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Table 2.
Selected Adverse Events
Risk
Search Criteria
Tumor Lysis Syndrome (TLS) 
SMQ – "Tumour lysis syndrome" (Narrow-scope)
Neutropenia
PT terms – "Neutropenia," "Neutrophil count decreased," 
"Febrile neutropenia," "Agranulocytosis," "Neutropenic 
infection," and "Neutropenic sepsis"
Serious Infection, Including 
Opportunistic Infections
SAEs in the SOC of "Infections and Infestations"
Second Primary Malignancy 
SMQ – "Malignant tumours" (Narrow) and 
"Myelodysplastic syndromes" (Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count 
decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count 
decreased"
Drug Induced Liver Injury (DILI)
SMQ – "Drug related hepatic disorders – comprehensive 
search"
Medication Error
SMQ – "Medication error" (broad)
Hemorrhage
SMQ – "Haemorrhagic disorders" (narrow)
7.3
Analysis of Laboratory Data
Definition of Baseline
The baseline value for laboratory variables will be defined as:
●
For subject hospitalized for TLS prophylaxis, the baseline value will be the lab 
value taken at hospital admission prior to the subject receiving hydration for 
TLS prophylaxis (the day prior to the first dose of study drug).
●
For subject not hospitalized for TLS prophylaxis, the baseline value will be the 
0 hour lab draw prior to the first dose of study drug on Day 1.
 


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Laboratory Assessments for TLS
To determine if a subject's laboratory values qualify for TLS, the Howard criteria will be 
assessed.  The Howard definition for laboratory TLS requires ≥ 2 of the metabolic 
abnormalities specified in Table 3 post-baseline and within 24 hours of each other.
Table 3.
Laboratory Criteria for TLS
Element
Value
Uric Acid
> 476 μmol/L (8 mg/dL)
Potassium
> 6.0 mmol/L (6 mEq/L)
Inorganic Phosphorus
> 1.5 mmol/L (4.5 mg/dL)
Calcium
< 1.75 mmol/L (7 mg/dL)
The following summaries of laboratory criteria will be provided:
●
Number and percentage of subjects meeting the definition of laboratory TLS 
(at least two values meeting the criteria in Table 4, occurring within 24 hours 
of each other). 
●
Listing of all values for these four analytes for each subject meeting the 
definition of laboratory TLS at least once during treatment.
Assessment of Drug-Induced Liver Injury
The number and percentage of subjects in each treatment group who have at least 
one observed post-baseline value meeting the following criteria will be tabulated:  
ALT > 3 × ULN, AST > 3 × ULN, AST or ALT > 3 × ULN, total bilirubin value 
> 2 × ULN, ALT or AST > 3 × ULN and total bilirubin > 2 × ULN within 24 hours.  A 
listing of all observed ALT, AST, and total bilirubin values will be generated for subjects 
with an observed value meeting any of these criteria.
 


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Analysis of Shift from Baseline in Clinical Laboratory Data
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse 
Events (NCI CTCAE version 5.0), baseline and post-baseline laboratory observations 
(maximum and final) will be categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 
according to NCI CTCAE grade version 5.0.  For laboratory tests for which a normal 
range limit is one end of the grade 1 range then values that are either within the normal 
range or outside it in opposite direction will be classified as grade 0 values.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of study drug unless specified differently, 
and as the last post-baseline measurement collected no more than 30 days after the last 
dose of study drug.  The maximum NCI toxicity grade value is the value with highest NCI 
toxicity grade collected after the first dose of study drug and within 30 days following the 
last dose of study drug.  In cases where multiple values are collected on the same day, the 
maximum grade value will be selected as the value for that day.
For each variable, shift tables will be generated that cross tabulate the number of subjects 
with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 versus maximum or 
final observations of grade 0, grade 1, grade 2, grade 3, or grade 4.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected,
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
7.4
Analysis of Vital Signs 
For selected vital signs variables, a listing of all observations collected (at both scheduled 
and unscheduled visits) will be generated for subjects that had at least one post-baseline 
observation meeting pre-defined criteria for potentially clinically significant values.  The 
number and percentage of subjects who have at least one post-baseline observation 
 


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meeting the pre-defined criteria for potentially clinically significant values will be 
provided for each variable.
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 4:
Table 4.
Criteria for Potentially Clinically Significant Vital Signs – Vital 
Signs Variables
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart rate
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value < 36°C
High
Value ≥ 38.5°C
7.5
Analysis of ECG Parameters
Each ECG will be evaluated to determine if any findings outside normal physiological 
variation are clinically significant.
The categories for ECG readings are:
●
Normal ECG
●
Abnormal ECG – Not clinically significant (NCS)
●
Abnormal ECG – Clinically significant (CS)
●
Unable to evaluate
ECG test will be required only for the screening assessment (or if clinically indicated).  
Due to limited collection of the data, abnormal ECG values will be presented in a data 
listing.
 


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8.0
Summary of Changes
8.1
Summary of Changes Between the Previous Version and the 
Current Version 
●
Response criteria changed to clinical response criteria proposed by the 
international T-PLL study group as per protocol amendment 1.
●
nPR deleted as per protocol amendment 1.
●
SAP-s changed to SPP as per the new SAP process.
8.2
Summary of Changes in Previous Version
Version
Date
Summary
1.0
05 Nov 2018
Original version
2.0
17 Jul 2019
Amendment 1
 


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9.0
Appendix
List of Abbreviations
ABT-199
Study Drug Compound, "Venetoclax" GDC-0199
AE
Adverse Event
CR
Complete Remission
CRi
Complete remission with incomplete bone marrow recovery
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough concentrations
DoR
Duration of Response
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFS 
Event-Free Survival
IRT
Interactive Response Technology
MedDRA 
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NCS
Not Clinically Significant 
ORR
Overall Response Rate
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial Remission
PT
Preferred Term
QA
Quality Assurance 
QC
Quality Control 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
SPP
Statistical Programming Plan
TEAE
Treatment-emergent Adverse Events
T-PLL
T-cell prolymphocytic leukemia
TLS
Tumor Lysis Syndrome
 


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10.0
References 
1.
Shan G, Wilding GE, Hutson AD.  Optimal adaptive two-stage designs for early 
Phase II clinical trials.  Stat Med.  2016;35(8):1257-66.