Clinical trial NCT04477486
Conditions: Mantle Cell Lymphoma (MCL)
Keywords: MCL Venetoclax ABT-199 Ibrutinib Imbruvica
Sponsor: AbbVie
Start date: 2020-09-23; Completion date: 2025-05-28
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Mantle Cell Lymphoma (MCL) is a form of Non-Hodgkin Lymphoma (NHL - cancer of the lymphatic system in blood) where cells from outer edge of the lymph nodes, called mantle zone become cancerous. In Japan, MCL accounts for about 3% of all NHL cases. Symptoms of MCL may include enlarged lymph nodes, stomach pain, fever, night sweats, and weight loss. Currently, MCL is not curable with standard therapies. The purpose of this study is to evaluate the safety, efficacy, and effect of venetoclax in combination with ibrutinib on best overall response of complete response in participants with relapsed (return of disease) or refractory (not responding to treatment) (R/R) MCL.

Venetoclax is an investigational drug being developed for the treatment of MCL. Ibrutinib is a drug approved for the treatment of MCL. Participants will receive venetoclax (increasing doses) and ibrutinib (fixed dose) for approximately 104 weeks, followed by ibrutinib alone. Adult participants with R/R MCL will be enrolled. Around 12 participants will be enrolled in Japan.

Participants will receive oral venetoclax tablet and oral ibrutinib capsule for 104 weeks. After 104 weeks, participants will receive ibrutinib once daily until their disease progresses, or they cannot tolerate the medication, or until they do not want to participate in the study.

There may be a higher treatment burden for participants in this study compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, bone marrow biopsies, checking for side effects, and completing questionnaires.

Detailed description:
Safety and efficacy data through 09 February 2022 are included in the interim analysis.

Arms: arm 1: Participants will receive Ibrutinib Dose A + Venetoclax in various doses until a target dose is reached, for up to 104 weeks, followed by Ibrutinib monotherapy.
Interventions: intervention 1: Ibrutinib intervention 2: Venetoclax
Intervention descriptions: intervention 1: Capsule; Oral intervention 2: Tablet; Oral

Protocol documents:
Prot_000.pdf: 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO SUBJECTS
11
3
OBJECTIVES AND ENDPOINTS
12
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
12
3.2
PRIMARY ENDPOINT
13
3.3
SECONDARY EFFICACY ENDPOINTS
13
3.4
SAFETY ENDPOINTS
14
3.5
PHARMACOKINETIC ENDPOINTS
14
3.6
BIOMARKER RESEARCH ENDPOINTS
14
4
INVESTIGATIONAL PLAN
14
4.1
OVERALL STUDY DESIGN AND PLAN
14
4.2
DISCUSSION OF STUDY DESIGN
16
5
STUDY ACTIVITIES
17
5.1
ELIGIBILITY CRITERIA
17
5.2
CONTRACEPTION RECOMMENDATIONS
21
5.3
PROHIBITED/CAUTIONARY MEDICATIONS AND THERAPY
23
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
GUIDELINES FOR IBRUTINIB MANAGEMENT WITH SURGERIES OR PROCEDURES
25
5.6
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
25
5.7
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
26
5.8
SURVIVAL FOLLOW-UP
27
5.9
STUDY DRUG
27
5.10 DRUG ASSIGNMENT
28
5.11 PROTOCOL DEVIATIONS
28
5.12 INDEPENDENT SAFETY MONITOR
28
6
SAFETY CONSIDERATIONS
28
Page 2 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.1
COMPLAINTS AND ADVERSE EVENTS
28
6.2
TOXICITY MANAGEMENT
32
6.3
DOSE-LIMITING TOXICITY CRITERIA
38
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
40
7.1
STATISTICAL AND ANALYTICAL PLANS
40
7.2
DEFINITION FOR ANALYSIS POPULATIONS
40
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
42
7.4
STATISTICAL ANALYSES FOR SAFETY
42
7.5
INTERIM ANALYSIS
42
7.6
OVERALL TYPE I ERROR CONTROL
43
7.7
SAMPLE SIZE DETERMINATION
43
8
ETHICS
43
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
43
8.2
ETHICAL CONDUCT OF THE STUDY
43
8.3
SUBJECT CONFIDENTIALITY
44
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
44
10 DATA QUALITY ASSURANCE
44
11 COMPLETION OF THE STUDY
44
12 REFERENCES
44
LIST OF TABLES
TABLE 1.
MANAGEMENT OF POTENTIAL IBRUTINIB AND VENETOCLAX INTERACTIONS WITH CYP3A 
INHIBITORS
24
TABLE 2.
RECOMMENDED DOSE MODIFICATIONS FOR VENETOCLAX-RELATED TOXICITIES
33
TABLE 3.
DOSE MODIFICATION FOR TOXICITY DURING VENETOCLAX TREATMENT
34
TABLE 4.
IBRUTINIB DOSE MODIFICATIONS FOR TOXICITIES
36
TABLE 5.
IBRUTINIB DOSE MODIFICATIONS FOR CARDIAC FAILURE OR CARDIAC ARRHYTHMIAS
37
Page 3 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE 6.
IBRUTINIB DOSE REDUCTION LEVELS
37
TABLE 7.
CHILD-PUGH SCORE FOR SUBJECTS WITH LIVER IMPAIRMENT33,34
38
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMA
16
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
48
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
51
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
52
APPENDIX D.
REVISED CRITERIA FOR RESPONSE ASSESSMENT FOR MALIGNANT LYMPHOMA
53
APPENDIX E.
ACTIVITY SCHEDULE
56
APPENDIX F.
SAMPLE LIST OF CAUTIONARY MEDICATIONS
60
APPENDIX G.
HOWARD CRITERIA FOR LABORATORY AND CLINICAL TUMOR LYSIS SYNDROME
62
APPENDIX H.
RECOMMENDATIONS FOR INITIAL MANAGEMENT OF ELECTROLYTE ABNORMALITIES AND 
PREVENTION OF TUMOR LYSIS SYNDROME
63
APPENDIX I.
COVID-19-RELATED INSTRUCTIONS
67
APPENDIX J.
PROTOCOL SUMMARY OF CHANGES
73
APPENDIX K.
OPERATIONS MANUAL
74
Page 4 of 110
 




  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Secondary Efficacy Endpoints

IRC-assessed best overall response of CR or PR, according to 
the Revised Criteria for Response Assessment.

Investigator-assessed best overall response of CR, according 
to the Revised Criteria for Response Assessment.

Investigator-assessed best overall response of CR or PR, 
according to the Revised Criteria for Response Assessment.

Investigator-assessed DOR, defined for subjects who achieve 
a best overall response, as the time from the first occurrence 
of response to disease progression or death, whichever 
occurs first, according to the Revised Criteria for Response 
Assessment.

IRC-assessed DOR, defined for subjects who achieve a best 
overall response, as the time from the first occurrence of 
response to disease progression or death, whichever occurs 
first, according to the Revised Criteria for Response 
Assessment.

Undetectable MRD in subjects who achieve a best overall 
response of CR as assessed by investigator, according to the 
Revised Criteria for Response Assessment.

Undetectable MRD in subjects who achieve a best overall 
response of CR as assessed by the IRC, according to the 
Revised Criteria for Response Assessment.

Progression-free survival (PFS), defined as the time from the 
date of the first dose of any study drug (venetoclax or 
ibrutinib) to the date of investigator-assessed disease 
progression, using the Revised Response Criteria for 
Response Assessment, or death from any cause, whichever 
occurs first.

Overall Survival, defined as the time from the date of the first 
dose of any study drug (venetoclax or ibrutinib) to death 
from any cause.
Safety Endpoints
Safety and tolerability will be assessed by evaluating DLTs, adverse 
events, physical examinations, and changes in laboratory data 
(hematology, chemistry, and urinalysis) and vital signs for the entire 
study treatment duration.
Pharmacokinetic Endpoints
Values for the pharmacokinetic parameters of venetoclax and ibrutinib 
will be determined at steady state using noncompartmental methods.  
The maximum observed plasma concentration (Cmax), the time to Cmax
(peak time, Tmax), the area-under-the-plasma concentration-time curve 
(AUC) over the dosing interval (AUCtau) will be determined.  Intensive 
pharmacokinetic blood samples will be collected.
Biomarker Endpoints
Biospecimens (blood and bone marrow aspirate) will be collected at 
specified time points throughout the study to evaluate known and/or 
Page 6 of 110
 






  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 INTRODUCTION
2.1 Background and Rationale
Why This Study Is Being Conducted?
Disease Background
Mantle cell lymphoma (MCL) is a distinct, clinical-pathologic entity within the non-Hodgkin's lymphomas 
(NHL).  Initially termed "centrocytic lymphoma" in the Kiel Classification system,1 MCL has subsequently 
been shown to harbor the translocation t(11;14)(q13;q32), which results in constitutive overexpression 
of cyclin D1.2  These features are now considered requisite for the diagnosis of the disease.
Mantle cell lymphoma accounts for about 6 to 9% of all NHL cases in the Western world.  The annual 
incidence of MCL has increased during recent decades to 1 to 2/100,000.  In Japan, MCL accounts for 
about 3% of all NHL cases.  Mantle cell lymphoma occurs more frequently in older adults.3  Most 
patients with MCL are men (median age 65 years) who present with advanced stage disease 
(i.e., Stage III or IV), and most cases follow an aggressive clinical course.4  The typical presentation is with 
generalized lymphadenopathy, and extranodal involvement frequently occurs in the gastrointestinal (GI) 
tract, spleen, bone marrow, and liver; less common extranodal sites are skin, lungs, and breast or soft 
tissues.  Though the clinical course of MCL may be somewhat indolent at diagnosis, the course invariably 
becomes aggressive over time.  Unlike other NHLs, MCL is considered incurable with standard therapies 
and is associated with a poor prognosis and a relatively short median overall survival (OS).5  There is no 
curative therapy for MCL.  A few patients may achieve long-term, disease-free survival after allogeneic 
stem cell transplantation,6 but in general, the disease is characterized by a series of relapses with a 
median OS of 4 to 5 years.  A number of MCL prognostic variables have been identified, including the 
presence or absence of extranodal disease, age, lactate dehydrogenase levels, performance status, 
Mantle Cell Lymphoma International Prognostic Index (MIPI), and Ki-67 proliferative index.7  
Current Treatment Options
Current initial therapy for the treatment of MCL includes cyclophosphamide, doxorubicin, vincristine, 
and prednisone (CHOP), or hyperfractionated cyclophosphamide, vincristine, doxorubicin, and 
dexamethasone alternating with methotrexate and cytarabine (Hyper-CVAD), often in combination with 
rituximab (R-CHOP or R-Hyper CVAD).  In recent years, treatment with bendamustine and rituximab has 
gained increasing use following studies showing that this combination significantly prolongs progression-
free survival (PFS), while maintaining a favorable safety profile among patients with previously 
untreated MCL.8,9  For patients who relapse after initial therapy, chemoimmunotherapy treatment 
options involve the use of rituximab in combination with one or more of the following:  bendamustine, 
cladribine, fludarabine, cyclophosphamide, mitoxantrone, etoposide, and procarbazine.10,11  Also in 
Japan, the use of bendamustine, bortezomib, fludarabine, ibrutinib, and cladribine monotherapy, the 
use of rituximab or other antineoplastic drug combinations with the above drugs, and 
radioimmunotherapy (90 Y ibritumomab tiuxetan) monotherapy are recommended.  In cases of early 
relapses or in patients with refractory disease, newer targeted approaches should be strongly 
considered.  Three non-cytotoxic drugs, ibrutinib, bortezomib, and lenalidomide, are Food and Drug 
Administration (FDA)-approved for previously treated patients with MCL in the United States (US).  In 
the European Union, approved treatment in the relapsed and refractory (R/R) MCL setting was limited 
Page 9 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
to temsirolimus until the approval of ibrutinib in 2014.  In Japan, ibrutinib is approved for R/R MCL and 
bortezomib is approved for MCL.  Based on registration trials, the overall response rate (ORR) for these 
drugs are 87.5% (12.5% complete response [CR]) in the Japanese population with ibrutinib, 33% (8% CR) 
with bortezomib, 28% (8% CR) with lenalidomide, and 22% (2% CR) with temsirolimus, with a median 
PFS of 13.9, 6.5, 4, and 4.8 months, respectively.12  Despite the fact that results from ibrutinib showed 
marked improvement over temsirolimus,13 the median PFS of approximately 14 months underscores the 
need to improve further on the dismal outcome for relapsed MCL patients.  New treatment strategies 
are needed that may substantially improve outcomes for R/R MCL patients and may in the long-term 
obviate intensive chemotherapy and/or transplantation in younger MCL patients and chemotherapy in 
older patients with MCL.12
Several in vitro studies have shown ibrutinib and venetoclax to be an active combination.  In one study, 
MCL cell lines and leukemic patient cells were exposed to ibrutinib, venetoclax, and the combination for 
72 hours.  The combination substantially increased induction of apoptosis compared to each agent alone 
(combination:  23%, ibrutinib:  3.8%, venetoclax:  3.0%).14  A separate study using MCL cell lines 
confirmed the synergistic effect of ibrutinib and venetoclax on proliferation inhibition and apoptosis 
through perturbation of the BTK, AKT and B-cell lymphoma-2 (BCL2) pathways15 providing further 
mechanistic rationale for co-targeting of these two oncogenic pathways.
Supportive in vivo data is derived from a CCMCL1/NSG mouse model where the ibrutinib and venetoclax 
combination was tested.  The combination produced apoptosis of MCL tumor cells, which was 
associated with a down-regulation of SOX11 and PAX5.  Simultaneous down regulation of MCL1 via 
ibrutinib and targeting of BCL2 was hypothesized to contribute to the in vitro synergism and in vivo 
activity observed in this report.16
With respect to venetoclax monotherapy activity, in clinical Study M12-175, venetoclax was tested in 
28 subjects with R/R MCL at target doses of 200 to 1200 mg.  The ORR was found to be 75% with a CR 
rate of 21%.17  Based on these data and prior ibrutinib studies, the AIM study (ibrutinib and venetoclax 
in MCL) is evaluating the combination of ibrutinib at 560 mg and venetoclax at a target dose of 400 mg 
in subjects with R/R MCL.  This study is using a 4-week venetoclax ramp-up after 4 weeks of ibrutinib 
monotherapy.  The CR according to computed tomography (CT) scan at Week 16 was 42%.  The CR rate 
as assessed by positron emission tomography (PET) was 62% at Week 16.  Sixteen subjects with relapsed 
or refractory MCL18 were dosed and have completed the ramp-up with tumor lysis syndrome (TLS) 
events reported in 2 subjects with high tumor burden, leading to revision of the protocol venetoclax 
starting dose from 50 mg to 20 mg per day.  Subsequently, 8 additional subjects have been treated using 
the revised schedule with no cases of TLS encountered.19  These data suggest that the combination had 
an acceptable safety profile without unexpected toxicities and resulted in high rates of deep remission.  
In addition, the flow minimal residual disease- (MRD) negative and allele-specific oligonucleotide-
polymerase chain reaction (ASO-PCR) MRD-negative rates were 67% and 38%, respectively, and for the 
current analysis, the median duration of response (DOR) and time to progression (TTP) had not been 
reached and were estimated to be 74% and 60% at 30 months, respectively.  The median PFS was 
29 months (95% confidence interval [CI] of 13-negative estimates [NE]), and the median OS was 
32 months (95% CI of 27-NE).20
Two other studies evaluating the combination of ibrutinib and venetoclax (one of which will also explore 
the addition of anti-CD20 therapy to the doublet) in subjects with R/R MCL have started enrollment, 
though no toxicity or safety data have yet been reported.21,22  Based on the early data in the AIM study 
Page 10 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
of ibrutinib and venetoclax in patients with relapsed or refractory MCL23 showing a best CR rate of 71% 
with an acceptable safety profile, coupled with the durability of responses observed with ibrutinib 
monotherapy and venetoclax monotherapy in patients with relapsed or refractory MCL who achieved 
CR observed with each,17,24,25 the combination of ibrutinib and venetoclax is expected to induce deep 
and durable responses in patients with R/R MCL.
The ongoing SYMPATICO Study (ibrutinib and venetoclax in R/R MCL), which is the basis of 
Study M20-075, is evaluating the combination of ibrutinib at 560 mg and venetoclax at a target dose of 
400 mg in subjects with R/R MCL.  The study started with an open-label safety run-in period to evaluate 
the occurrence of TLS and dose-limiting toxicities (DLTs) with the concurrent administration of ibrutinib 
and venetoclax.  The safety run-in period of the study included 21 patients with R/R MCL, 15 patients at 
high-risk for TLS, and 6 patients at low risk for TLS.  One laboratory TLS event occurred in a patient at 
high-risk for TLS.  No clinical TLS events occurred.  No TLS event occurred in patients at low risk for TLS.  
Dose-limiting toxicities were observed in 3 patients at high-risk for TLS; Grade 4 neutropenia (n = 1), 
Grade 4 infection (n = 1), and Grade 3 atrial fibrillation plus grade 3 hypotension (n = 1).  No DLT event 
occurred in patients at low risk for TLS.  As pre-specified in the protocol, the combination dosing 
schedule of ibrutinib 560 mg + venetoclax 400 mg was recommended for both subjects at high and low 
risk for TLS, and the randomization part of the study is ongoing with the same schedule as the safety 
run-in period.  The CR rate was 48% in all patients, 67% in patients at low risk for TLS, and 40% in 
patients at high-risk for TLS, with a longer follow-up time for patients at low risk for TLS than high-risk 
for TLS (median follow-up, 14 versus 8 months).26
Study M20-075 will evaluate the safety and efficacy of the combination of venetoclax at a target dose of 
400 mg and ibrutinib at 560 mg in Japanese subjects with R/R MCL.
Clinical Hypothesis
The combination of venetoclax and ibrutinib can be safely administered and will result in high CRs in 
Japanese subjects that is similar to that observed in non-Japanese subjects.
2.2 Benefits and Risks to Subjects
Mantle cell lymphoma is considered incurable with standard therapies and is associated with a poor 
prognosis and a relatively short median OS.  New strategies are needed that may substantially improve 
outcomes for R/R MCL patients and may in the long-term obviate intensive chemotherapy and/or 
transplantation in younger MCL patients and chemotherapy in older patients with MCL.
The combination of venetoclax and ibrutinib is being evaluated in subjects with R/R MCL in 3 ongoing 
studies.  Early data from the AIM study suggest the combination has an acceptable safety profile without 
unexpected toxicities and results in high rates of deep remission.  Data from the safety run-in period of 
the SYMPATICO study evaluating the occurrence of TLS and DLTs support the same dosing schedule of 
ibrutinib 560 mg + venetoclax 400 mg in the ongoing randomization phase and initiation of this Phase 2 
study in Japanese subjects at both high and low risk of TLS with R/R MCL.
The benefit of potentially high rates of response and prolonged PFS are favorable when compared to a 
potentially increased rate of adverse events (AEs) that remains acceptable and is without unexpected 
toxicities for both venetoclax and ibrutinib.
Page 11 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Protocol instructions and information related to Coronavirus Disease - 2019 (COVID-19) are listed in 
Appendix I.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary Objective
1.
To evaluate the effect on best overall response of CR of the concurrent administration of 
venetoclax and ibrutinib in Japanese subjects with R/R MCL.
The hypothesis corresponding to the primary objective is to demonstrate superiority of venetoclax in 
combination with ibrutinib against a historical reference of 12.5% complete response rate (CRR) in the 
ibrutinib only Japanese study with R/R MCL.27
The estimand corresponding to the primary objective is:
Proportion of best overall response of CR as assessed by IRC, for subjects receiving venetoclax in 
combination with ibrutinib (with approximately 104 weeks on combination therapy, followed by 
ibrutinib monotherapy until disease progression [PD]), regardless of whether or not the subject is 
receiving study drugs as long as the subject's disease assessment occurs, and regardless of the use of 
other anti-MCL treatments, in the R/R MCL subjects. 
Secondary Objectives
1.
To evaluate the effect on best overall response of CR or partial response (PR), duration of 
response (DOR), MRD, PFS, and OS of the concurrent administration of venetoclax and ibrutinib
in Japanese subjects with R/R MCL.
2.
To evaluate the safety and tolerability of the concurrent administration of venetoclax and 
ibrutinib in Japanese subjects with R/R MCL.
3.
To evaluate the pharmacokinetics of venetoclax and ibrutinib in Japanese subjects with R/R 
MCL.
Hypotheses corresponding to the secondary objectives, are to achieve superior results with venetoclax 
in combination with ibrutinib (i.e., greater proportion of subjects achieving favorable outcomes or 
longer duration of positive benefits, etc).
The estimands corresponding to the secondary objectives are:

Proportion of subjects achieving:

Best overall response of CR or PR (as assessed by Independent Review Committee 
[IRC]/investigator) 

Best overall response of CR (as assessed by investigator)
Page 12 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Undetectable MRD (disease assessed by IRC/investigator) 
With venetoclax in combination with ibrutinib (with approximately 104 weeks on 
combination therapy, followed by ibrutinib monotherapy until PD), regardless of whether or 
not the subject is receiving study drugs as long as subject's disease assessment occurs, and 
regardless of the use of other anti-MCL treatments, in the R/R MCL subjects. 

The median survival time measured from subject's: 

Duration of response (as assessed by IRC/investigator)

PFS (as assessed by investigator)

OS 
with venetoclax in combination with ibrutinib (with approximately 104 weeks on 
combination therapy, followed by ibrutinib monotherapy until PD), regardless of whether or 
not the subject is receiving study drugs as long as the subject's disease assessment occurs, 
and regardless of the use of other anti-MCL treatments, in the R/R MCL subjects. 
3.2 Primary Endpoint
The primary endpoint is best overall response of CR according to the Revised Criteria for Response 
Assessment as assessed by the Independent Review Committee (IRC) (Appendix D).28
3.3 Secondary Efficacy Endpoints
The secondary endpoints are:

IRC-assessed best overall response of CR or PR, according to the Revised Criteria for Response 
Assessment (Appendix D).

Investigator-assessed best overall response of CR, according to the Revised Criteria for Response 
Assessment (Appendix D).

Investigator-assessed best overall response of CR or partial response (PR), according to the 
Revised Criteria for Response Assessment (Appendix D).

Investigator-assessed DOR, defined for subjects who achieve a best overall response, as the time 
from the first occurrence of response to disease progression or death, whichever occurs first, 
according to the Revised Criteria for Response Assessment (Appendix D).

IRC-assessed DOR, defined for subjects who achieve a best overall response, as the time from 
the first occurrence of response to disease progression or death, whichever occurs first, 
according to the Revised Criteria for Response Assessment (Appendix D).

Undetectable MRD in subjects who achieve a best overall response of CR as assessed by 
investigator, according to the Revised Criteria for Response Assessment (Appendix D).

Undetectable MRD in subjects who achieve a best overall response of CR as assessed by the IRC, 
according to the Revised Criteria for Response Assessment (Appendix D).
Page 13 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Progression-free survival, defined as the time from the date of the first dose of any study drug 
(venetoclax or ibrutinib) to the date of investigator-assessed disease progression, using the 
Revised Response Criteria for Response Assessment (Appendix D), or death from any cause, 
whichever occurs first.

Overall Survival, defined as the time from the date of the first dose of any study drug 
(venetoclax or ibrutinib) to death from any cause.
3.4 Safety Endpoints
Safety and tolerability will be assessed by evaluating DLTs, AEs, physical examinations, and changes in 
laboratory data (hematology, chemistry, and urinalysis) and vital signs for the entire study treatment 
duration.
3.5 Pharmacokinetic Endpoints
Values for the pharmacokinetic parameters of venetoclax and ibrutinib will be determined at steady 
state using noncompartmental methods.  The maximum observed plasma concentration (Cmax), the time 
to Cmax (peak time, Tmax), the area-under-the-plasma concentration-time curve (AUC) over the dosing 
interval (AUCtau) will be determined.  Intensive pharmacokinetic blood samples will be collected.
3.6 Biomarker Research Endpoints
Biospecimens (blood and bone marrow aspirate) will be collected at specified time points (Appendix E) 
throughout the study, to evaluate known and/or novel disease-related or drug-related biomarkers.  
Types of biomarkers may include nucleic acids, proteins, lipids, and/or metabolites, either free or in 
association with particular cell types.  The biomarker research may be exploratory in nature and the 
results may not be included with the clinical study report.  Further details regarding the biomarker 
research rationale and collection time points are located in the Operations Manual, Section 3.7.
Provision of biospecimens for biomarker research is mandatory, but they will not be collected from sites 
where local regulations do not allow for the collection, use, and storage of samples as described in the 
protocol.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This Phase 2, open-label, single-arm study is designed to evaluate the efficacy and safety of the 
combination of venetoclax and ibrutinib in Japanese subjects with R/R MCL.
Approximately 12 subjects will receive ibrutinib at 560 mg once daily and venetoclax starting at 20 mg 
once daily and gradually ramped up to a target dose of 400 mg once daily over a 5 week period.
Page 14 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Dose-limiting toxicities will be evaluated in the first 6 subjects, from Day 1 for a minimum of 5 weeks 
and at least 1 week of venetoclax dosing at 400 mg, in order to confirm the initial safety and tolerability 
in Japanese subjects.  After the completion of the DLT evaluation period in the first 6 subjects, the 
AbbVie Study Team and investigators who enrolled the 6 treated subjects will review all available safety 
and PK data to evaluate the tolerability of venetoclax in combination with ibrutinib in Japanese subjects 
with R/R MCL.  If there are zero or 1 DLTs in the first 6 subjects, enrolment of the additional 6 subjects 
will proceed.  If DLTs are observed in 2 or more of the first 6 subjects, further enrollment in Japan will be 
interrupted and additional, a detailed safety assessment will be conducted.  The Sponsor will consult the 
Independent Safety Monitor (ISM) with results of the safety evaluation and Sponsor's conclusion on 
tolerability, then receive the answer from ISM.
To mitigate the risk of TLS, a ramp-up period of approximately 5 weeks will be employed with a stepwise 
increase of the venetoclax dose (Figure 1).  Subjects will receive a venetoclax dose of 20 mg on Week 1 
Day 1 of the ramp-up period and continue with dose increases every 7 days as tolerated.  Ramp-up 
doses of venetoclax include 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg.  Subjects will receive ibrutinib 
at 560 mg once daily starting on Week 1 Day 1.
If one or more electrolyte changes suggestive of TLS occur within 24 hours of the 20 mg dose, no 
additional venetoclax doses will be administered until resolution.  If correction of electrolytes 
abnormalities is performed, the subsequent dose of venetoclax can only be given when electrolytes 
have been stable without any more treatment for at least 24 hours.  Refer to Table 2, Recommended 
Dose Modifications for Venetoclax-Related Toxicities, for additional TLS management guidelines.  Upon 
resolution of laboratory abnormalities, the subject will resume at the ramp-up dose.  When venetoclax 
dose interruptions are required during the ramp-up period, the next highest dose level may be initiated 
7 days from the start of the current dose level, once the toxicity has resolved to Grade 1 or baseline 
level and at the investigator's discretion.  At the investigator's discretion, the duration of a single dose 
level during the ramp-up period may be longer than 7 days before increasing to the next highest dose 
level.
For all ramp-up doses, laboratory values for subject management must be reviewed in real time by the 
investigator or designee, and prior to the subject's next dose, to ensure appropriate subject 
management.  Based on the laboratory values, the subject may continue dosing, may need to hold dose 
until resolution, may require hospitalization for further monitoring, or may need additional post-dose
laboratory checks.
Initially, subjects at high-risk for TLS will be hospitalized at the start of the venetoclax 20 mg ramp-up 
dose and again at the start of the 50 mg ramp-up dose for monitoring and prophylaxis of TLS.  Subjects 
will be considered as high-risk for TLS if they have a high tumor burden (at least one lesion > 10 cm; or at 
least one lesion > 5 cm and circulating lymphocytes > 25,000 cells/mm3) and/or with baseline creatinine 
clearance (CrCl) < 60 mL/min.  Subjects not meeting the high-risk criteria will be considered low risk for 
TLS.  Subjects will be discharged from hospital if there is no evidence of TLS.  AbbVie will review the 
safety data during the course of the study to determine whether continued hospitalization of subjects at 
high-risk for TLS during ramp-up remains warranted.
Subjects may be treated with venetoclax and ibrutinib for up to 104 weeks, starting with the Week 1 
Day 1 venetoclax dose of 20 mg dose during the ramp-up period, followed by ibrutinib monotherapy 
until disease progression, unacceptable toxicity, or withdrawal of consent.  Venetoclax will discontinued 
Page 15 of 110
 




STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
drugs, and radioimmunotherapy (90 Y ibritumomab tiuxetan) monotherapy are recommended.  
However, new strategies are needed that may substantially improve outcomes and may in the long-term 
obviate intensive chemotherapy and/or transplantation in younger MCL patients and chemotherapy in 
older patients with MCL.12
This study is designed to confirm the safety and tolerability of the combination of ibrutinib 560 mg + 
venetoclax 400 mg in Japanese subjects with R/R MCL.
Selection of Doses in the Study
The dose selection in this study is based on data from the safety run-in period of the SYMPATICO study, 
evaluating the combination of ibrutinib at 560 mg once daily and venetoclax at a target dose of 400 mg 
once daily in subjects at high and low risk of TLS with R/R MCL.  In this study, venetoclax will be ramped 
up starting at 20 mg with weekly increases to 50 mg, 100 mg, 200 mg, to the target daily dose of 
400 mg, per the SYMPATICO safety run-in regimen.  In the AIM study, venetoclax was initiated at 50 mg 
which resulted in TLS in 13% of subjects.  This resulted in reduction of venetoclax initiation to 20 mg, 
after which TLS was not observed.18,23
This dose regimen is expected to be efficacious with an acceptable safety profile in Japanese subjects.
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.
Consent
1. Subjects or their legally authorized representative must voluntarily sign and date an informed 
consent (and assent for minors as required by applicable regulation), 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 20 years old.
3. Adequate hematologic function independent of transfusion and growth factor support for at 
least 7 days prior to first dose with the exception of pegylated granulocyte-colony stimulating 
factor (G-CSF; pegfilgrastim) which requires at least 14 days prior to the first dose, defined as:

Absolute neutrophil count (ANC) > 1000 cells/mm3 (1.0 × 109/L)

Platelet count > 50,000 cells/mm3 (50 × 109/L)

Hemoglobin > 8.0 g/dL.
Page 17 of 110


STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
At the discretion of the investigator: Subjects with bone marrow involvement may be enrolled 
without meeting the above hematologic function criteria after documented discussion with the 
AbbVie Therapeutic Area Medical Director (TA MD).
4. Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 × upper limit of 
normal (ULN).

Bilirubin ≤ 1.5 × ULN; Subjects with documented Gilbert's syndrome may be allowed with a 
total bilirubin of < 5 × ULN.

Estimated CrCl ≥ 30 mL/min (Cockcroft-Gault or 24 hour urine collection).
5. Prothrombin time (PT)/international normal ratio (INR) < 1.5 × ULN and PTT (partial 
thromboplastin time, activated partial thromboplastin time [aPTT]) < 1.5 × ULN (unless 
abnormalities are unrelated to coagulopathy or bleeding disorder).  When treated with warfarin 
or other vitamin K antagonists, then INR ≤ 3.0.
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
7. Able to swallow capsules or tablets.
8. Are willing and able to comply with procedures required in this protocol.
Disease Activity
9. Pathologically confirmed MCL (tumor tissue) by local testing, with documentation of either 
overexpression of cyclin D1 in association with other relevant markers (e.g., CD19, CD20, PAX5, 
CD5) or evidence of the t(11;14) translocation, as assessed by cytogenetics, fluorescent in situ 
hybridization (FISH), or polymerase chain reaction (PCR).
10. At least 1 measurable site of disease on cross-sectional imaging that is ≥ 2.0 cm in the 
longest diameter and measurable in 2 perpendicular dimensions per CT.
11. At least 1, but no more than 5, prior treatment regimens for MCL including at least 1 prior 
rituximab/anti-CD20 containing regimen.
12. Failure to achieve at least PR with, or documented disease progression after, the most 
recent treatment regimen.
Subject History
13. No history or current evidence of central nervous system (CNS) lymphoma.
14. No history of other malignancies, except:

Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first dose of study drug and felt to be at low risk for recurrence by 
treating physician.

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.

Adequately treated carcinoma in situ without evidence of disease.
Page 18 of 110


STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
15. No uncontrolled active systemic infection.
16. No unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, v5.0), Grade 0 or 1, or to the levels 
dictated in the inclusion/exclusion criteria with the exception of alopecia.
17. No known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
18. No history of stroke or intracranial hemorrhage within 6 months prior to the first dose of 
study drug.
19. Subject has not undergone an allogeneic stem cell transplant within the last 6 months or 
currently does not have active graft-versus-host disease requiring the use of 
immunosuppressants.
20. No history of human immunodeficiency virus (HIV) infection (due to potential drug-drug 
interactions between antiretroviral medications and venetoclax); HIV testing will only be 
performed at Screening if required per local guidelines or institutional standards.
21. No active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

History of HCV may enroll if their HCV RNA level is undetectable after antiviral therapy.

History of HBV infection (without active infection at Screening) may enroll if there is no 
evidence of active HBV infection.  Subjects with hepatitis B surface antigen (HBsAg) negative 
and anti-HBs antibody positive or anti-HBc antibody positive may participate if HBV DNA 
quantitative is < 20 IU/ml.  Refer to the latest Japan Society of Hepatology guideline.29
22. No major surgery within 4 weeks of the first dose of study drug.
23. No life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator's opinion, could compromise the subject's safety or put the study outcomes at 
undue risk.
24. No clinically significant cardiovascular disease, such as:

Currently or a history of uncontrolled arrhythmia.

Currently Class 3 or 4 congestive heart failure as defined by the New York Heart Association 
Functional Classification.

History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 
months prior to the first dose of study drug.
25. No history of malabsorption syndrome, disease significantly affecting gastrointestinal 
function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease 
or ulcerative colitis, or partial or complete bowel obstruction.  Note:  a subject with 
gastrointestinal infiltration by MCL may be enrolled in the study if study drug can be taken and 
gastrointestinal absorption is possible.
26. No history of interstitial lung disease or pneumonitis that required treatment with systemic 
corticosteroids, or any current evidence of active interstitial lung disease or pneumonitis.
27. No contraindications of xanthine oxidase inhibitors and rasburicase.
28. No history of chronic liver disease with hepatic impairment Child-Pugh class B or C (refer to 
Table 7).
Page 19 of 110


STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
29. No known hypersensitivity to the active ingredient or other components of one or more 
study drugs.
30. No known active COVID-19 infection.  Subject must not have signs/symptoms associated 
with COVID-19 infection or known exposure to a confirmed case of COVID-19 infection during 
14 days prior to Screening.
Subjects who do not meet COVID-19 eligibility criteria must be screen failed and, may only 
rescreen after they meet the following COVID-19 viral clearance criteria:

Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since resolution of symptoms, defined as resolution of fever without 
use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of 
breath)

Asymptomatic subjects (if acceptable locally):  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)
Frequency or timing of COVID-19 testing and interval between testing for the above viral 
clearance criteria may be adjusted to account for epidemiological trends, updated information 
regarding infectivity and local/institutional guidelines.
Contraception
31. If female, subject must not be pregnant, breastfeeding, or considering becoming pregnant 
during the study or for approximately 90 days after the last dose of study drug.
32. Male and female subjects of reproductive potential who agree to use both a highly effective 
method of birth control (e.g., implants, injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method 
(e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the 
last dose of study drug.
33. For all females of child-bearing potential; a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
34. If male, subject must not be considering fathering a child or donating sperm during the study 
or for approximately 90 days after the last dose of study drug
35. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through 90 days after the last dose of study drug, to practice the 
protocol-specified contraception.
Concomitant Medications
36. No concurrent enrollment in another therapeutic investigational study or prior therapy with 
ibrutinib or other BTK inhibitors.
37. No prior treatment with venetoclax or other BCL2 inhibitors.
Page 20 of 110


STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
38. No anticancer therapy, including chemotherapy, radiotherapy, small molecule, and 
investigational agents, and/or monoclonal antibody ≤ 21 days (or at least 5 drug half-lives, 
whichever is shorter) prior to the first dose of study drug.
39. No corticosteroids for treatment of the underlying malignancy ≤ 21 days (or at least 5 drug 
half-lives, whichever is shorter) prior to the first dose of study drug.
40. Not vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
41. No clinically significant infection requiring intravenous (IV) systemic treatment that was 
completed ≤ 14 days before the first dose of study drug.
42. No treatment with any of the following within 7 days prior to the first dose of study drug:

moderate or strong cytochrome P450 3A (CYP3A) inhibitors 

moderate or strong CYP3A inducers.
43. No administration or consumption of any of the following within 3 days prior to the first 
dose of study drug:

grapefruit or grapefruit products

Seville oranges (including marmalade containing Seville oranges)

star fruit.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females of Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent sterility due to a hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy.

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.
2.
Postmenopausal female:

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulating hormone (FSH) level > 30 IU/L.
Page 21 of 110


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Females of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 90 days after the last dose of study drug(s).

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral) 
associated with inhibition of ovulation initiated at least 30 days prior to study baseline 
Day 1.

Progestogen-only hormonal birth control (oral) associated with inhibition of ovulation 
initiated at least 30 days prior to study baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

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).

Practice 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, post-ovulation methods] and withdrawal are 
not acceptable).

If required per local practices, male condom with or without spermicide should be used in 
addition to one of the birth control methods listed above (excluding true abstinence).
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential must agree to use 
male condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 
through at least 90 days after the last dose of study drug:

His female partner(s) must also use at least 1 of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral) associated 
with inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Progestogen-only hormonal birth control (oral) associated with inhibition of ovulation 
initiated at least 1 month prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).
Page 22 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

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).
5.3 Prohibited/Cautionary Medications and Therapy
Prohibited Concomitant Medications and Products
Any non-study protocol-related chemotherapy, anticancer immunotherapy, experimental therapy, or 
radiotherapy are prohibited while the subject is receiving study treatment.
Corticosteroids for the treatment of the underlying malignancy are prohibited with the exception of 
inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids.
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
Subjects may not consume grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit within the 3 day period prior to the first venetoclax and ibrutinib 
administration and until the last day of treatment is completed due to possible CYP3A mediated 
metabolic interaction.
Do not administer live attenuated vaccines prior to, during, or up to 4 weeks after treatment with 
venetoclax.  The safety and efficacy of immunization with live or attenuated viral vaccines during or 
following venetoclax therapy have not been studied.  Advise subjects that vaccinations may be less 
effective.
Cautionary Medications and Products
The following concomitant medications are cautionary during study treatment:

P-gp substrate:

To avoid a potential interaction in the GI tract, coadministration of narrow therapeutic index 
P-glycoprotein (P-gp) substrates such as digoxin with venetoclax should be avoided.  If a 
narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours 
before venetoclax.

To avoid a potential interaction in the GI tract, narrow therapeutic range P-gp substrates 
such as digoxin should be taken at least 6 hours before or after ibrutinib.

Antiplatelet Agents and Anticoagulants:

To avoid potential interaction with warfarin, which is a narrow therapeutic index drug, it is 
recommended that the INR be monitored closely in subjects receiving warfarin.

Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit 
platelet function, and supplements such as fish oil and vitamin E preparations should be 
avoided during treatment with ibrutinib.  In subjects requiring the initiation of 
anticoagulation therapy (e.g., atrial fibrillation), consider the risks and benefits of continuing 
ibrutinib treatment.
Page 23 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

CYP3A Inhibitors and Inducers:  Table 1 summarizes the recommended dose modifications with 
moderate and strong CYP3A inhibitors.  Avoid concomitant use of systemic strong CYP3A 
inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John's Wort).  Consider alternative 
agents with less CYP3A induction.
Table 1.
Management of Potential Ibrutinib and Venetoclax Interactions with CYP3A 
Inhibitors
Inhibitors
Venetoclaxa
Ibrutinib
Initiation and Ramp-Up 
Period
Target Daily Dose (After 
Ramp-Up)
At Any Time
Strong CYP3A 
inhibitor
Contraindicated (from 
7 days prior to first dose)
Avoid inhibitor use, consider 
alternative agent.  If must be 
used, reduce the venetoclax 
dose by at least 75%
Avoid inhibitor use, consider 
alternative agent.  If must be 
used, withhold ibrutinib for 
duration of inhibitor use, or 
reduce ibrutinib to 140 mg
Moderate CYP3A 
inhibitor
Avoid inhibitor use, consider alternative agent.  If must 
be used, reduce the venetoclax dose by at least 50%
Avoid inhibitor use, consider 
alternative agent.  If must be 
used, reduce ibrutinib to 
140 mg
CYP 3A = cytochrome P450 3A
a.
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor, 2 to 3 days after discontinuation of the 
inhibitor.
A sample list of cautionary medications that fall into the categories within section can be found in 
Appendix F.  Since it is not possible to provide an exhaustive list of medications that fall into these 
categories, please refer to the appropriate local product label and/or FDA website.30
5.4 Prior and Concomitant Therapy
Concomitant medications are collected from 14 days before the first dose through 30 days after the last 
dose of study drug.
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or vaccine (note that live attenuated vaccines are prohibited during study treatment) that 
the subject is receiving at the time of enrollment or receives during the study must be recorded.
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) are 
permitted.
Usage of antimicrobial prophylaxis in accordance with standard practice (e.g., ASCO guidelines)31 is 
permitted and should be considered in subjects who are at increased risk for opportunistic infections.
Use of neutrophil growth factors (filgrastim and pegfilgrastim) and transfusion is permitted in 
accordance with institutional policy (e.g., ASCO Guidelines).32
Page 24 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
In addition, short courses (≤ 14 days) of steroid treatment for non-cancer 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.  Information regarding potential drug interactions with venetoclax and ibrutinib can be located 
in the venetoclax Investigator's Brochure and ibrutinib package insert, respectively.
Subjects must be able to safely discontinue any prohibited medications prior to initial study drug 
administration.  Subjects must be consented for the study prior to discontinuing any prohibited 
medications for the purpose of meeting study eligibility.
Protocol instructions and information related to COVID-19 and COVID-19 vaccination are listed in 
Appendix I.
5.5 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.
Minor Surgical Procedures
For minor procedures (e.g., a central line placement, skin or 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 (except for emergency procedures) 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.
5.6 Withdrawal of Subjects and Discontinuation of Study
Venetoclax and ibrutinib will be discontinued in the event of any of the following events:

Progressive disease including clinical progression

Unacceptable toxicity:  an intercurrent illness or AE that prevents further ibrutinib or venetoclax 
administration regardless relatedness of study drugs as determined by the investigator or 
Sponsor.

Withdrawal of consent for treatment by subject

Investigator decision (such as chronic noncompliance, significant protocol deviation, or best 
interest of the subject)
Page 25 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Subject becomes pregnant

Study discontinuation at the time that the venetoclax and ibrutinib combination becomes 
commercially available in Japan for R/R MCL

Study termination by Sponsor.
Withdrawal from study (including all follow-up) will occur under the following circumstances:

Withdrawal of consent for follow-up observation by the subject

Lost to follow-up

Death

Study termination by Sponsor.
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 their site if they have safety concerns.  If AbbVie terminates the study for safety 
reasons, AbbVie will promptly notify the investigator.
Coronavirus Disease - 2019-related acceptable protocol modifications and COVID-19 
interruption/discontinuation instructions are discussed in Appendix I.
5.7 Follow-Up after Subject Discontinuation of Study Drug or 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 treatment (withdrawal of informed consent), the procedures 
outlined for the end-of-treatment visit should be completed as soon as possible.  In addition, a 30-day 
safety follow-up visit should be completed to ensure all treatment-emergent AEs/serious adverse events 
(SAEs) have been resolved.
Subjects who discontinue for reasons other than disease progression will continue disease assessment 
as follow-up response assessments every 12 weeks for the first year; every 16 weeks during the second 
and third years, and every 24 weeks thereafter until disease progression. 
If a subject withdraws from study follow-up or withdraws permission for the collection of their personal 
data, the study staff may still use available public records to obtain information about survival status 
only, as appropriate per local regulations.
Page 26 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
In the event a subject withdraws consent from the clinical study and confirms research should no longer 
be conducted upon biomarker samples, research will continue unless the subject explicitly requests 
analyses to be stopped.  When AbbVie is informed that samples are withdrawn from research, samples 
will not be analyzed, and no new biomarker analysis data will be collected for the withdrawn subject or 
added to the existing data or database(s).  Data generated for biomarker research before a subject's 
withdrawal of consent will remain part of the study results.
5.8 Survival Follow-Up
For all subjects, after disease progression, survival status, other malignancies, and subsequent 
anticancer therapy will be collected approximately every 12 weeks after the 30-day safety follow-up or 
the last visit when 30-day safety follow-up is not implemented until death by clinic visit or telephone 
call, withdrawal by the subjects, lost to follow-up, study discontinuation, or study termination by the 
Sponsor, whichever comes first.
5.9 Study Drug
Study drugs refer to drugs that are used (or can be used) in this study to assess the safety and the 
efficacy of the Investigational Product. Investigators will assess the relationship of adverse events to the 
use of study drugs (refer to Operations Manual Section 5.2, Table 2) for the list of study drugs. 
Venetoclax tablets (10 mg, 50 mg, and 100 mg) and ibrutinib capsules (140 mg) will be provided by the 
Sponsor for oral administration once daily beginning on Day 1 and should be taken at approximately the 
same time each day with water within 30 minutes after the completion of a meal, preferably breakfast.  
Venetoclax tablets and ibrutinib capsules should be swallowed whole and not chewed, crushed, or 
broken prior to swallowing.  If subjects should forget to take their venetoclax and/or ibrutinib dose at 
their regularly scheduled dosing time, they should take the forgotten dose as soon as they remember 
within 8 hours with a return to the normal schedule the following day.  In cases of vomiting after taking 
study drug, no additional dose (tablets) should be taken that day.
Subject dosing will be recorded on 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.
Venetoclax and 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.
Further information on study drug, packaging, labeling, etc. is provided in the Operation Manual, 
Section 6.  Protocol instructions and information related to COVID-19, including direct-to-patient study 
drug shipment, are discussed in Appendix I.
Page 27 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.10 Drug Assignment
All subjects will be assigned a unique identification number by IRT at the screening visit.  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 by IRT at the screening visit 
throughout the study and receipt of study drug will be acknowledged in the IRT system.
5.11 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), and AbbVie.
5.12 Independent Safety Monitor
The ISM will be a Japan medical oncologist with experience in clinical studies and who is familiar with 
the safety assessment of antitumor agents.  To avoid any conflict of interest, the ISM must not be 
associated with or be an employee of the participating study institutions.  The Sponsor will recommence 
subject enrolment based on the safety review and only if agreed by the ISM.  Depending on the results 
of the safety review by ISM, revising the protocol will be considered where necessary.  The ISM must be 
available for the AbbVie Clinical Team to contact for urgent evaluation of any safety issues.  Detailed 
procedures for safety assessments will be described in a separately prepared document for operational 
procedures.
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 
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 
Page 28 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  
Reporting will be done via electronic data capture (EDC).  The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie.  A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue.  If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie.
All follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.  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, meet 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/or the surgery/procedure has 
been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If any TLS AEs are reported, the TLS supplemental report (electronic case report form [eCRF]) must be 
completed.
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 as a serious adverse event (SAE) within 24 hours of the 
Page 29 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
site being made aware of the SAE (refer to Section 4.2 of the Operations Manual for reporting details 
and contact information):
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.  After 
30 days following the last dose of study drug or completion of study treatment only spontaneously 
reported SAEs will be collected (nonserious AEs will not be collected).  In addition, study procedure-
related serious and nonserious AEs will be collected from the time the subject signs the study-specific 
informed consent.
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study:
Page 30 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Tumor lysis syndrome

Major hemorrhage
Tumor lysis syndrome events are defined as:

Clinical TLS:  any event that meets Howard criteria (Appendix G) with the following exceptions:

For the purpose of TLS assessment during the DLT evaluation period, only those increases in 
serum creatinine > 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS.

In subjects with renal dysfunction at baseline (CrCl < 60 mL/min), clinical TLS is defined as 
the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death.

Laboratory TLS:  any event that meets Howard criteria (Appendix G) for laboratory TLS, that 
does not resolve within 72 hours despite protocol required management.
Major hemorrhage events are defined as:

Any treatment-emergent Grade ≥ 3 hemorrhage AEs (all hemorrhagic events requiring 
transfusion of red blood cells should be reported as Grade 3 or higher AE per National Cancer 
Institute (NCI) CTCAE v5.0).

Any treatment-emergent SAEs of bleeding of any grade

Any treatment-emergent CNS hemorrhage/hematoma of any grade.
Adverse Event Severity and Relationship to Study Drug
The investigator will rate the severity of each AE according to the NCI CTCAE Version 5.0.  If a reported 
AE increases in severity, the initial event should be given an outcome date and a new AE must be 
reported to reflect the change in severity.  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 criteria should be used:
Grade 1
Mild; asymptomatic or mild symptoms; clinical diagnostic observations only; 
intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self- care activities of daily living.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to adverse event.
Page 31 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug (venetoclax and ibrutinib):
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 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.6).  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 90 days following the last dose of study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Toxicity Management
Venetoclax
Dose Modification for Adverse Reactions
Venetoclax dosing interruption and/or dose reduction may be required.  See Table 2 for dose 
modifications for hematologic and other toxicities related to venetoclax.  For subjects who have had a 
dosing interruption greater than 1 week during the ramp-up period or greater than 2 weeks when at 
target dose, reassess for risk of TLS to determine if re-initiation with a reduced dose is necessary.  
Venetoclax dose reduction is not allowed during the DLT assessment period. 
Page 32 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 2.
Recommended Dose Modifications for Venetoclax-Related 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, once 
the toxicity has resolved to Grade 1 or baseline level, 
resume at the same dose.
For any blood chemistry changes requiring more than 
48 hours to resolve, once the toxicity has resolved to 
Grade 1 or baseline level, resume at a reduced dosea
(see Table 3)
For any events of clinical TLS, once the toxicity has 
resolved to Grade 1 or baseline level, resume at a 
reduced dose following resolution (see Table 3)
Non-Hematologic Toxicities
Grade 3 or 4 non-hematologic 
toxicities
First
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.
Second and 
subsequent
Interrupt venetoclax 
Once the toxicity has resolved to Grade 1 or baseline 
level, resume at a reduced dose following resolution 
(see Table 3).  A larger 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)
First
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 
may be resumed at the same dose.a
Second and 
subsequent 
occurrence
Interrupt venetoclax.
Consider using G-CSF as clinically indicated.
Once the toxicity has resolved to Grade 1 or baseline 
level, resume at a reduced dose following resolutiona
(see Table 3).  A larger dose reduction may occur at 
the discretion of the investigator.
DLT = dose limiting toxicity; G-CSF = granulocyte-colony stimulating factor; TLS = tumor lysis syndrome
a.
Venetoclax dose reduction is not allowed during the DLT assessment period.
Consider discontinuing venetoclax for subjects who require dose reductions to less than 100 mg for 
more than 2 weeks.
If the dose of venetoclax is reduced, at the investigator's discretion, the dose of venetoclax may be re-
escalated after 2 months of a dose reduction in the absence of a recurrence of the toxicity that led to 
the reduction.  Subsequent dose re-escalations should be discussed with the AbbVie TA MD.
Page 33 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 3.
Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption
Restart Dosea
400 mg
300 mg
300 mg
200 mg
200 mg
100 mg
a.
Continue the reduced dose for at least 1 week before increasing the dose.
Prophylaxis and Management of Tumor Lysis Syndrome
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the ramp-up period.  
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 and at each dose increase.  The risk of TLS is a continuum 
based on multiple factors, including comorbidities.  Subjects with high tumor burden are at greater risk 
of TLS when initiating venetoclax.  Reduced renal function further increases the risk.  The risk may 
decrease as tumor burden decreases with continued venetoclax treatment.
Tumor burden assessments, including radiographic evaluation (e.g., CT scan) should be performed at 
Screening as well as blood chemistry assessments (potassium, phosphorus, calcium, uric acid, creatinine, 
lactate dehydrogenase, and, if available, albumin, corrected calcium, and ionized calcium) in all subjects.  
Pre-existing abnormalities should be corrected prior to initiation of treatment with venetoclax.

High risk for TLS: Subjects with high tumor burden (at least one lesion > 10 cm; or at least one 
lesion > 5 cm and circulating lymphocytes > 25,000 cells/mm3) and/or with baseline 
CrCl < 60 mL/min.

Low risk for TLS:  Subjects not meeting the criteria described above.
The prophylaxis measures listed below should be followed and more intensive measures (including 
hospitalization) should be employed for subjects at high-risk for TLS based on local guidelines or 
institutional standards:

Hydration:  Ensure adequate hydration (1.5 L to 2 L) 48 hours prior to initiating therapy with 
venetoclax and throughout the ramp-up period, especially on the first day of each ramp-up 
dose.  Administer IV fluids as indicated based on the overall risk of TLS or for those who cannot 
maintain adequate oral hydration.

Anti-hyperuricemic agents:  Administer anti-hyperuricemic agents (e.g., allopurinol) within 
72 hours prior to initiation of venetoclax; consider continuing through the ramp-up period.  
Rasburicase is recommended for subjects at high-risk, especially those with high tumor burden.

Laboratory Assessments:

Pre-dose:  Assess blood chemistries prior to initiating venetoclax to evaluate kidney function 
and correct pre-existing abnormalities.  Reassess blood chemistries before starting each 
subsequent ramp-up dose of venetoclax.
Page 34 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Post-dose:  For hospitalized subjects, monitor blood chemistries 4 hours, 8 hours, 12 hours, 
24 hours and, as needed, 48 hours after the venetoclax dose.  For outpatient subjects, 
monitor blood chemistries at 6 to 8 hours and at 24 hours after the venetoclax dose.  
Electrolyte abnormalities should be corrected promptly (see Appendix G).  The next dose of 
venetoclax should not be administered until the 24 hour blood chemistry results have 
been evaluated.  The monitoring schedule should be followed in the Operations Manual 
(Appendix K) when starting each subsequent ramp-up dose.  Refer to Appendix G for 
definitions of laboratory and clinical TLS.

Subjects at low risk of TLS may have laboratory assessments conducted on an outpatient 
basis.  If low risk subjects are hospitalized for logistical reasons, laboratory assessments will 
be conducted per the outpatient schedule.

Hospitalization:  Based on investigator assessment, subjects with a high-risk of TLS require 
hospitalization at the 20 mg and the 50 mg ramp-up doses of venetoclax for more intensive 
prophylaxis and monitoring.  The timing of discharge from hospital will be decided based on 
investigator assessment of available data at that time.  Consider hospitalization for subsequent 
ramp-up doses based on the reassessment of risk.  Subjects at low risk of TLS may also be 
hospitalized, at the investigator's discretion.  During the course of the study, the investigators 
and Sponsor will review TLS data to determine whether continued hospitalization of these 
subjects is warranted.
Ibrutinib
Dose Modification for Adverse Reactions
Ibrutinib interruption and/or dose reduction may be required for toxicities related to ibrutinib.  The dose 
of study drug must be modified according to the dose modification guidance in Table 4 and Table 5 if 
any of the following ibrutinib related toxicities occur:

Grade 3 or greater neutropenia with infection or fever

Grade 4 neutropenia (ANC < 500/μL) for more than 7 days

Grade 3 thrombocytopenia (platelets < 50,000/μL) in the presence of Grade ≥ 2 bleeding

Grade 4 thrombocytopenia (platelets < 25,000/μL)

Grade 3 or greater non-hematological toxicity (Note: Table 5 recommendations for Grade 3 or 
greater cardiac failure and cardiac arrhythmias)

Grade 2 cardiac failure (Table 5)

Any other Grade 4 or unmanageable Grade 3 toxicity.
If clinically indicated, the use of anticoagulants or antiplatelet agents should be considered for the 
thromboprophylaxis of atrial fibrillation.
Dose changes must be recorded in the Dose Administration eCRF.  Ibrutinib dose reduction is not 
allowed during the DLT assessment period.
Page 35 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 4.
Ibrutinib Dose Modifications for Toxicities
Event
Occurrence
Action
Hematologic Toxicities 
(neutrophil decrease and 
platelet decrease)
First
Withhold ibrutinib until recovery to an ANC ≥ 750/µL 
or platelets > 25,000/µL with no evidence of Grade ≥ 2 
bleeding; may restart at the same dose level.
Subsequent
Withhold ibrutinib until recovery to an ANC ≥ 750/µL 
or platelets > 25,000/µL with no evidence of Grade ≥ 2 
bleeding; may restart at 1 dose level lower (refer to 
Table 6).
Other Hematologic and Non-
Hematological Toxicities (for 
events not specified in Table 5)
First
Withhold ibrutinib until recovery to Grade ≤ 1 or 
baseline; may restart at the same dose level.a
Second
Withhold ibrutinib until recovery to Grade ≤ 1 or 
baseline; restart at 1 dose level lower (i.e., 420 mg 
daily) (refer to Table 6).
Third
Withhold ibrutinib until recovery to Grade ≤ 1 or 
baseline; restart at 1 dose level lower (i.e., 280 mg 
daily) (refer to Table 6).
Fourth
Discontinue ibrutinib
ANC = absolute neutrophil count; DLT = dose limiting toxicity
a.
When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation.  If the toxicity reoccurs, 
reduce daily dose by 140 mg.
Notes:

Ibrutinib dose reduction is not allowed during the DLT assessment period.

Do not dose below 280 mg daily except in case of required concomitant administration of strong or moderate CYP3A 
inhibitors or moderate hepatic impairment.

Refer to Table 5 for Ibrutinib Dose Modifications for Cardiac Failure or Cardiac Arrhythmias.
Page 36 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 5.
Ibrutinib Dose Modifications for Cardiac Failure or Cardiac Arrhythmias
Event
Occurrence
Action
Grade 2 cardiac failure
First
Hold ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (i.e., 420 mg daily)
Second
Hold ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (i.e., 280 mg daily)
Third
Discontinue ibrutinib
Grade 3 cardiac arrhythmias
First
Hold ibrutinib until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (i.e., 420 mg daily)a
Second
Discontinue ibrutinib
Grade 3 or 4 cardiac failure; 
Grade 4 cardiac arrhythmias
First
Discontinue ibrutinib
a.
Evaluate the benefit-risk before resuming treatment.
Notes:

Ibrutinib dose reduction is not allowed during the DLT assessment period.

Refer to Table 4 for additional ibrutinib dose modifications.
Table 6.
Ibrutinib Dose Reduction Levels
Starting Dose Level
560 mg
Dose Reduction Level 1
420 mg
Dose Reduction Level 2
280 mg
Dose Reduction Level 3
140 mg
Dose Reduction Level 4
Discontinue
Leukocytosis/Leukostasis
A high number of circulating white blood cells (> 400,000/μL) may confer increased risk of leukostasis; 
these subjects should be closely monitored.  Administer supportive care such as hydration and/or 
leukapheresis as indicated.  Ibrutinib may be temporarily held.
Dose Modification for Hepatic Impaired Subjects
Ibrutinib is metabolized in the liver, and therefore subjects with clinically significant chronic hepatic 
impairment at Screening (Child-Pugh class B or C) are excluded from study participation.

For subjects with existing chronic mild hepatic impairment (Child-Pugh class A) at enrollment, 
the starting dose will be adjusted to a level of 280 mg daily (two capsules).

For subjects who develop mild hepatic liver impairment while on study (Child-Pugh class A), the 
recommended dose reduction for ibrutinib is to a level of 280 mg daily (two capsules) unless 
lower doses had already been implemented.
Page 37 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Subjects who develop moderate or severe hepatic impairment while on study (Child-Pugh class 
B or C) must hold study drug(s) until resolved to mild impairment (Child-Pugh class A) or better.

Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines.
Table 7.
Child-Pugh Score for Subjects with Liver Impairment33,34
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
< 34 (< 2)
34 to 50 (2 to 3)
> 50 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28 to 35 (2.8 to 3.5)
< 28 (< 2.8)
PT/INR
< 1.7
1.71 to 2.30
> 2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I to II (or suppressed 
with medication)
Grade III to IV (or 
refractory)
Points
Class
5 to 6
A
7 to 9
B
10 to 15
C
INR = international normalized ratio; PT = prothrombin time
6.3 Dose-Limiting Toxicity Criteria
Tolerability in the first 6 Japanese subjects (DLT assessment period) will be determined considering all 
available data, including information on AEs, laboratory results, and PK data.  For each of the first 6 
subjects, DLTs will be assessed during the venetoclax ramp-up period for a minimum of 5 weeks and at 
least 1 week of venetoclax dosing at 400 mg.
A DLT is defined as any Grade ≥ 3 AE considered to be at least possibly related to study drug (ibrutinib 
and/or venetoclax) and occurring during the DLT assessment period with the following clarifications:
Non-Hematologic DLTs:

Grade ≥ 3 nausea, vomiting, or diarrhea, uncontrolled despite maximum medical supportive 
care and persisting > 5 days

Grade 3 fatigue persisting > 7 days

Grade 3 infection is not a DLT; however, an infection with life-threatening consequences or 
requiring urgent intervention (Grade 4) will be considered a DLT

Treatment delay of any study drug of > 7 consecutive days for toxicity.
Page 38 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Hematologic DLTs:

Grade 3 neutropenia is not a DLT; however, Grade 4 neutropenia (ANC < 500/mm3) lasting for 
> 7 days is a DLT

Grade 3 or 4 neutropenia complicated by fever ≥ 38.5°C or infection

Grade 4 thrombocytopenia (< 25,000/mm3) that persists for > 7 days

Grade 3 or 4 thrombocytopenia associated with Grade 2 or greater bleeding

Grade 3 anemia is not a DLT; however, Grade 4 anemia is a DLT

Treatment delay of any study drug > 7 consecutive days for hematologic toxicity.
In addition, clinically important or persistent toxicities that are not included in the above criteria will be 
considered a DLT following review by the Sponsor and the investigators.
Subjects who miss ≥ 20% of the planned doses of venetoclax or ibrutinib for reasons other than toxicity 
(e.g., non-compliance, withdrawal of consent, disease progression) during the DLT assessment period, or 
subjects who do not complete the DLT assessment period for any reason other than a DLT will be 
considered non-evaluable and will need to be replaced.
A subject must be on study from Day 1 for a minimum of 5 weeks and at least 1 week of venetoclax 
dosing at 400 mg to be evaluable for DLT assessment.  However, in circumstances of an event not 
related to study drug (e.g., traffic accident, clear disease progression) that leads to study discontinuation 
before the end of the defined DLT assessment period, the subject might be deemed evaluable if the 
Sponsor and investigators and agree.
Subjects who are replaced for DLT assessments are also included in the planned total 12 subjects.
Enrollment of subjects will be suspended after the first 6 subjects are enrolled for DLT assessment.  The 
decision around tolerability will be based on data from all subjects who received at least 1 dose of the 
study drug, regardless of whether the subjects are DLT evaluable or not.
Evaluation of Tolerability:
Dose-limiting toxicities will be evaluated in the first 6 subjects from the planned total of 12 subjects in 
order to confirm the initial safety and tolerability in Japanese subjects.  Enrollment of new subjects will 
be suspended once the first 6 subjects evaluable for tolerability are enrolled.  Dose-limiting toxicities will 
be evaluated during the venetoclax ramp-up period, from Day 1 for a minimum of 5 weeks and at least 
1 week of venetoclax dosing at 400 mg.  After the completion of the DLT evaluation period in the first 
6 subjects, the AbbVie Study Team and investigators who enrolled the treated subjects will review all 
available safety and PK data to evaluate whether venetoclax in combination with ibrutinib is tolerable in 
Japanese subjects with R/R MCL.  If there is 0 or 1 DLT in the first 6 subjects, enrolment of the additional 
6 subjects will proceed.  If DLTs are observed in 2 or more of the first 6 subjects, further enrollment will 
be interrupted and additional, detailed safety assessment will be conducted, including discussions to 
determine if other doses should be explored.  The Sponsor will consult the ISM with the results of safety 
evaluation and the Sponsor's conclusion on tolerability, then receive the response from the ISM.
Page 39 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be utilized for primary and secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).
The primary analysis will be conducted after the last subject has completed the Week 13 disease 
assessments or all subjects have discontinued the study, whichever is earlier.
In the DLT assessment period, the first 6 study subjects enrolled will be evaluated for the tolerability of 
the venetoclax and ibrutinib combination for a minimum of 5 weeks and at least 1 week of venetoclax 
dosing at 400 mg.
7.2 Definition for Analysis Populations
The full analysis set (FAS) includes all subjects who received at least 1 dose of study drug.  The FAS will 
be used for all efficacy (except the endpoints based on IRC assessment), safety, pharmacokinetic, and 
baseline analyses.  The per protocol (PP) population excludes FAS subjects who have been determined 
as non-evaluable disease at baseline based on IRC assessment.  For endpoints based on IRC assessment, 
PP population will be used.  For investigator assessed endpoints, PP population may be used as 
appropriate. 
Statistical Analyses for Efficacy
Summary and Analysis of the Primary Endpoint
The primary efficacy endpoint will be the best overall response of CR (defined as achieving complete 
metabolic and/or radiologic response at any time point during the study), according to the Revised 
Criteria for Response Assessment as assessed by the IRC28 in the PP population.  The primary endpoint 
will be evaluated using complete response rate (CRR), defined as the proportion of subjects achieving a 
best overall response of CR for the venetoclax and ibrutinib combination in the PP population, and will 
be compared to the threshold CRR of 12.5% using the exact binomial test at a 1-sided overall 
significance level of 0.025.  The CRR will be estimated using exact binomial distribution, the estimate and 
95% CI for CRR will be constructed.
Subjects who are enrolled but have no disease assessment post-baseline will be considered as non-
responders in the calculation of CRR.
Summary and Analysis of Secondary Endpoints
The secondary efficacy analysis will be based on the following endpoints:

Best overall response of CR by investigator
Page 40 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

Best overall response of CR or PR (defined as achieving partial metabolic and/or radiologic 
response at any time point during the study), DOR, and undetectable MRD, as assessed by 
investigator and IRC, respectively.

PFS by investigator

OS
The same methodology as for the analysis of CR assessed by IRC will be applied to the analysis of CR 
assessed by investigator.
Endpoint of best overall response of CR or PR will be evaluated using ORR.  The ORR will be defined as 
the proportion of subjects with a best overall response of CR or PR, according to the Revised Criteria for 
Response Assessment as assessed by the investigator.28 The estimate and 95% CI for ORR based on exact 
binomial distribution will be constructed.  Similarly, analysis of ORR assessed by IRC will be performed.
DOR will be defined as the time from the first occurrence of response to disease progression or death, 
whichever occurs first, according to the Revised Criteria for Response Assessment as assessed by the 
investigator.28  If a subject is still responding, subjects will be censored at the date of the last adequate 
disease assessment.  DOR will be analyzed for subjects who achieve a best overall response of CR/PR.  
The distribution of the DOR will be estimated using Kaplan-Meier methodology.  If estimable, median 
DOR and the corresponding 95% CI will be provided.  Similarly, analysis of DOR will be performed using 
IRC-assessed data.
Minimal residual disease (MRD) rate will be defined as the proportion of subjects with undetectable 
MRD who achieve a best overall response of CR, according to the Revised Criteria for Response 
Assessment as assessed by the investigator28 will be estimated and the corresponding 95% CI for the 
proportion based on exact binomial distribution will be constructed.  Similarly, analysis of the proportion 
of subjects with undetectable MRD who achieve a best overall response of CR, as assessed by the IRC, 
will be estimated.
Progression-free survival will be defined as the time from the date of the first dose of any study drug 
(venetoclax or ibrutinib) to the date of investigator-assessed disease progression, using the Revised 
Response Criteria for Response Assessment,28 or death from any cause, whichever occurs first.  All 
events of disease progression will be included, regardless of whether the event occurred while the 
subject was still taking study drug or after the subject discontinued study drug.  If the subject does not 
experience disease progression or death, then the data will be censored at the date of the last adequate 
disease assessment.  Data for subjects without any disease assessments performed after the baseline 
visit will be censored at the date of the first dose.  The distribution of the PFS events will be estimated 
using Kaplan-Meier methodology.  If estimable, median PFS and the corresponding 95% CI will be 
provided.
Overall survival will be defined as the time from the date of the first dose of any study drug (venetoclax 
or ibrutinib) to death from any cause.  All events of death will be included, regardless of whether the 
event occurred while the subject was still taking study drug or after the subject discontinued study drug.  
If a subject has not died, then the data will be censored at the date the subject was last known to be 
alive.  The distribution of the OS will be estimated using Kaplan-Meier methodology.  If estimable, 
median OS and the corresponding 95% CI will be provided.
Page 41 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Details on the secondary efficacy analyses are provided in the SAP.
Summary and Analysis of Additional Efficacy Endpoints
Details on other efficacy analyses are provided in the SAP.
Subgroup Analysis for Efficacy
There is no separate subgroup analysis planned for this study.
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
The primary endpoint of best overall response of CR (defined in Section 3.2) will be analyzed based on 
the PP population and the secondary endpoints (defined in Section 3.3) will be analyzed based on the 
PP/FAS population, as appropriate, the following potential intercurrent events (ICEs)will be considered:

ICE1: Subjects with study drug discontinuation 

ICE2: Subjects with the use of anti-MCL treatment
And will be handled for both primary and secondary endpoints based on the following strategy:

The disease assessments after ICE1 (if available) and ICE2 will be used for the derivation of all 
endpoints.
7.4 Statistical Analyses for Safety
The safety and tolerability of venetoclax in combination with ibrutinib will be assessed by evaluation of 
study drug exposure, DLTs, AEs, SAEs, and deaths, as well as changes in laboratory parameters, physical 
examinations, electrocardiogram (ECG), and vital sign measurements.
Tolerability of venetoclax and ibrutinib combination will be assessed for the first 6 evaluable subjects, 
where an evaluable subject is defined as a subject who has received the combination for a minimum of 
5 weeks and at least 1 week of venetoclax dosed at 400 mg.
Details on the statistical analyses for safety are provided in the SAP.
7.5 Interim Analysis
There is no plan for an interim efficacy analysis.  However, an interim safety analysis of tolerability of the 
venetoclax and ibrutinib combination will be performed after the first 6 evaluable subjects have been on 
the combination for a minimum of 5 weeks and at least 1 week of venetoclax dosed at 400 mg.
Page 42 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.6 Overall Type I Error Control
The overall type I error rate of 1-sided 0.025 will be used to determine the statistical significance of the 
primary endpoint at the time of primary analysis.  All other analyses will be done for descriptive 
purpose.  Hence, no multiplicity adjustment of type I error is needed.
7.7 Sample Size Determination
Approximately 12 subjects will be enrolled in the study.  The tolerability of the combination of 
venetoclax and ibrutinib will be assessed after the first 6 subjects enrolled in the study have received the 
combination for a minimum of 5 weeks and at least 1 week of venetoclax dosed at 400 mg.
Using exact binomial test, with an expected CRR of 50% for venetoclax in combination with ibrutinib and 
a threshold CRR of 12.5%, 12 subjects will provide 80% power to demonstrate superiority of venetoclax 
in combination with ibrutinib against a historical reference of 12.5% CRR in the ibrutinib only Japanese 
study with R/R MCL,34 at a 1-sided overall significance level of 0.025.  A significant test result is achieved 
when at least 5 CRs are observed among 12 subjects, corresponding to a minimal observed CRR of 
41.7%.
If the first 12 subjects include subject(s) who are assessed by the IRC as non-evaluable at baseline, then 
additional subject(s) will be enrolled at the Sponsor's discretion to ensure that there are 12 evaluable 
subjects per IRC assessment for primary endpoint analysis.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
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 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
Page 43 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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).  Refer to Appendix I for COVID-19 remote data review/verification details.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
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 
with the subject, whichever is later.
12
REFERENCES
1.
Lennert K. Histopathology of Non-Hodgkin's Lymphomas (Based on the Kiel Classification): Springer-
Verlag Berlin Heidelberg; 1981.
2.
Zucca E, Stein H, Coiffier B. European Lymphoma Task Force (ELTF): Report of the workshop on 
Mantle Cell Lymphoma (MCL). Ann Oncol. 1994;5(6):507-11.
3.
Zhou Y, Wang H, Fang W, et al. Incidence trends of mantle cell lymphoma in the United States 
between 1992 and 2004. Cancer. 2008;113(4):791-8.
4.
Dreyling M, Campo E, Hermine O, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2017;28(suppl_4):iv62-iv71.
Page 44 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.
Lenz G, Dreyling M, Unterhalt M, et al. [Current strategies in the treatment of advanced stage 
mantle cell lymphoma]. Dtsch Med Wochenschr. 2004;129(45):2429-33.
6.
Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol 
Hematol. 2011;80(1):69-86.
7.
Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-
stage mantle cell lymphoma. Blood. 2008;111(2):558-65.
8.
Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus 
rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin 
Oncol. 2008;26(27):4473-9.
9.
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus 
rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-
label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-10.
10. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO Consensus conferences: guidelines on 
malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell 
lymphoma. Ann Oncol. 2013;24(4):857-77.
11. NCCN clinical practice guidelines in oncology (NCCN guidelines).  Non-Hodgkin's Lymphomas v2.0 
[Internet]. 2016.
12. Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125(1):48-55.
13. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or 
refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 
2016;387(10020):770-8.
14. Portell CA, Axelrod M, Brett LK, et al. Synergistic Cytotoxicity of Ibrutinib and the BCL2 Antagonist, 
ABT-199(GDC-0199) in Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL): 
Molecular Analysis Reveals Mechanisms of Target Interactions. Blood. 2014;124(21):509.
15. Zhao X, Bodo J, Sun D, et al. Combination of ibrutinib with ABT-199: synergistic effects on 
proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, 
AKT and BCL2 pathways. Br J Haematol. 2015;168(5):765-8.
16. Zhao X, Bodo J, Sun D, et al. Combination Of Ibrutinib With ABT-199, a BCL-2 Pathway Inhibitor: 
Effective Therapeutic Strategy In a Novel Mantle Cell Lymphoma Cell Line Model. Blood. 
2013;122(21):645-.
17. Gerecitano J, Roberts A, Seymour J, et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) 
Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood. 2015;126:254-.
Page 45 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
18. Tam CSL, Roberts AW, Anderson MA, et al. Combination ibrutinib (Ibr) and venetoclax (Ven) for the 
treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of the phase 2 AIM study. 
Journal of Clinical Oncology. 2017;35(15_suppl):7520-.
19. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell 
Lymphoma. N Engl J Med. 2018;378(13):1211-23.
20. Handunnetti SM, Khot A, Anderson MA, et al. Safety and Efficacy of Ibrutinib in Combination with 
Venetoclax in Patients with Marginal Zone Lymphoma: Preliminary Results from an Open Label, 
Phase II Study. Blood. 2019;134(Supplement_1):3999-.
21. Portell CA, Chen RW, Wages N, et al. Initial Report of a Multi-Institution Phase I/Ib Study of Ibrutinib 
with Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma. Blood. 2016;128(22):2958-.
22. Gouill SL, Davies A, Bouabdallah K, et al. OAsis: An international phase I trial of obinutuzumab, 
venetoclax plus ibrutinib in relapsed/refractory mantle cell lymphoma. Journal of Clinical Oncology. 
2016;34(15_suppl):TPS7583-TPS.
23. Tam CSL, Roberts AW, Anderson MA, et al. The combination of ibrutinib and venetoclax (ABT-199) to 
achieve complete remissions in patients with relapsed/refractory mantle cell lymphoma: Preliminary 
results of the phase II AIM study. Journal of Clinical Oncology. 2016;34(15_suppl):7548.
24. Rule S, Dreyling M, Hess G, et al. Overall Survival Outcomes in Patients with Mantle-Cell Lymphoma 
(MCL) Treated with Ibrutinib in a Pooled Analysis of 370 Patients From 3 International Open-Label 
Studies.  European Hematology Association (EHA) Annual Meeting; Copenhagen Denmark2016.
25. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients 
with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-33.
26. Wang M, Ramchandren R, Chen R, et al. Results from the safety run-in period of the sympatico study 
evaluating ibrutinib in combination with venetoclax in patients with relapsed/refractory mantle cell 
lymphoma. Hematological oncology. 2019;37(S2):333-5.
27. Maruyama D, Nagai H, Fukuhara N, et al. Efficacy and safety of ibrutinib in Japanese patients with 
relapsed or refractory mantle cell lymphoma. Cancer Sci. 2016;107(12):1785-90.
28. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
2014;32(27):3059-68.
29. The Japan Society of Hepatology. Japan Society of Hepatology Guidelines for the Management of 
Hepatitis B Virus Infection.version 3.1.
30. U.S. Food and Drug Administration. Drug Development and Drug Interactions Table of Substrates, 
Inhibitors and Inducers. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers [
Page 46 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
31. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of 
fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology 
clinical practice guideline. J Clin Oncol. 2013;31(6):794-810.
32. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white 
blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 
2006;24(19):3187-205.
33. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver and portal 
hypertension. Philadelphia: Saunders; 1964. p. 50-64.
34. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973;60(8):646-9.
35. McIntosh LJ, Bankier AA, Vijayaraghavan GR, et al. COVID-19 Vaccination-Related Uptake on FDG 
PET/CT: An Emerging Dilemma and Suggestions for Management. AJR Am J Roentgenol. 
2021;217(4):975-83.
36. Eifer M, Tau N, Alhoubani Y, et al. Covid-19 mRNA Vaccination: Age and Immune Status and its 
Association with Axillary Lymph Node PET/CT Uptake. J Nucl Med. 2021.
37. McIntosh LJ, Rosen MP, Mittal K, et al. Coordination and optimization of FDG PET/CT and COVID-19 
vaccination; Lessons learned in the early stages of mass vaccination. Cancer Treat Rev. 
2021;98:102220.
38. The Tumor Lysis Syndrome. New England Journal of Medicine. 2018;379(11):1094-.
Page 47 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial prothromboplastin time
ASO
Allele-specific oligonucleotide
AST
Aspartate aminotransferase
AUC
Area-under-the-plasma concentration-time curve
AUCtau
Area-under-the-plasma concentration-time curve over the dosing interval
BCL2
B-cell lymphoma-2
BCRP
Breast cancer resistance protein
CHOP
Cyclophosphamide, doxorubicin, vincristine, and prednisone
CI
Confidence interval
Cmax
Maximum observed plasma concentration
CMR
Complete Metabolic Response
CNS
Central nervous system
COVID-19
Coronavirus Disease - 2019
CR
Complete response
CrCl
Creatinine clearance
CRR
Complete response rate
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CYP3A
Cytochrome P450 3A
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response
DTP
Direct-to-patient
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
FAS
Full analysis set
Page 48 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
FDA
Food and Drug Administration
FDG
flurodeoxyglucose
FISH
Fluorescent in situ hybridization
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator's Brochure
ICE
intercurrent event
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IMP
Investigational Medicinal Product
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive response technology
ISM
Independent safety monitor
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
MCL
Mantle cell lymphoma
MIPI
Mantle Cell Lymphoma International Prognostic Index
MRD
Minimal residual disease
mRNA
messenger Ribonucleic acid [mRNA]
NCI
National Cancer Institute
NE
Negative estimate
NHL
Non-Hodgkin's lymphoma
OAT
Organic ion transporter
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
Page 49 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
PD
Disease progression
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PP
Per-protocol
PR
Partial response
PT
Prothrombin time
PTT
Partial thromboplastin time
RNA
Ribonucleic acid
R/R
Relapsed/refractory
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
TA MD
Therapeutic Area Medical Director
TLS
Tumor lysis syndrome
Tmax
Time to maximum observed plasma concentration
TTP
Time to progression
ULN
Upper limit of normal
US
United States
Page 50 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M20-075:  Phase 2 Study of the Efficacy and Safety of Venetoclax in Combination with Ibrutinib in 
Japanese Subjects with Relapsed/Refractory Mantle Cell Lymphoma
Protocol Date:  17 November 2023
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws and 
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 to AbbVie, the ethics committees/institutional review boards (as required) and other 
appropriate individuals (e.g., coordinating investigator, institution director):

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others.

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
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)
Page 51 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Statistics Therapeutic Area Lead
Japan TA Oncology and Medical 
Monitor
Japan TA Oncology
Clinical Pharmacology
Clinical Study Leadership
Page 52 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX D. REVISED CRITERIA FOR RESPONSE ASSESSMENT
FOR MALIGNANT LYMPHOMA
Site
PET-CT-Based Response
CT-Based Response
Complete Metabolic Response (CMR)
Complete Radiologic Response (ALL of 
the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3* with or without a 
residual mass on 5PS.**
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiological 
uptake or with activation within spleen 
or marrow, e.g., with chemotherapy or 
myeloid colony stimulating factors, 
uptake may be greater than normal 
mediastinum and/or liver.  In this 
circumstance, CMR may be inferred if 
uptake at sites of initial involvement is 
no greater than surrounding normal 
tissue even if the tissue has high 
physiological uptake.
Target nodes/nodal masses must 
regress to < 1.5 cm in LDi
No extralymphatic sites of disease
Non-measured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid diseases in 
marrow
Normal by morphology; if 
indeterminate, IHC negative
Partial Metabolic Response (PMR)
Partial Remissions (PR) 
(ALL of the following)
Lymph nodes and 
extralymphatic sites
Score 4, 5** with reduced uptake 
compared with baseline and residual 
mass(es) of any size.
At interim these findings suggest 
responding disease 
At end-of-treatment these findings 
indicate residual disease
> 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites
(When a lesion is too small to measure 
on CT, assign 5 mm × 5mm as the 
default value.  When no longer visible, 0 
× 0 mm
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement 
for calculation.)
Non-measured lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed by > 50% in 
length beyond normal
Page 53 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Site
PET-CT-Based Response
CT-Based Response
Complete Metabolic Response (CMR)
Complete Radiologic Response (ALL of 
the following)
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from 
chemotherapy allowed).
If there are persistent focal changes in 
the marrow in the context of a nodal 
response, consideration should be given 
to further evaluation with MRI or biopsy, 
or an interval scan
Not applicable
No Metabolic Response (NMR)
Stable Disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant change in 
FDG uptake from baseline, at interim or 
end-of-treatment.
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes 
and extranodal sites; no criteria for PD 
are met
Non-measured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive Metabolic Disease (PMD)
Progressive disease requires at least 
ONE of the following:
Individual target 
nodes/nodal masses, 
Extranodal lesions
Score 4, 5 with an increase in intensity of 
uptake from baseline and/or New FDG-
avid foci consistent with lymphoma at 
interim or end-of-treatment assessment
PPD Progression:  
An individual node must be abnormal 
with: 
LDi > 1.5 cm AND Increase by ≥ 50% 
from PPD nadir AND an increase in LDi 
or SDi from nadir 
0.5 cm for lesions < 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 50% of 
the extent of its prior increase beyond 
baseline (e.g., a 15 cm spleen must 
increase to > 16 cm).
If no prior splenomegaly, must increase 
by at least 2 cm from baseline
New or recurrent splenomegaly
Non-measured lesions
None
New or clear progression of pre-existing 
non-measured lesions
Page 54 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Site
PET-CT-Based Response
CT-Based Response
Complete Metabolic Response (CMR)
Complete Radiologic Response (ALL of 
the following)
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology, 
e.g., infection, inflammation.  If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered.
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any 
axis if less than 1.0 cm in any axis, its 
presence must be unequivocal and must 
be attributable to lymphoma. 
Assessable disease of any size 
unequivocally attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
CT = computed tomography; FDG = flurodeoxyglucose; LDi = longest transverse diameter of a lesions; PD = disease progression; 
PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SPD = sum of the product of 
the perpendicular diameters for multiple lesions; SPDi = shortest axis perpendicular to the LDi
Measured dominant lesions:  Up to 6 of the largest dominant nodes, nodal masses and extranodal lesions selected to be clearly
measurable in 2 diameters.  Nodes should preferably be from disparate regions of the body, and should include, where 
applicable, mediastinal and retroperitoneal areas.  Non-nodal lesions include those in solid organs, e.g., liver, spleen, kidneys, 
lungs, etc., GI involvement, cutaneous lesions of those noted on palpation.
Non-measured lesions:  Any disease not selected as measured, dominant disease and truly assessable disease should be 
considered not measured.  These sites include any nodes, nodal masses, and extranodal sites not selected as dominant, 
measurable or which do not meet the requirements for measurability but are still considered abnormal.  As well as truly 
assessable disease which is any site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses and other lesions that cannot be
confirmed and followed by imaging.
In Waldeyer's ring or in extranodal sites, e.g., GI tract, liver, and bone marrow, FDG uptake may be greater than mediastinum 
with CMR, but should be no higher than surrounding normal physiologic uptake, e.g., with marrow activation due to 
chemotherapy or myeloid growth factors.
*
Score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  
However, in trials involving PET where de-escalation is investigated, it may be preferable to consider score 3 as inadequate 
response (to avoid under-treatment).
**
PET Five Point Scale (5-PS):
1.
No update above background
2.
Uptake < mediastinum***
3.
Uptake > mediastinum, but < liver
4.
Uptake moderately > liver
5.
Uptake markedly higher than liver and/or new lesions
X.
New areas of uptake unlikely to be related to lymphoma
Source:  Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for initial evaluation, staging, and response assessment
of Hodgkin and non-Hodgkin lymphoma:  the Lugano classification.  J Clin Oncol.  2014;32(27):3059-68.
Page 55 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX E. ACTIVITY SCHEDULE
The following table shows the required study activities.  The individual activities are described in detail 
in the Operations Manual.
Allowed activity schedule modifications due to COVID-19 are detailed within the Operations Manual.
Page 56 of 110
 








  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. SAMPLE LIST OF CAUTIONARY MEDICATIONS
INHIBITORS OR INDUCERS
SUBSTRATES
Strong CYP3A Inhibitors:
Strong CYP3A Inducers:
Substrates of P-gp:
Boceprevir
Avasimibe
Aliskiren
Clarithromycin
Carbamazepine
Ambrisentan
Cobicistat
Phenobarbital
Colchicines
Conivaptan
Phenytoin
Dabigatran etexilate
Indinavir
Rifabutin
Digoxin
Itraconazole
Rifampicin
Everolimus
Ketoconazole
St John's Wort
Fexofenadine
Lopinavir
Lapatinib
Mibefradil
Loperamide
Nefadozone
Moderate CYP3A Inducers:
Maraviroc
Nelfinavir
Bosentan
Nilotinib
Posaconazole
Efavirenz
Ranolazine
Ritonavir
Etravirine
Saxagliptin
Saquinavir
Modafinil
Sirolimus
Telaprevir
Nafcillin
Sitagliptin
Telithromycin
Oxcarbazepine
Talinolol
Troleandomycin
Troglitazone
Tolvaptan
Voriconazolea
Topotecan
Moderate CYP3A Inhibitors:
Weak CYP3A Inducers:
Substrates of BCRP (venetoclax only):
Aprepitant
Amprenavir
Methotrexate
Amprenavir
Aprepitant
Mitoxatrone
Atazanavir
Armodafanil
Irrinotecan
Ciprofloxacin
Clobazamechinacea
Lapatinib
Crizotinib
Glucocorticoids (e.g., prednisone)
Rosuvastatin
Darunavir/ritonavir
Nevirapine
Sulfasalazine
Dronedarone
Pioglitazone
Topotecan
Erythromycin
Rufinamide
Diltiazem
Vemurafenib
Page 60 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
INHIBITORS OR INDUCERS
SUBSTRATES
Fluconazole
Fosamprenavir
Imatinib
Verapamil
Weak CYP3A Inhibitors:
Inhibitors of OATP1B1/B3 
(venetoclax only):
Substrates of OATP1B1/B3 
(venetoclax only):
Alprazolam
Gemfibrozil
Atrasentan
Amiodarone
Eltrombopag
Atorvastin
Amlodipine
Cyclosporine
Ezetimibe
Atorvastatin
Tipranavir
Fluvastatin
Bicalutamide
Glyburide
Cilostazol
Olmesartan
Cimetidine
Inhibitors of BCRP (venetoclax only):
Rosuvastatin
Cyclosporine
Cyclosporine
Simvastatin acid
Fluvoxamine
Geftinib
Pitavastatin
Fluoxetine
Pravastatin
Ginkgo
Repaglinide
Goldenseal
Inhibitors of P-gp (venetoclax only):
Telmisartan
Isoniazid
Amiodarone
Valsartan
Nilotinib
Azithromycin
Oral contraceptives
Captopril
Pazopanib
Carvedilol
Ranitidine
Cyclosporine
Ranolazine
Dronedarone
Suboxone
Felodipine
Tipranavir/ritonavir
Quercetin
Ticagrelor
Quinidine
Zileutin
Ranolazine
Ticagrelor
BCRP = breast cancer resistance protein; CYP3A = cytochrome P450 3A; OAT = organic ion transporter; P-gp = P-glycoprotein
a.
Allowed to dose with 140 mg ibrutinib based on clinical data.
Note:
This is not an exhaustive list.  Further information can be found at:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093
664.htm.
Page 61 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX G. HOWARD CRITERIA FOR LABORATORY AND 
CLINICAL TUMOR LYSIS SYNDROME
Metabolic Abnormality
Criteria for Classification of 
Laboratory Tumor Lysis Syndromea
Criteria for Classification of Clinical 
Tumor Lysis Syndromea
Hyperuricemia
Uric acid > 8.0 mg/dL 
(475.8 µmol/liter) in adults or above 
the upper limit of the normal range 
for age in children
Hyperphosphatemia
Phosphorus > 4.5 mg/dL 
(1.5 mmol/liter) in adults or 
> 6.5 mg/dL (2.1 mmol/liter) 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/liter) or ionized calcium 
< 4.5 mg/dL (1.12 mmol/liter)b
Cardia dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesia, 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 injuryc
Not applicable
Increase in the serum creatinine level of 
0.3 mg/dL (26.5 µmol/liter) (or a single 
value > 1.5 times 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 of 
< 0.5 mL/kg/hr for 6 hours
a.
In laboratory TLS, two or more metabolic abnormalities must be present during the same 24 hour period within 3 days 
before the start of therapy or up to 7 days afterward.  Clinical TLS requires the presence of laboratory TLS plus an 
increased creatinine level, seizures, cardiac dysrhythmia, or death.
b.
The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × 
(4 - albumin in grams per deciliter).
c.
Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µmol per liter) or a 
period of oliguria lasting 6 hours or more.  By definition, if acute kidney injury is present, the patient has clinical TLS.  Data 
about acute kidney injury are from Levin A, Warnock DG, Mehta RL, et al.  Improving outcomes from acute kidney injury:  
report of an initiative.  Am J Kidney Dis.  2007;50:1-4.
Page 62 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX H. RECOMMENDATIONS FOR INITIAL 
MANAGEMENT OF ELECTROLYTE 
ABNORMALITIES AND PREVENTION OF TUMOR 
LYSIS SYNDROME
Section 1:  First Dose of Venetoclax or Dose Escalation

Within the first 24 hours after either the first dose or dose escalation, if any laboratory criteria 
below are met, the patient should be hospitalized for monitoring and the investigator notified.  
No additional venetoclax doses should be administered until resolution.  A rapidly rising serum 
potassium is a medical emergency.

Nephrology (or other acute dialysis service) should be contacted/consulted (per institutional 
standards to ensure emergency dialysis is available) on admission for any subject hospitalized 
prophylactically or in response to laboratory changes.

IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr rounded 
to the nearest 10 mL (target 150 to 200 mL/hr; not < 50 mL/hr).  Modification of fluid rate 
should also be considered for individuals with specific medical needs.

Monitor for symptoms or signs of tumor lysis syndrome (TLS) (e.g., fever, chills, tachycardia, 
nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, 
mental status changes, confusion, seizures).  If any clinical features are observed, recheck 
potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT.

Vital signs should be taken at time of all blood draws or any Intervention.

The management recommendations below focus on the minimum initial responses required.  If 
a diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary 
management will be per institutional protocols.
In addition to the recommendations in the table below:

For potassium increase ≥ 0.5 mmol/L from baseline, or any value > 5.0 mmol/L, recheck 
potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT and follow 
first guideline.

For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate binder and 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT.
Page 63 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Abnormality
Management Recommendations1,2
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 discretion of 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 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 – 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.
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/kg 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.
Page 64 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Abnormality
Management Recommendations1,2
Hyperuricemia
Uric acid ≥ 8.0 mg/dL (476 μmol/L)

Consider rasburicase (0.2 mg/kg as an intravenous infusion over 
30 minutes).

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 pre-dose level

Administer rasburicase (0.2 mg/kg as an intravenous infusion over 
30 minutes).

When rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate precipitation.

Consult 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.
Hypocalcemia
Calcium ≤ 7.0 mg/dL (1.75 mmol/L)
AND
Patient 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.
Page 65 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Abnormality
Management Recommendations1,2
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.
Section 2:  Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals >24 hours after either the first dose or 
dose escalation (e.g., 48 or 72 hours) are as below.
Note:  If the patient is hospitalized, no additional venetoclax doses should be administered until 
resolution.

For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level > upper 
limit of normal.

Refer to the management guidelines for electrolyte changes observed within the first 24 hours 
after either the first dose or dose escalation (see table above).

If a smaller potassium increase is observed that does not meet the criteria for admission above, 
recheck potassium, phosphorus, uric acid, calcium and creatinine in 24 hours and confirm no 
evidence of tumor lysis prior to further venetoclax dosing.

For uric acid, calcium, phosphorus and creatinine, refer to the management guidelines for 
electrolyte changes observed within the first 24 hours after either the first dose or dose 
escalation (see table above).
References
1.
Coiffier B, Altman A, Pui CH, et al.  Guidelines for the management of pediatric and adult tumor 
lysis syndrome: an evidence-based review.  J Clin Oncol.  2008;26(16):2767-78.
2.
Cairo MS, Bishop M.  Tumour lysis syndrome:  new therapeutic strategies and classification.  Br J 
Haematol.  2004;127(1):3-11.
Page 66 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX I.
COVID-19-RELATED INSTRUCTIONS
Instructions related to the COVID-19 pandemic are listed below.
Benefits and Risks to Subjects
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects participating in this 
study has been re-evaluated.  Subjects receiving venetoclax and ibrutinib may be at an increased risk for 
COVID-19 infection or experience serious illness if infected.  Management of these AEs will be made on a 
case-by-case basis with consideration of benefit/risk by the investigators.  However, based on the 
population, the disease being studied, and the anticipation that COVID-19-related risks are unknown 
between study subjects and the broader population of subjects receiving treatment for mantle cell 
lymphoma, no known change to the benefit/risk balance for subjects in this study is expected.
Refer to Section 5.1 for COVID-19 specific eligibility criteria.
Study Subject Information and Informed Consent
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.  An appropriately signed and dated informed consent form 
should be obtained from the subject afterwards, as soon as possible.
COVID-19 Pandemic-Related Acceptable Protocol Modifications for Study Procedures 
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: 

Some study visits and/or activities (e.g., physical examination, vital signs, ECOG) may be 
performed by phone/virtually.  Refer to the sections below for further details. 

Some study visits and/or activities (e.g., ECG) may be performed by a local 
clinic/hospital/laboratory.  These study visits and/or activities are listed in the operations 
manual under 'Local Labs & Exam'.  All procedures performed at local facilities must be 
performed by appropriately qualified personnel.

Some study visits cannot be performed locally or virtually and can only be performed at the 
central lab (e.g., PK and MRD assessment).  Refer to the sections below for further details.

Study Visits and/or activities should be performed as scheduled whenever possible.  If it is not 
possible to do so due to the pandemic, the following modifications are allowed:

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 from the scheduled visit.
Study procedures to be Completed at the Site at Next Feasible Visit
In the event sample collections may not be performed at the primary research site due to study 
modifications related to the COVID-19 pandemic the following procedures can be completed at the next 
earliest feasible visit:
Page 67 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

PK assessments

Biomarker sample collection

ECG (If necessary, the 12-lead ECG may be completed at an alternative local facility)

PET/CT (or MRI) scan (If necessary, the PET/CT [or MRI] scan may be completed at an alternative 
local facility

Endoscopy (If necessary, the endoscopy may be completed at an alternative local facility)
and/or

Disease assessments
The study site will use CB Trial Laboratory provided supplies and collect PK and biomarker samples as 
detailed in the CB Trial Laboratory Manual.  These samples must be collected only after proper dosing 
and other specific requirements per the protocol have been met.  If a subject is unable to go on-site for 
these samples due to COVID-19, these samples may be delayed until the subject is able to return to the 
study site at a later date, following proper dosing and other requirements per-protocol.
Study Procedures that can be Completed virtually via Phone or Video Conference due to 
COVID-19
If permitted by local regulations, the IRB/IEC, and the subject, some study visits may be conducted via 
phone or video conference if disease assessment is not required, and no dose modifications are 
anticipated.  In these situations, vital signs may be obtained by the subject or caregiver as needed. 
The physical examination can be performed via video, if possible.  If not possible, the examination can 
be completed at the next visit when the subject is able to go to the site or can be completed by the 
subject's local physician.  If subject has a home blood pressure and pulse kit and weight scale, subject 
may report these readings over the phone or via video.  In these situations, height and weight may be 
performed by the subject or caregiver as needed.  Additionally, the procedures outlined below can be 
conducted over the phone or via video. 
Adverse event and ECOG assessment can be done over the phone or via video.
Clinical Laboratory Tests
If travel restrictions or other changes in local regulations in light of the COVID-19 pandemic prevent the 
subject from having blood drawn for laboratory testing at the study site, if possible, arrange for subjects 
to have laboratory work done at a local lab, hospital, or other facility.  Local laboratory results should be 
obtained along with reference ranges and kept within the subjects' source documentation.  The 
investigator should review local laboratory results as soon as possible.  
The investigator or designee should confirm with the subject when the lab samples were collected.
Once subject is on a stable dose of venetoclax and ibrutinib for at least 4 weeks, if safety laboratory 
samples cannot be obtained, study drug administration may be continued provided the investigator has 
reviewed all prior laboratory results within 4 weeks 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 
Page 68 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
labs.  The subject should be scheduled for laboratory draws as soon as feasible within 3 days from the 
scheduled visit.
Urine pregnancy tests can be done at a local lab or test kits can be shipped by site staff to the subject.  
Home pregnancy tests should be performed monthly, regardless of ability to obtain other laboratory 
testing.
Withdrawal of Subjects and Discontinuation of Study: 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 K.
The investigator should contact the Sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol to ensure all acceptable mitigation steps have 
been explored. 
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 COVID19 
infection can only be dosed with study drug(s) if the following COVID-19 viral clearance criteria are met:

At least 10 days since first positive test result have passed in asymptomatic patients or at least 
10 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms.
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie medical contact, along with the possibility of premature discontinuation from the study 
drug dosing period.  Follow 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.
Direct-to-patient Study Drug Shipment 
If a subject is unable to come to the study 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.  
The following DTP criteria must be 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, paper copies of 
the patient-reported outcomes).  Instructions will be provided by AbbVie as to how a study 
Page 69 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
site can initiate a DTP shipment using Marken, a global vendor selected by AbbVie to 
provide this service when necessary.  Shipments of study drugs from the study site to a 
subject's home will be appropriately temperature controlled (qualified shipper or 
temperature monitoring) within the labeled storage conditions.  Signature is required upon 
delivery; due to COVID-19-related social distancing, this may be provided by the courier 
after delivery.  Documentation of the shipment is to be retained by the clinical site.

AbbVie will not receive subject identifying information related to these shipments, as the 
site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP shipments of 
study drug, and for obtaining consent to provide delivery information to the courier and documenting 
this consent in source documents.  
Ethical Conduct of the Study
Investigators should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard.
Source Documents and Case Report Form Completion
During the COVID-19 pandemic, remote data review/verification may be employed if allowed by the 
local regulatory authority, IRB/IEC, and the study site.
Supplemental study case report forms should be completed in the event of COVID-19-related 
missed/virtual visits, study drug interruptions or discontinuations, or adverse events (including capture 
of specific signs/symptoms of infection and testing results).
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections should be captured as adverse 
events.  If the event meets the criteria for a SAE, then follow the SAE reporting directions per the 
protocol.  The following COVID-19-related supplemental eCRFs should be completed (for both serious 
and nonserious events of SARS-CoV-2 infections):

COVID-19 Supplemental Signs/Symptoms

COVID-19 Status Form
If a subject has a confirmed or suspected SARS-CoV-2 infection and study drug was interrupted, the 
investigator should contact the Sponsor emergency medical contact listed above before reintroducing 
study drug.
Reactions known to be associated with the SARS-CoV-2 vaccine should be reported as adverse events.  If 
the event meets the criteria for an SAE, then follow the SAE reporting directions.  All adverse events 
associated with the SARS-CoV-2 vaccine will be linked to the vaccine on the COVID-19 Vaccine eCRF.
COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., messenger Ribonucleic acid 
[mRNA], non-replicating viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be 
Page 70 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
administered during screening or the treatment period, as long as components of the vaccine are not 
contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of venetoclax and ibrutinib on SARS-CoV-2 vaccination is unknown and there is no 
restriction related to the administration of study drugs in this study.  
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
vaccination course.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in patients with mantle cell lymphoma and as more data are collected in real-world 
scenarios and clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
'Source Documents and Case Report Form Completion' section of Appendix I for instructions on 
reporting any adverse events associated with the COVID-19 vaccine.
COVID-19 Vaccine-related Lymphadenopathy and FDG PET/CT Timing 
Transient flurodeoxyglucose (FDG) uptake in normal or enlarged axillary, supraclavicular, and cervical 
lymph nodes have been reported after an ipsilateral deltoid vaccination.  This phenomenon may 
confound interpretation in oncology patients undergoing FDG PET/CT.  It is recommended to consider 
influence of the COVID-19 vaccination to PET/CT, this includes leaving an interval of 4-6 weeks after 
inoculation by the Japan Cancer Treatment Society. 
Given increased immunogenicity of mRNA vaccines and to allow resolution of lymphadenopathy, the 
optimal timing for disease assessment is 4-6 weeks after COVID-19 vaccination.  Although, vaccine-
related lymphadenopathy and FDG uptake on PET/CT can mimic cancer and lead to confounding imaging 
results in some cases, it is reported that PET/CT should not be delayed when clinically indicated to be 
performed sooner.35-37
As per the discussion with AbbVie's internal study team, we propose the following strategies to be 
followed for the Disease Assessments:

Please schedule the study visits including the PET/CT imaging and the Disease Assessments as 
outlined in Appendix E and the Operations Manual.

If a COVID-19 vaccination (1st or 2nd dose) is also scheduled around the same time as of the 
scheduled study visits, it is preferable that the vaccine to be injected after all the study 
procedures including the PET/CT scans have already been performed. 

If a Disease Response assessment shows Partial remission, Stable Disease, or Disease 
Progression after COVID-19 vaccination, the Sponsor may ask investigator to perform 
confirmatory PET/CT scans to determine the validity of this assessment. 
Page 71 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in patients with relapsed/refractory Mantle Cell Lymphoma and as more data are 
collected in real-world scenarios and clinical trials. 
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  If you have 
any questions, please do not hesitate to contact your responsible CRA or the study Medical 
Monitor/Therapeutic Area Medical Director.
Page 72 of 110
 


  
STUDY M20-075 | Version 5.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX J.
PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
07 May 2020
Version 2.0
31 October 2020
Version 3.0
17 February 2022
Administrative Change 1
12 July 2022
Version 4.0
04 January 2023
The purpose of this version is to correct clerical errors for consistency throughout the protocol and 
incorporate necessary protocol modifications, including those outlined as follows:

The list of signatories in Appendix C was updated.

In Appendix E and Appendix K requirements for PET scans during response assessments and 
scheduled follow-up visits were removed reflect that primary analysis was completed and 
further IRC assessment will not be conducted.

Appendix G replaced hypocalcemia classification for lab TLS from "Corrected calcium < .75 
mg/dL (1.75 mmol/liter) or ionized calcium < 1.12 mg/dL (0.03 mmol/liter)") to "Corrected 
calcium < 7.0 mg/dL (1.75 mmol/liter) or ionized calcium < 4.5 mg/dL (1.12 mmol/liter)" to align 
with the review article from which the value was cited.38

The SAE reporting fax numbers in Appendix K were updated.
Page 73 of 110
 

SAP_001.pdf: 
Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
1
Statistical Analysis Plan for Study M20-075
Phase 2 Study of the Efficacy and Safety of 
Venetoclax in Combination with Ibrutinib in 
Japanese Subjects with Relapsed/Refractory Mantle 
Cell Lymphoma
Date:  16 April 2022
Version 2.0
 
NCT04477486


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
2
Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses and Estimands................................................... 5
2.2
Study Design Overview.......................................................................... 7
2.3
Treatment Assignment and Blinding....................................................... 8
2.4
Sample Size Determination .................................................................... 8
3.0
Endpoints...............................................................................9
3.1
Primary Endpoint ................................................................................... 9
3.2
Secondary Endpoints.............................................................................. 9
3.3
Other Efficacy Endpoints ..................................................................... 10
3.4
Safety Endpoints .................................................................................. 10
3.5
Pharmacokinetic Endpoints .................................................................. 11
4.0
Analysis Populations ...........................................................11
5.0
Subject Disposition..............................................................11
6.0
Study Drug Duration and Compliance ..............................12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................13
7.1
Demographics and Baseline Characteristics.......................................... 13
7.2
Medical History.................................................................................... 15
7.3
Prior and Concomitant Medications...................................................... 15
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary endpoints.....................................16
9.0
Efficacy Analyses.................................................................16
9.1
General Considerations......................................................................... 16
9.2
Handling of Missing Data..................................................................... 17
9.3
Primary Efficacy Endpoint and Analyses.............................................. 17
9.3.1
Primary Efficacy Endpoint ................................................................... 17
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 17
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 18
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 18
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
3
9.4.1
Secondary Efficacy Endpoints.............................................................. 18
9.4.2
Main Analyses of Secondary Efficacy Endpoints.................................. 20
9.4.3
Supportive Secondary Efficacy Analyses.............................................. 21
10.0
Safety Analyses....................................................................21
10.1
General Considerations......................................................................... 21
10.2
Adverse Events..................................................................................... 21
10.2.1
Treatment-Emergent Adverse Events.................................................... 22
10.2.2
Adverse Event Overview...................................................................... 23
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 24
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 24
10.2.5
Adverse Events of Special Interest........................................................ 24
10.3
Analysis of Laboratory Data................................................................. 25
10.4
Analysis of Vital Signs......................................................................... 27
11.0
Pharmacokinetic Analyses..................................................27
11.1
Tabulations and Summary Statistics ..................................................... 27
12.0
Interim Analyses..................................................................28
12.1
Independent Safety Monitor ................................................................. 28
13.0
Overall Type-I Error Control.............................................28
14.0
Version History ...................................................................29
15.0
References............................................................................29
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint............................................................................................... 18
Table 2.
Summary of the Estimand Attributes of the Key Secondary 
Efficacy Endpoints ............................................................................... 20
Table 3.
SAP Version History Summary ............................................................ 29
List of Figures
Figure 1.
Study Schematic..................................................................................... 8
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
4
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 30
Appendix B.
Definition of Adverse Events of Special Interest................................... 31
Appendix C.
Potentially Clinically Important Criteria for Safety............................... 32
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for venetoclax 
Study M20-075:  "Phase 2 Study of the Efficacy and Safety of Venetoclax in Combination 
with Ibrutinib in Japanese Subjects with Relapsed/Refractory Mantle Cell Lymphoma," 
protocol amendment 3.0 dated February 17, 2022.
Study M20-075 examines the efficacy and safety of venetoclax and ibrutinib in subjects 
with relapsed/refractory (R/R) mantle cell lymphoma (MCL).
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The primary objective of the study is to evaluate the effect on best overall response of 
complete response (CR) of the concurrent administration of venetoclax and ibrutinib in 
Japanese subjects with R/R MCL.
The hypothesis corresponding to the primary objective is to demonstrate superiority of 
venetoclax in combination with ibrutinib against a historical reference of 12.5% complete 
response rate (CRR) in Japanese subjects with R/R MCL treated with ibrutinib only.
The estimand corresponding to the primary objective is:
Proportion of best overall response of CR as assessed by IRC, for subjects receiving 
venetoclax in combination with ibrutinib (with approximately 104 weeks on combination 
therapy, followed by ibrutinib monotherapy until disease progression [PD]), regardless of 
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
6
whether or not the subject is receiving study drugs and regardless the use of other 
anti-MCL treatments, in the R/R MCL subjects. 
The secondary objectives of the study are:
●
To evaluate the effect on best overall response of CR or partial response (PR), 
duration of response (DOR), MRD, PFS, and OS of the concurrent 
administration of venetoclax and ibrutinib in Japanese subjects with R/R MCL.
●
To evaluate the safety and tolerability of the concurrent administration of 
venetoclax and ibrutinib in Japanese subjects with R/R MCL.
●
To evaluate the pharmacokinetics of venetoclax and ibrutinib in Japanese 
subjects with R/R MCL.
Hypotheses corresponding to the secondary objectives, are to achieve positive results with 
venetoclax in combination with ibrutinib (i.e., greater proportion of subjects achieving 
favorable outcomes or longer duration of positive benefits, etc.).
The estimands corresponding to the secondary objectives are:
●
Proportion of subjects achieving:
○
Best overall response of CR or PR (as assessed by Independent Review 
Committee [IRC]/investigator)
○
Best overall response of CR (as assessed by investigator)
○
Undetectable MRD (disease assessed by IRC/investigator)
With venetoclax in combination with ibrutinib (with approximately 
104 weeks on combination therapy, followed by ibrutinib monotherapy 
until PD), regardless of whether or not the subject is receiving study drugs 
and regardless of the use of other anti-MCL treatments, in the R/R MCL 
subjects.
●
The median time-to-event (if estimable) will be estimated for the following 
endpoints:
○
Duration of response (as assessed by IRC/investigator)
○
PFS (as assessed by investigator)
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
7
○
OS
with venetoclax in combination with ibrutinib (with approximately 
104 weeks on combination therapy, followed by ibrutinib monotherapy 
until PD), regardless of whether or not the subject is receiving study drugs 
and regardless of the use of other anti-MCL treatments, in the R/R MCL 
subjects. 
2.2
Study Design Overview
This Phase 2, open-label, single-arm study is designed to evaluate the efficacy and safety 
of the combination of venetoclax and ibrutinib in Japanese subjects with R/R MCL.
Approximately 12 subjects will receive ibrutinib at 560 mg once daily until progression 
and venetoclax starting at 20 mg once daily and gradually ramped up to a target dose of 
400 mg once daily over a 5-week period for a maximum period of 104 weeks.
Dose-limiting toxicities will be evaluated in the first 6 subjects, from Day 1 for a 
minimum of 5 weeks and at least 1 week of venetoclax dosing at 400 mg, in order to 
confirm the initial safety and tolerability in Japanese subjects.  After the completion of the 
DLT evaluation period in the first 6 subjects, the AbbVie Study Team and investigators 
who enrolled the 6 treated subjects will review all available safety and PK data to evaluate 
the tolerability of venetoclax in combination with ibrutinib in Japanese subjects with R/R 
MCL.  If there are zero or 1 DLTs in the first 6 subjects, enrollment of the additional 
6 subjects will proceed.  If DLTs are observed in 2 or more of the first 6 subjects, further 
enrollment in Japan will be interrupted and additional, a detailed safety assessment will be 
conducted.
A DLT is defined as any Grade ≥ 3 adverse events considered to be at least possibly 
related to study drug (ibrutinib and/or venetoclax) and occurring during the DLT 
assessment period as defined in protocol Section 6.3.  Under certain circumstances as 
defined in protocol Section 6.3, a subject is not evaluable for DLT, that subject will be 
replaced but are included for efficacy analysis.
 




Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
9
in the study have received the combination for a minimum of 5 weeks and at least 1 week 
of venetoclax dosed at 400 mg.
Using exact binomial test, with an expected complete response rate (CRR) of 50% for 
venetoclax in combination with ibrutinib and a threshold CRR of 12.5%, 12 subjects will 
provide 80% power to demonstrate superiority of venetoclax in combination with 
ibrutinib against a historical reference of 12.5% CRR in the ibrutinib only Japanese study 
with R/R MCL, at a 1-sided overall significance level of 0.025.  A significant test result is 
achieved when at least 5 CRs are observed among 12 subjects, corresponding to a 
minimal observed CRR of 41.7%.
If the first 12 subjects include one or more subjects who are assessed by the IRC as non-
evaluable at baseline, then additional subject(s) will be enrolled at the Sponsor's discretion 
to ensure that there are 12 evaluable subjects per IRC assessment for primary endpoint 
analysis.
3.0
Endpoints
3.1
Primary Endpoint
The primary endpoint is best overall response of CR according to the Revised Criteria for 
Response Assessment (Cheson 2014)1 as assessed by the Independent Review Committee 
(IRC).  The best overall response of CR is defined as achieving an overall response of CR 
at any time point during the study.
3.2
Secondary Endpoints
The secondary efficacy endpoints are listed below:
●
Investigator-assessed best overall response of CR, according to the Revised 
Criteria for Response Assessment (Cheson 2014).1
●
IRC-assessed best overall response of CR or PR (defined as achieving partial 
metabolic and/or radiologic response at any time point during the study 
according to the Revised Criteria for Response Assessment (Cheson 2014).1
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
10
●
Investigator-assessed best overall response of CR or PR, according to the 
Revised Criteria for Response Assessment (Cheson 2014).1
●
Investigator-assessed DOR, defined for subjects who achieve a best overall 
response, as the time from the first occurrence of response to disease 
progression or death, whichever occurs first, according to the Revised Criteria 
for Response Assessment (Cheson 2014).1
●
IRC-assessed DOR, defined for subjects who achieve a best overall response, 
as the time from the first occurrence of response to disease progression or 
death, whichever occurs first, according to the Revised Criteria for Response 
Assessment (Cheson 2014).1
●
Undetectable MRD in subjects who achieve a best overall response of CR as 
assessed by investigator, according to the Revised Criteria for Response 
Assessment (Cheson 2014).1
●
Undetectable MRD in subjects who achieve a best overall response of CR as 
assessed by IRC, according to the Revised Criteria for Response Assessment 
(Cheson 2014).1
●
Progression-free survival (PFS), defined as the time from the date of the first 
dose of any study drug (venetoclax or ibrutinib) to the date of investigator-
assessed disease progression, using the Revised Response Criteria for Response 
Assessment (Cheson 2014),1 or death from any cause, whichever occurs first.
●
Overall Survival, defined as the time from the date of the first dose of any study 
drug (venetoclax or ibrutinib) to death from any cause.
3.3
Other Efficacy Endpoints
Not applicable. 
3.4
Safety Endpoints
Safety and tolerability will be assessed by evaluating DLTs, adverse events, physical 
examinations, and changes in laboratory data (hematology, chemistry, and urinalysis) and 
vital signs for the entire study treatment duration.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
11
3.5
Pharmacokinetic Endpoints
Intensive blood samples for analysis of venetoclax and ibrutinib PK will be collected at 
Week 6 Day 1.  Values for the pharmacokinetic parameters of venetoclax and ibrutinib 
will be determined at steady state using noncompartmental methods.  The maximum 
observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the area-under-
the-plasma concentration-time curve (AUC) over the dosing interval (AUCtau) will be 
determined.  Additional analyses may be performed as appropriate based on data 
availability.
4.0
Analysis Populations
The following population set will be used for the analyses:
The full analysis set (FAS) includes all subjects who received at least 1 dose of study 
drug.  The FAS will be used for all efficacy (except the endpoints based on IRC 
assessment), safety, pharmacokinetic, and baseline analyses.
The per protocol (PP) population excludes FAS subjects who have been determined as 
having non-evaluable disease at baseline, based on IRC assessment.  PP population will 
be used for IRC assessed endpoints. PP population will be used to compare the sensitivity 
of IRC endpoints with investigator assessed endpoints.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled, and treated will be 
summarized.  Reasons for exclusion, including screen failure, will be listed.  Analysis for 
subject disposition will be based on FAS.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects enrolled in the study
●
Subjects in each analysis population, FAS, and PP population.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
12
●
Subjects who discontinued study drug (venetoclax and ibrutinib) (all reasons 
and primary reason)
●
Subjects who discontinued study.
6.0
Study Drug Duration and Compliance
For the FAS, duration of treatment will be summarized for each study drug 
(venetoclax/ibrutinib) and for venetoclax and ibrutinib combination.  Duration of 
treatment is defined for each subject as last dose date minus first dose date +1.  Duration 
of study drug (venetoclax/ibrutinib) and the combination will be summarized using the 
number of subjects treated, mean, standard deviation, median, minimum, and maximum.  
In addition, the number and percentage of subjects in each study drug and the combination 
duration interval will be summarized as below:
●
0 to 4 weeks
●
> 4 weeks to 8 weeks
●
> 8 weeks to 12 weeks
●
> 12 weeks to 16 weeks
●
> 16 weeks to 20 weeks
●
> 20 weeks to 24 weeks
●
> 24 weeks to 28 weeks
●
> 28 weeks to 32 weeks
●
> 32 weeks to 36 weeks
●
> 36 weeks to 52 weeks
●
52 weeks 
The number and percentage of subjects with dose reduction and dose interruption of 
venetoclax/ibrutinib will be summarized by the number of occurrences of dose reduction 
or interruption as no, 1 time, 2 times, or > 2 times.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
13
Relative dose intensity (RDI) will be calculated for venetoclax/ibrutinib using observed 
dose intensity (ODI) and planned dose intensity (PDI):
●
ODI: Actual total dose/ Actual total duration of treatment exposure (days)
●
PDI: 
○
PDI (mg/day) for venetoclax is calculated as the total amount of the 
planned dose (mg) during the maximum treatment period allowed (104 
weeks) divided by the duration of the maximum treatment period allowed 
(104 weeks).  Venetoclax started at 20 mg once daily and gradually ramped 
up to a target dose of 400 mg once daily over a 5-week period for a 
maximum period of 104 weeks.
○
PDI for Ibrutinib is based on fixed daily dosing of 560 mg/day.
●
RDI (%) will be calculated as ODI/PDI *100 %.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the PP population and FAS.  Categorical 
variables will be summarized with the number and percentage of subjects; percentages 
will be calculated based on the number of non-missing observations.  Continuous 
variables will be summarized with descriptive statistics (number of non-missing 
observations, mean and standard deviation, median, minimum, and maximum).
7.1
Demographics and Baseline Characteristics
All baseline characteristic summary statistics and analyses are based on characteristics 
prior to the first dose of study drug.
Distributions of the continuous demographic and baseline characteristic variables will be 
summarized by treatment arm with the number of non-missing observations, mean, 
standard deviation, and median, as well as the minimum and maximum values.  For the 
categorical demographic and baseline characteristic variables, the frequency and 
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
14
percentages of subjects within each category will be summarized.  The number of subjects 
with missing information will also be summarized.
The following demographic and baseline characteristics will be summarized:
Demographics:
●
Age (years) and age categories age (< 40, 40 – 65, ≥ 65 years)
●
Gender (Male, Female)
●
Race (Asian, Others)
●
If Asian (Japanese, non-Japanese)
●
Height (cm)
●
Weight (kg)
●
Tobacco user (current, former, never, unknown)
●
Alcohol user (current, former, never, unknown).
Baseline and Disease-Related Characteristics:
●
ECOG performance status (Grade 0, 1, 2)
●
Relapsed or refractory
●
Prior bone marrow involvement (Yes/No)
●
Prior GI involvement (Yes/No)
●
TLS risk category (High, Low)
●
B-symptoms (Yes, No)
●
Child-Pugh Classification (A, B, C)
●
Number of prior regimens (1, 2, ≥ 3)
●
MIPI score (Low, Intermediate, High)
●
Bulky disease (< 5 cm, ≥ 5 cm)
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
15
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA 23.0).  The actual version of the MedDRA coding dictionary will be noted in 
the statistical tables and clinical study report.  The number and percentage of subjects in 
each medical history category (by MedDRA system organ class and preferred term) will 
be summarized.  The system organ class (SOC) will be presented in alphabetical order, 
and the preferred terms will be presented in alphabetical order within each SOC.  Subjects 
reporting more than one condition/diagnosis will be counted only once in each row (SOC 
or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug, but not 
after the date of the last dose of study drug.  The number and percentage of prior 
medication will be summarized.  The number and percentage of subjects taking 
medications will be summarized by generic drug name based on the World Health 
Organization (WHO) Drug Dictionary for both prior and concomitant medications.  The 
number and percentage of subjects who received CYP3A inhibitors and/or P-gp 
inhibitors, and/or antiplatelet agents and anticoagulants will be summarized by 
moderate/strong CYP3A inhibitors, moderate P-gp inhibitors and antiplatelet agents and 
anticoagulants.
In addition, post-treatment oncology medications will be summarized and/or listed.  A 
post-treatment oncology medication is defined as any oncology medications taken after 
the discontinuation of study drug.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
16
8.0
Handling of Potential Intercurrent Events for the 
Primary and Secondary endpoints
The primary endpoint of best overall response of CR will be analyzed based on the PP 
population and the secondary endpoints will be analyzed based on the PP/FAS population, 
as appropriate, the following potential intercurrent events (ICEs) will be considered:
●
ICE1: Subjects with study drug discontinuation 
●
ICE2: Subjects with the use of other anti-MCL treatment
And will be handled for both primary and secondary endpoints based on the following 
strategy:
●
The disease assessments after ICE1 and ICE2 will be used for the derivation of 
all endpoints.
9.0
Efficacy Analyses
9.1
General Considerations
PP population will be used for primary endpoint.  PP population/FAS will be used for 
other efficacy endpoints, as appropriate.
All tests will be 1-sided at an alpha level of 0.025.
In the DLT assessment period, the first 6 study subjects enrolled was evaluated for the 
tolerability of the venetoclax and ibrutinib combination for a minimum of 5 weeks and at 
least 1 week of venetoclax dosing at 400 mg.  DLT assessment committee along with ISM 
recommended that 'the study to be continued for full enrollment'.
The primary analysis will be performed after all subjects enrolled in the study have 
completed Week 13 disease assessment or have discontinued study, whichever is early.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
17
The best overall response will be derived for each subject based on timepoint-wise disease 
assessments, according to the response categories ordered as CR > PR > SD > PD > NE 
(Not evaluable).  Each subject will be assigned a "best overall response" based on the 
above-mentioned rule.
Unless otherwise specified, "Baseline" refers to the last non-missing observation before 
the first administration of study drug.
9.2
Handling of Missing Data
Details on the handling of missing data are described in the analysis section corresponding 
to each endpoint.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the best overall response of CR based on IRC 
assessment and will be evaluated using complete response rate (CRR), defined as 
proportion of subjects achieving best overall response of CR.
Subjects in PP population but have no post-baseline disease assessment will be considered 
as non-responders in the calculation of CRR.  Subjects who have not achieved best overall 
response of CR at the time of analysis will be considered as non-responders in the 
calculation of CRR.
9.3.2
Main Analysis of Primary Efficacy Endpoint
The attributes of the estimand corresponding to the primary efficacy endpoint are 
summarized in Table 1.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
18
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Attributes of the Estimand
Estimand 
Label
Treatment
Population
Endpoint
Handling of 
Intercurrent events
Statistical 
Summary
CRR
Venetoclax 
+ Ibrutinib 
combination 
for a 
maximum of 
104 weeks 
followed by 
Ibrutinib 
monotherapy 
until PD
PP 
population
IRC-
assessed 
best overall 
response of 
CR
ICE1: Study drug 
discontinuation
ICE2: Use of other 
anti-MCL treatment 
All data will be used 
regardless of ICE1 or 
ICE2.
CRR and 95% CI
The analysis of CRR will be based on exact binomial distribution.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
A sensitivity analysis of best overall response of CR will be performed based on 
investigator's assessment.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Secondary Efficacy Endpoints
The secondary endpoints (except for MRD and OS) will be assessed according to the 
Revised Criteria for Response Assessment (Cheson 2014)1.  Endpoint of best overall 
response of CR or PR will be evaluated using overall response rate (ORR).  ORR is 
defined as the proportion of subjects with a best overall response of CR or PR.  This 
endpoint is assessed separately per IRC and investigator's assessment.
DOR of CR is defined as the time from the first occurrence of response of best overall 
response of CR to disease progression or death, whichever occurs first.  If a subject is still 
responding, subjects will be censored at the date of the last adequate disease assessment.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
19
DOR of CR or PR is defined as the time from the first occurrence of best overall response 
of CR or PR to disease progression or death, whichever occurs first.  If a subject is still 
responding, subjects will be censored at the date of the last adequate disease assessment.
DOR (of CR, of CR or PR) analyses will be performed separately for IRC and 
investigator assessed responses.
Endpoint of undetectable MRD (uMRD) is defined as subject achieving uMRD (defined 
as subjects having < 0.05% MCL cells per 10,000 leukocytes) and a best overall response 
of CR.  MRD will be assessed by flow cytometry of peripheral blood sample per central 
laboratory for all subjects.  The proportion of subjects with undetectable MRD who 
achieve a best overall response of CR will be provided, separately for IRC and 
investigator assessed CR.
Progression-free survival is defined as the time from the date of the first dose of any study 
drug (venetoclax or ibrutinib) to the date of investigator-assessed disease progression, or 
death from any cause, whichever occurs first.  All events of disease progression will be 
included, regardless of whether the event occurred while the subject was still taking study 
drug or after the subject discontinued study drug.  If the subject does not experience 
disease progression or death, then the data will be censored at the date of the last adequate 
disease assessment.  Data for subjects without any disease assessments performed after 
the baseline visit will be censored at the date of the first dose.
Overall survival is defined as the time from the date of the first dose of any study drug 
(venetoclax or ibrutinib) to death from any cause.  All events of death will be included, 
regardless of whether the event occurred while the subject was still taking study drug or 
after the subject discontinued study drug or the subject was on other anti-MCL treatment.  
If a subject has not died, then the data will be censored at the date the subject was last 
known to be alive.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
20
9.4.2
Main Analyses of Secondary Efficacy Endpoints 
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
summarized in Table 2.
Table 2.
Summary of the Estimand Attributes of the Key Secondary Efficacy 
Endpoints
Attributes of the Estimand
Estimand 
Label
Treatment
Population
Endpoint
Handling of 
Intercurrent 
Events
Statistical 
Summary
Best 
overall 
response
Venetoclax + 
Ibrutinib
combination 
for a 
maximum of 
104 weeks 
followed by 
Ibrutinib 
monotherapy 
until PD
PP 
population/FAS, 
as appropriate
Investigator-
assessed best 
overall 
response of 
CR.
IRC-assessed 
best overall 
response of 
CR or PR
ICE1: Study 
drug 
discontinuation
ICE2: Use of 
other anti-MCL
treatment
All data will be 
used regardless 
of ICE1 or ICE2.
CRR and 95% CI
ORR and 95% CI
uMRD
PP 
population/FAS, 
as appropriate
Undetectable 
MRD for a 
subject with 
IRC-assessed 
BOR of CR
Undetectable 
MRD for a 
subject with 
investigator-
assessed 
BOR of CR
uMRD rate and 
95% CI
DOR
PP 
population/FAS, 
as appropriate
IRC-assessed 
DOR of CR, 
DOR of CR 
or PR 
Investigator-
assessed 
DOR of CR, 
DOR of CR 
or PR
K-M estimate at 
specified time-
points and their 
corresponding 
95% CI 
Median DOR and 
95% CI 
KM curve
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
21
Attributes of the Estimand
Estimand 
Label
Treatment
Population
Endpoint
Handling of 
Intercurrent 
Events
Statistical 
Summary
PFS
PP 
population/FAS, 
as appropriate
Investigator-
assessed PFS 
K-M estimate at 
specified time-
points and their 
corresponding 
95% CI
Median PFS and 
95% CI
KM curve
OS
FAS
OS 
K-M estimate at 
specified time-
points and their 
corresponding 
95% CI
Median OS and 
95% CI
KM curve
The analysis of CRR, ORR and uMRD rates will be based on exact binomial distribution.
The analysis of DOR, PFS and OS will be based on Kaplan-Meier methodology.
9.4.3
Supportive Secondary Efficacy Analyses
Not applicable.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Full Analysis Set defined in Section 4.0.
10.2
Adverse Events
Adverse events (Aes) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
22
coding dictionary used for the study at the time of database lock.  The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report.  Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise.  In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent Aes are defined as any AE with the onset that is after the first dose of 
study drug until 30 days after the last dose of the study drug for subjects.  Events where 
the onset date is the same as the study drug start date are assumed to be treatment-
emergent.  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.
All treatment-emergent Aes will be summarized overall, as well as by primary MedDRA 
SOC and Preferred Term.  The SOCs will be presented in alphabetical order, and the PTs 
will be presented in alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
23
10.2.2
Adverse Event Overview
An overview of Aes will be presented consisting of the number and percentage of subjects 
experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent adverse event
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE 
version 4.03) grade 3, adverse events
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE 
version 4.03) grade 4 adverse events
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE 
version 4.03) grade 5 adverse events
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE 
version 4.03) grade 3 or 4 adverse events
●
Any treatment-emergent adverse events leading to DLT
●
Any treatment-emergent adverse events related to COVID-19 infection
●
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 serious adverse event
●
Any treatment-emergent adverse event leading to death
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
24
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum grade and SOC and PT; and by 
subject number and SOC and PT.  Specific adverse events will be counted once for each 
subject for calculating percentages, unless stated otherwise.  In addition, if the same 
adverse event occurs multiple times within a subject, the highest grade and level of 
relationship to investigational product will be reported.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency.
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and Aes leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
The number of subject deaths will be summarized/listed:
●
All deaths in this study regardless of the number of days after the last dose of 
study drug 
●
Deaths occurring ≤ 30 days after the last dose of study drug
10.2.5
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs).  Adverse events of 
special interest along with the detailed information about the search criteria are provided 
in Appendix B.  Tabular listings of selected adverse events of special interest will be 
provided.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
25
10.3
Analysis of Laboratory Data
Data collected from local laboratories, including additional laboratory testing due to an 
SAE, will be used in all analyses, except for Baseline where SAE-related laboratory 
assessments on or before the first dose of study drug will be excluded.  The clinical 
laboratory tests defined in the protocol operations manual (e.g., hematology and clinical 
chemistry) will be summarized.
Baseline is defined as the last non-missing observation before the first administration of 
study drug if no study drug is given.
Changes from baseline will be analyzed for each chemistry, hematology parameters.  The 
change from baseline mean, standard error, min, median, max and 95% confidence 
interval will be presented for the mean change from baseline for the post-baseline 
maximum value.
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse 
Events (NCI CTCAE version 4.03), baseline and post-baseline laboratory observations 
will be categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 according to NCI
CTCAE grade version 4.03.  The baseline and final grades will be defined respectively as 
the grade of the last measurement collected on or prior to the first dose of study drug, and 
as the last post-baseline measurement collected no more than 30 days after 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.  If a subject had missing baseline 
and non-missing post-baseline for a given lab, the baseline grade will be assumed to be 
grade 0.  The maximum NCI toxicity grade value is the value with highest NCI toxicity 
grade collected after the first dose of study drug.
For each lab test, cross tabulate will be generated for the number of subjects with baseline 
values of grade 0, grade 1, grade 2, grade 3, grade 4, or missing grade versus maximum 
post-baseline values of grade 0, grade 1, grade 2, grade 3, grade 4, or missing grade.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
26
An upward shift table from grade 0 – 2 at baseline to grade 3 or 4 post-baseline 
(maximum) will be provided.
Treatment emergent laboratory abnormalities based on the two criteria below will be 
generated for each laboratory tests related to CTCAE:
1.
Shifts from grade 0 (normal) at baseline to grade 1– 4 post-baseline (maximum) 
and worsening from an abnormal baseline value of at least one grade up post-
baseline (maximum)
2.
Shifts from grade 0 – 2 at baseline to grade 3 or 4 post-baseline (maximum) and 
from grade 3 at baseline value to grade 4 post-baseline (maximum).
For above shift tables, baseline grade of 0 (normal) will be imputed for all subjects with at 
least one post-baseline but missing a baseline value for each lab test.
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.
Number and percentage of subjects meeting the Howard criteria for tumor lysis syndrome 
(TLS) will be presented.
The Howard Criteria for TLS is defined as two or more of the following treatment-
emergent lab changes within a 24-hour period.  The evaluation period for TLS is the first 
7 days from the date of the first dose:
●
Uric Acid > 475.8 mcmol/L,
●
Potassium > 6 mmol/L,
●
Inorganic Phosphorus > 1.5 mmol/L
●
Calcium < 1.75 mmol/L.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
27
TLS events are defined as:
●
Clinical TLS: any event that meets Howard criteria with the following 
exceptions:
○
For the purpose of TLS assessment during the DLT evaluation period, only 
those increases in serum creatinine > 1.0 mg/dL from pre-treatment 
baseline will be considered clinical TLS.
○
In subjects with renal dysfunction at baseline (CrCl < 60 mL/min), clinical 
TLS is defined as the presence of laboratory TLS plus either seizures, 
cardiac dysrhythmia, or death.
●
Laboratory TLS: any event that meets Howard criteria for laboratory TLS, that 
does not resolve within 72 hours despite protocol required management.
A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions simultaneously, will be provided:  ALT > 3 × ULN or AST > 3 × ULN that is 
associated with an increase in bilirubin > 2 × ULN within 72 hours of each other.
10.4
Analysis of Vital Signs
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix C, Table C-1).  For each vital sign PCI criterion, the number and 
percentage of subjects who have a vital sign value meeting the criteria will be 
summarized.  Listings will be provided to summarize subject-level vital sign data for 
subjects meeting PCI criteria.
11.0
Pharmacokinetic Analyses
11.1
Tabulations and Summary Statistics
Summary statistics of plasma concentrations of venetoclax and ibrutinib will be computed 
for each sampling time.  Pharmacokinetic parameter values of venetoclax and ibrutinib
will be summarized as applicable.  Additional analyses will be performed if useful and 
appropriate.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
28
12.0
Interim Analyses
There is no planned interim efficacy analysis for this study.  However, a safety analysis of 
tolerability of the venetoclax and ibrutinib combination will be performed after the first 6 
evaluable subjects have been on the combination for a minimum of 5 weeks and at least 1 
week of venetoclax dosed at 400 mg.
12.1
Independent Safety Monitor
For DLT assessments of the first 6 evaluable subjects enrolled, sponsor will appoint an 
Independent Safety Monitor (ISM), who will be a Japan medical oncologist with 
experience in clinical studies and who is familiar with the safety assessment of antitumor 
agents.  The Sponsor will consult the Independent Safety Monitor (ISM) with results of 
the safety evaluation and Sponsor's conclusion on tolerability, then receive the answer 
from ISM.  The Sponsor will recommence subject enrolment based on the safety review 
and only if agreed by the ISM.  Depending on the results of the safety review by ISM, 
revising the protocol will be considered where necessary.  Detailed procedures for safety 
assessments will be described in a separately prepared document for operational purposes.
Since only safety and PK data (if available at the time of tolerability assessment meeting) 
are to be assessed for DLT, so no alpha adjustment is needed.
13.0
Overall Type-I Error Control
The overall type I error rate of 1-sided 0.025 will be used to determine the statistical 
significance of the primary endpoint at the time of primary analysis.  All other analyses 
will be done for descriptive purpose.  Hence, no multiplicity adjustment of type I error is 
needed.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
29
14.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
12 Nov 2020
Original version
2.0
16 Apr 2022
Amendment 1
15.0
References
1.
Cheson BD, Fisher RI, Barrington SF, et al.  Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin 
lymphoma:  the Lugano classification.  J Clin Oncol.  2014;32(27):3059-68.
 
 
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
30
Appendix A.
Protocol Deviations
A listing of subjects who reported at least one (but not limited to) of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
31
Appendix B.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESI) and Selected AEs will be identified using the 
following search criteria:
Risk
Search Criteria
Tumor Lysis Syndrome 
SMQ 20000219 – "Tumour lysis syndrome" (Narrow-scope)
Neutropenia – expanded search
Neutropenia CMQ 80000171
Neutropenia
PT terms – "Neutropenia" and "Neutrophil count decreased"
Serious Infection
SAEs in the SOC of "Infections and Infestations"
Second Primary Malignancy 
SMQ 20000194 – "Malignant tumours" (Narrow) and SMQ 
20000217 - "Myelodysplastic syndromes" (Narrow)
Lymphopenia
PT terms – "Lymphopenia" and "Lymphocyte count 
decreased"
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count 
decreased"
Major Hemorrhage
SMQ – "Haemorrhagic disorders" (narrow)
Cardiac arrhythmia
1.
Atrial fibrillation: PT= Atrial fibrillation
2.
Cardiac arrhythmias: Cardiac arrhythmias SMQ broad 
(excluding PT of Atrial fibrillation)
3.
Ventricular tachyarrhythmias (as a sub-analysis under 
Cardiac arrhythmias recognizing there is overlap): 
Ventricular tachyarrhythmias SMQ narrow
 


Venetoclax (ABT-199)
M20-075 – Statistical Analysis Plan
Version 2.0 – 16 April 2022
32
Appendix C.
Potentially Clinically Important Criteria for Safety
Table C-1.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart rate (bpm)
Low
Value < 50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value < 36°C
High
Value ≥ 38.0°C