Conditions: Indolent Non-Hodgkin Lymphoma
Keywords: PI3K Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
This study examined the effects of predefined 2-week duvelisib dose holidays on tumor responses and safety/tolerability.

Detailed description:
This was a Phase 2, randomized, open-label, 2-arm study designed to evaluate the efficacy and safety of prescribed drug holidays of duvelisib treatment in participants with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) who have received at least 1 prior systemic therapy.

Arms:
arm 1: Duvelisib 25 milligrams (mg) twice daily (BID) continuously for 10 weeks, followed by 25 mg BID dosed 2 weeks off and 2 weeks on for each subsequent 4-week cycle. arm 2: Duvelisib 25 mg BID dosed 2 weeks on and 2 weeks off.

Interventions: intervention 1: Duvelisib
Intervention descriptions: intervention 1: Phosphoinositide 3-kinase (PI3K) inhibitor

Protocol document:
Prot_000.pdf: 
19 May 2021 
CONFIDENTIAL 
Page 1 of 80 
STUDY PROTOCOL VS-0145-229 
Protocol Title: 
A Phase 2, Randomized, Open-label, 2-Arm Study Comparing 
2 Intermittent Dosing Schedules of Duvelisib in Subjects with Indolent 
Non-Hodgkin Lymphoma (iNHL) 
Protocol Number: 
VS-0145-229 
Protocol Date: 
19 May 2021 
Version: 
4.0 
Compound: 
Duvelisib 
Study Phase: 
Phase 2 
Short Title: 
A Phase 2 Study of Intermittent Dosing Schedules of Duvelisib in Indolent 
Non-Hodgkin Lymphoma (iNHL) 
Sponsor: 
Secura Bio, Inc. 
1995 Village Center Circle 
Suite 128 
Las Vegas, NV 89134 
Tel: (858) 251-1414 
Regulatory Agency Identifier Numbers: 
IND Number: 
112,486 
EudraCT number: 
2019-001381-14 
Not for Distribution – Do Not Copy 
This study protocol contains confidential information and is the proprietary property of 
Secura Bio, Inc. The protocol is for use by the Principal Investigator and his/her designated 
representatives participating in this investigational trial. This protocol may not be copied or made 
available for review by an unauthorized person or firm without the prior written authorization of 
Secura Bio, Inc. 
NCT #: NCT04038359


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Sponsor Signatory: 
I have read this protocol for Study VS-0145-229, Version 4.0 and I approve the design of this 
study: 
 
Secura Bio, Inc. 
 
 
 
Medical Monitor Contact Information: 
Medical Monitor contact information will be provided separately in a study contact list. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES ..........................................................................................................................6 
1. 
PROTOCOL SUMMARY ............................................................................................7 
1.1. 
Synopsis ........................................................................................................................7 
1.2. 
Schema ........................................................................................................................ 10 
1.3. 
Schedule of Activities (SoA) ...................................................................................... 11 
2. 
INTRODUCTION....................................................................................................... 17 
2.1. 
Study Rationale ........................................................................................................... 17 
2.2. 
Background ................................................................................................................. 17 
2.3. 
Benefit/Risk Assessment............................................................................................. 19 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................ 21 
4. 
STUDY DESIGN........................................................................................................ 23 
4.1. 
Overall Design ............................................................................................................ 23 
4.2. 
Scientific Rationale for Study Design......................................................................... 23 
4.3. 
Justification for Dose .................................................................................................. 24 
4.4. 
End of Study Definition .............................................................................................. 24 
5. 
STUDY POPULATION ............................................................................................. 25 
5.1. 
Inclusion Criteria ........................................................................................................ 25 
5.2. 
Exclusion Criteria ....................................................................................................... 25 
5.3. 
Lifestyle Considerations ............................................................................................. 27 
5.4. 
Definition of Enrolled ................................................................................................. 27 
5.5. 
Screen Failures............................................................................................................ 28 
6. 
STUDY INTERVENTION ......................................................................................... 29 
6.1. 
Study Intervention(s) Administered ............................................................................ 29 
6.2. 
Administration ............................................................................................................. 29 
6.3. 
Preparation/Handling/Storage/Accountability ............................................................. 30 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................................ 30 
6.5. 
Study Intervention Compliance .................................................................................. 30 
6.6. 
Concomitant Therapy.................................................................................................. 31 
6.7. 
Dose Modification ...................................................................................................... 36 


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6.8. 
Intervention after the End of the Study ...................................................................... 36 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .................................................................. 37 
7.1. 
Discontinuation of Study Intervention ....................................................................... 37 
7.2. 
Subject Withdrawal from the Study ........................................................................... 37 
7.3. 
Lost to Follow-up....................................................................................................... 38 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 39 
8.1. 
Efficacy Assessments ................................................................................................. 39 
8.2. 
Safety Assessments .................................................................................................... 40 
8.3. 
Adverse Event Management ...................................................................................... 42 
8.4. 
Quality of Life Assessments ...................................................................................... 46 
8.5. 
Pharmacokinetics ....................................................................................................... 47 
8.6. 
Pharmacodynamics ..................................................................................................... 47 
8.7. 
Genetics ...................................................................................................................... 47 
8.8. 
Biomarkers ................................................................................................................. 47 
8.9. 
Medical Resource Utilization and Health Economics ............................................... 48 
9. 
STATISTICAL METHODOLOGY ........................................................................... 49 
9.1. 
Statistical Hypotheses ................................................................................................ 49 
9.2. 
Sample Size Determination ........................................................................................ 49 
9.3. 
Populations for Analyses ........................................................................................... 49 
9.4. 
Statistical Analyses .................................................................................................... 49 
9.5. 
Interim Analyses ........................................................................................................ 52 
9.6. 
Data Monitoring Committee (DMC) ......................................................................... 52 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS: APPENDICES ....................................................................... 53 
10.1. 
Appendix 1: Overview of Disease Response Criteria ................................................ 54 
10.2. 
Appendix 2: CYP3A Inhibitors, Inducers, and Substrates ......................................... 58 
10.3. 
Appendix 3: Clinical Laboratory Tests ...................................................................... 60 
10.4. 
Appendix 4: Contraception Guidance ........................................................................ 62 
10.5. 
Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance 
Status .......................................................................................................................... 64 
10.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations .................... 65 
10.7. 
Appendix 7: Abbreviations ........................................................................................ 69 


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10.8. 
Appendix 8: Protocol Summary of Changes and Version History ............................. 72 
11. 
REFERENCES ............................................................................................................ 78 


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LIST OF TABLES 
Table 1: 
Study Activities for Duvelisib Monotherapy (Cycle 1: 10 Weeks; Cycles ≥2: 
4 Weeks) .................................................................................................................... 11 
Table 2: 
Pharmacokinetic and Biomarker Samplinga,b ........................................................................................... 16 
Table 3: 
Objectives and Endpoints .......................................................................................... 21 
Table 4: 
Study Intervention Arms ............................................................................................ 29 
Table 5: 
Recommendations for the Management of Toxicities ............................................... 32 
Table 6: 
Prohibited Concomitant Therapies ............................................................................. 34 
Table 7: 
Concomitant Therapies: Use with Caution ................................................................ 35 
Table 8: 
Duvelisib Dosing Levels ............................................................................................ 36 
Table 9: 
CTCAE AE Grading .................................................................................................. 44 
Table 10: Biomarker Samples and Assessments ........................................................................ 48 
Table 11: Appendices ................................................................................................................. 53 
Table 12: Revised Response Criteria for Malignant Lymphoma (Cheson 2007) ...................... 54 
Table 13: 5-Point Scale for Positron Emission Tomography Assessment (Barrington 
2014) .......................................................................................................................... 55 
Table 14: Lugano Response Criteria for Malignant Lymphoma (Cheson 2014) ....................... 55 
Table 15: Classification of In Vivo Inhibitors of CYP3A ......................................................... 58 
Table 16: Classification of In Vivo Inducers of CYP3A ........................................................... 59 
Table 17: Cytochrome P450 3A (CYP3A) Substrates ............................................................... 59 
Table 18: Protocol-required Safety Laboratory Assessments .................................................... 60 
Table 19: List of Abbreviations and Definitions ........................................................................ 69 
Table 20: Summary of Changes for Version 4.0........................................................................ 72 
Table 21: Summary of Changes for Version 3.0........................................................................ 73 
Table 22: Primary Reason for Each Version ............................................................................. 77 
 
LIST OF FIGURES 
Figure 1: 
Treatment Scheme ..................................................................................................... 10 
Figure 2: 
Two-stage Design for Each Arm ............................................................................... 10 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Study Title: A Phase 2, randomized, open-label, 2-arm study comparing 2 intermittent dosing 
schedules of duvelisib in subjects with indolent non-Hodgkin lymphoma (iNHL) 
Protocol Number: VS-0145-229 
Phase: 2 
Rationale: Dosing with duvelisib 25 mg twice daily (BID) has been shown to be efficacious in 
multiple Phase 1-3 studies including subjects with iNHL. The efficacy, safety and tolerability of this 
dose supported the US approval of duvelisib for the treatment of adult patients with relapsed or 
refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) after at 
least 2 prior therapies and accelerated approval in adult patients with R/R follicular lymphoma (FL) 
after at least 2 prior systemic therapies. The current study will evaluate whether efficacy can be 
achieved and maintained, with acceptable or improved safety and tolerability, by inclusion of 
pre specified 2-week drug holidays in 2 different 25 mg BID schedules in subjects with R/R iNHL. 
Objectives and Endpoints 
Objective 
Endpoint 
(see Section 9.4 for definitions) 
Primary 
Evaluate the efficacy of duvelisib administered 
with prescribed drug holidays in subjects with 
iNHL 
Overall Response Rate (ORR) according to the 
2007 revised International Working Group (IWG) 
Criteria (Cheson 2007) 
Secondary 
Evaluate supportive efficacy measures of 
duvelisib administered with prescribed drug 
holidays in subjects with iNHL 
• ORR according to 2014 Lugano criteria 
(Cheson 2014) 
Note: all additional secondary response 
endpoints as well as progression-free survival 
(PFS), will be assessed separately using 2007 
revised IWG criteria (Cheson 2007) and 2014 
Lugano criteria (Cheson 2014) 
• ORR, at 6, 12, 18, and 24 months after first 
dose of study intervention 
• Progression-free Survival 
• Time to Treatment Failure (TTF) 
• Duration of Response (DOR) 
• Overall Survival (OS) 
• Lymph Node Response Rate (LNRR) 
• Time to the First Response (TTFR) 


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Evaluate the safety and tolerability of duvelisib 
administered with prescribed drug holidays in 
subjects with iNHL 
Adverse events (AEs), serious AEs (SAEs), vital 
signs, physical examinations, and clinical 
laboratory values 
Characterize the pharmacokinetics (PK) of 
duvelisib and metabolite IPI-656 when duvelisib 
is administered with prescribed drug holidays in 
subjects with iNHL 
PK parameters for duvelisib and metabolite 
IPI-656 
Exploratory 
Evaluate Quality of Life (QoL) in subjects with 
iNHL treated with duvelisib with prescribed drug 
holidays 
• Eastern Cooperative Oncology Group (ECOG) 
Performance Score 
• EQ-5D-3L questionnaire responses 
Evaluate potential biomarkers of clinical efficacy 
and/or safety of duvelisib administered with 
prescribed drug holidays in subjects with iNHL 
• Blood assessments of immune cell 
populations, chemokines, cytokines, 
phosphorylated proteins, and/or circulating 
tumor ctDNA 
• Fecal assessments of protein, DNA, and or 
RNA 
• Tumor biopsy evaluation of biomarkers such 
as gene and copy number variation, RNA 
expression, protein expression, and/or immune 
cell content 
Overall Design: 
This is a Phase 2, randomized, open-label, 2-arm study designed to evaluate the efficacy and safety of 
prescribed drug holidays of duvelisib treatment in subjects with R/R iNHL who have received at least 1 
prior systemic therapy. 
Subjects will be stratified by number of prior therapies (1 or > 1), bulky disease status (longest 
diameter of baseline lesion < 5 cm or ≥ 5 cm) and time since last recurrence (≥ 24 months or < 24 
months). Subjects will be randomized to Arm 1 or Arm 2 in a 1:1 fashion. Each treatment arm will be 
analyzed separately. 
The study is a 2-stage design. For each arm: in the first stage, approximately 15 subjects will be 
enrolled. Responses will be assessed by the Investigator according to the 2007 revised IWG criteria 
(Cheson 2007) (primary endpoint) and 2014 Lugano criteria (Cheson 2014). The evaluation of the first 
stage will take place after the 15 enrolled subjects have been followed for a minimum of 3 cycles. If 
there are fewer than 6 responders (partial response [PR] or complete response [CR]) among the first 
15 subjects in each arm, consideration may be given to stopping the arm. Otherwise, 36 additional 
subjects will be enrolled for a total of 51 per arm. Enrollment will be continuous between Stage 1 and 
Stage 2. 
Number of Subjects: 
Approximately 102 subjects will be enrolled and randomized at multiple sites globally. The study will 
employ a 2-stage approach with a planned enrollment of approximately 30 subjects for Stage 1 and up 
to approximately 72 additional subjects for Stage 2. 


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Intervention Groups and Duration: 
• Arm 1: duvelisib 25 mg BID for one 10-week cycle followed by 25 mg BID in Weeks 3 and 4 of 
each subsequent 4-week cycles until disease progression, unacceptable toxicity, or withdrawal. 
• Arm 2: duvelisib 25 mg BID on Weeks 1, 2, 5, 6, 9 and 10 of one 10-week cycle, then in Weeks 3 
and 4 of each subsequent 4-week cycles until disease progression, unacceptable toxicity, or 
withdrawal. 
It is anticipated that the study enrollment will occur over approximately 2 years. The last subject visit 
will occur 2 years after the last subject is randomized. If the study is ended prior to all subjects 
discontinuing treatment, any subject continuing to receive benefit will be provided the opportunity to 
continue to receive duvelisib. Long-term continued treatment may be provided via an expanded access 
program consistent with local regulations, such as the Secura Bio NPP. 
Data Monitoring Committee: None. 
Disclosure Statement: This is a parallel-group unblinded treatment study with 2 arms. 


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1.2. 
Schema 
Figure 1: 
Treatment Scheme 
 
Abbrevia tions: BID: twice daily. 
 
Solid sections: duvelisib 25 mg BID; hashed sections: drug holiday. Subjects will be randomized 1:1 to Arms 1 and 
2. Subjects will be assessed for disease response after approximately 10 weeks (i.e., within 7 days of the start of 
Cycle 2) and then within 7 days of the start of Cycles 4, 6, 9, 13, 17, and every 4th cycle thereafter until disea se 
progression, unacceptable toxicity or withdrawal. (*): a ssessment of ORR a fter a minimum of 3 cycles of treatment 
in first-sta ge subjects (see Figure 2) to determine Stage 2 enrollment. 
 
 
Figure 2: 
Two-stage Design for Each Arm 
 
Abbrevia tions: CR: complete response; N: number of subjects; PR: partial response; ORR: overall response rate. 
The decision to proceed to Stage 2 will be supported by the totality of data observed, including types of responses, 
safety data, and discontinuation rates. A trea tment arm may also not proceed to the second stage if the totality of the 
data is compelling (e.g., accumulating enough data in Stage 1 to conclude the ORR exceeds 30%). 


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1.3. 
Schedule of Activities (SoA) 
Table 1: 
Study Activities for Duvelisib Monotherapy (Cycle 1: 10 Weeks; Cycles ≥2: 4 Weeks) 
 
Activity 
Screening 
D-30 to 
D-1 
Cycle 1 
Cycle 2 
Cycle 
3+ 
EoTa 
Safety 
F/Ub 
30d (+7) 
postdose 
Notes 
D1 
D14 
(-3) 
D29 
(+3) 
D43 
(±3) 
D57 
(±3) 
D1 
(±3 
D14 
(-3) 
D1 
(±3) 
Informed Consent 
X 
Potentially eligible subjects must sign an ICF prior 
to initiating any study specific procedures. 
Standard of care assessments that fulfill study 
eligibility requirements may be performed prior to 
subject signing the ICF. 
Inclusion/Exclusion 
Criteria 
X 
Randomization 
X 
(D -7 
to -1) 
Subject must sign informed consent, meet 
inclusion/exclusion criteria, and complete all other 
screening activities prior to randomization. 
Medical History, 
Demographics 
X 
Medical History includes histologic lymphoma 
diagnostic and prior treatment and response 
information, FLIPI-1 score 
Archival Tumor Tissue 
X 
Tumor tissue is not required for enrollment, but 
should be submitted from all enrolled subjects, if 
available. Sample should be FFPE tissue and will 
be used to evaluate prognostic biomarkers. 
Tumor Biopsy 
(optional) 
X 
If a transformation to a more aggressive subtype of 
lymphoma is suspected, a biopsy may be 
performed at Investigator’s discretion. 
If this sample is collected, please see Archival 
Tumor Tissue instructions above. 
Full Physical 
Examination 
X 
X 
If performed within 7 days of C1D1, then 
screening results can be used for C1D1. 
Focused Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-focused assessments including liver/spleen 
size, clinical assessment of tumor masses, and B 
symptoms. 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs measured in a semi-supine position 
after 5 minutes rest. 
Computed 
Tomography (CT) 
X 
X 
All subjects require CT or FDG-PET-CT scans. 
MRI may be used instead of CT scans if CT cannot 


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Activity 
Screening 
D-30 to 
D-1 
Cycle 1 
Cycle 2 
Cycle 
3+ 
EoTa 
Safety 
F/Ub 
30d (+7) 
postdose 
Notes 
D1 
D14 
(-3) 
D29 
(+3) 
D43 
(±3) 
D57 
(±3) 
D1 
(±3 
D14 
(-3) 
D1 
(±3) 
Scans of the Chest, 
Abdomen and Pelvis 
Day 1 of Cycles 2, 4, 6, 9, 13, 17, and Every 4th 
Cycle Thereafter 
(Window: Day -7 to Day 1 of Each Cycle) 
be done, but the same method must be used 
throughout the study. A scan will be performed at 
the EoT if one was not performed within 30 days 
of the EoT Visit. 
Response Assessment 
X 
Response will be assessed separately using 2007 
revised IWG criteria (Cheson 2007) and 2014 
Lugano criteria (Cheson 2014) 
Bone Marrow Aspirate 
and/or Biopsy 
As necessary to confirm CR 
If a bone marrow/aspirate is performed within 
60 days before C1D1 as part of standard of care, 
the pathology report will be provided to the 
Sponsor. If a radiologic CR according to 2007 
revised IWG criteria (Cheson 2007) is observed 
during the course of the study, then a bone marrow 
biopsy should be done to confirm CR. The 
pathology report will be provided to the Sponsor. 
ECG (12-lead) 
X 
QTc measurements (as measured by triplicate 
readings) will use the Fridericia’s correction 
method. Additional on-treatment or follow-up 
ECGs may be performed at the Investigator’s 
discretion as clinically indicated. 
ECHO/ 
MUGA 
X 
ECHO or MUGA scan. Additional on-treatment or 
follow-up echocardiograms may be performed at 
the Investigator’s discretion as clinically indicated. 
Concomitant 
Medications and 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation tests 
X 
Prothrombin time, partial thromboplastin time and 
international normalized ratio 
Viral screening 
X 
Hepatitis serology: HCV Ab, HBsAg, HBcAb. 
CMV/EBV serology or viral load. HIV test is not 
required if a prior negative test within 9 months is 
available. 


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Activity 
Screening 
D-30 to 
D-1 
Cycle 1 
Cycle 2 
Cycle 
3+ 
EoTa 
Safety 
F/Ub 
30d (+7) 
postdose 
Notes 
D1 
D14 
(-3) 
D29 
(+3) 
D43 
(±3) 
D57 
(±3) 
D1 
(±3 
D14 
(-3) 
D1 
(±3) 
CMV Reactivation 
Monitoring 
Subjects with a history of CMV infection/reactivation or viremia 
should be monitored for reactivation by PCR or antigen test at least 
monthly 
C-Reactive Protein 
X 
Obtain when Grade ≥ 2 diarrhea or any colitis occurs 
Endocrine function 
X 
Free thyroxine and thyroid-stimulating hormone 
HLA Typing 
X 
Testing for HLA types A, B, C, DRB1, and DQB1. 
Do not need to perform if previous typing results 
are available. 
Serum hCG Pregnancy 
Test 
X 
X 
X 
X 
X 
X 
For WCBP, a serum pregnancy test must be 
performed within 7 days of C1D1. At subsequent 
time points, serum testing is preferred but urine 
testing is allowed if a blood draw for other 
assessments is not performed. A positive urine test 
must be confirmed by a serum test. 
Clinical Chemistry, 
including Liver 
Function Tests 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function tests include LDH, serum ALT, 
serum AST, total and direct bilirubin, and ALP. 
Testing must be conducted, and results available, 
within 7 days prior to administration of first dose 
of duvelisib. Screening test results can be used for 
C1D1 if tests are performed within 7 days of 
C1D1. 
Immunoglobulin blood 
levels 
X 
X 
X 
X 
(even # 
cycles) 
IgA, IgG, IgM 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology panel plus a 5-part differential. 
Testing must be conducted, and results available, 
within 7 days prior to administration of first dose 
of duvelisib. Screening test results can be used for 
C1D1 if tests are performed within 7 days of 
C1D1. 
Urinalysis 
X 
X 
X 
X 
X 
X 
Qualitative analysis for protein performed at 
Screening, at C1D1, C2D1 and C6D1. If positive, 
quantitative analysis is needed if not previously 
noted as part of medical history. Testing must be 
conducted, and results available, within 7 days 


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Activity 
Screening 
D-30 to 
D-1 
Cycle 1 
Cycle 2 
Cycle 
3+ 
EoTa 
Safety 
F/Ub 
30d (+7) 
postdose 
Notes 
D1 
D14 
(-3) 
D29 
(+3) 
D43 
(±3) 
D57 
(±3) 
D1 
(±3 
D14 
(-3) 
D1 
(±3) 
prior to administration of first dose of duvelisib. 
Screening test results can be used for C1D1 if tests 
are performed within 7 days of C1D1. 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
If the ECOG Performance Status assessed at 
Screening is performed within 7 days of C1D1, the 
Screening assessment can be used and does not 
need to be repeated at C1D1 (predose). 
EQ-5D-3L 
Questionnaire 
X 
X 
X 
X 
X 
X 
Administered predose and prior to other procedures 
during treatment visits 
Pharmacokinetic and 
Biomarker 
Assessments 
X 
X 
X 
X 
X 
X 
X 
see 
note 
For Cycles ≥ 3, obtain stool sample if subject has 
Grade ≥ 3 diarrhea or colitis. Request 
representative fragment of tissue and/or 
representative section of paraffin block from 
biopsy if taken for colitis or Grade ≥ 3 diarrhea. 
See Table 2 for detailed schedule 
Duvelisib Self- 
Administration Diary 
X 
X 
X 
X 
X 
X 
X 
First year on treatment only 
Duvelisib 
Administration 
(Please see required 
and recommended 
prophylaxis in 
Section 6.6.1) 
X 
(C1D14 
AM dose in 
clinic) 
X 
X 
X 
X 
X 
X 
Administration of the first dose should be 
scheduled to occur within 1 week after 
randomization. See Section 6.1 for dosing 
schedule. 
Abbreviations: AE/SAE: adverse event/serious adverse event; ALP: a lkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; 
BID: twice da ily; CxDx: Cycle x, Day x; CMV: cytomegalovirus; CR: complete response; CT: computed tomography; EBV: Epstein-Barr virus; ECG: 
electrocardiogram; ECOG: Eastern Cooperative Oncology Group; ECHO: echocardiogram; EoT: end of treatment; FDG-PET: 18fluoro-2-deoxy-d-glucose- 
positron emission tomography; FFPE: formalin-fixed paraffin-embedded ; FLIPI-1: Follicula r Lymphoma International Prognostic Index; F/U: follow-up; 
HBcAb: hepatitis B core antibody; HBsAg: hepatitis B surface antigen; HCVAb: hepatitis C antibody; hCG: human chorionic gonadotropin; HIV: human 
immunodeficiency virus; HLA: human leukocyte antigen; ICF: informed consent form; iNHL: indolent non-Hodgkin lymphoma; IWG: international working 
group; LDH: lactate dehydrogenase; MRI: magnetic resonance imaging; MUGA: multi-gated acquisition; PCR: polymerase chain reaction; WCBP: women of 
childbearing potential. 


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a. An EoT Visit will be performed for all subjects who permanently discontinue study intervention within 7 days following the decision to discontinue study 
intervention. EoT assessments need not be repeated if performed within the previous 14 days, or 30 days for CT scan. 
b. Sa fety follow-up visit to be performed 30 + 7 days from last dose. If possible, this visit should occur prior to the initiation of any subsequent anticancer 
thera py. This can be performed by telephone call if the subject does not require laboratory and/or other procedures related to any new or ongoing AEs, in 
which case a clinical visit will be required. 


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Table 2: 
Pharmacokinetic and Biomarker Samplinga,b 
 
Cycle 
Study 
Day 
Time Points 
Whole 
blood 
for PKc 
Whole blood for 
pharmacodynamic 
biomarkers 
(U.S. sites only) 
Serum and 
plasma for 
biomarkers 
Whole blood 
for immune 
cell analysis 
Stool sample 
for biomarker 
analysis 
1 
1 
Predose 
X 
X 
X 
X 
Xe 
1 hour (± 5 min) postdose 
X 
X 
2 hours (± 10 min) postdose 
X 
X 
4 hours (± 10 min) postdose 
X 
14 (-3)d 
Predose 
X 
X 
1 hour (± 5 min) postdose 
X 
2 hours (± 10 min) postdose 
X 
4 hours (± 10 min) postdose 
X 
29 (+3)d 
Predose 
X 
1 hour (± 5 min) postdose 
X 
2 hours (± 10 min) postdose 
X 
4 hours (± 10 min) postdose 
X 
57 (±3)d 
Predose 
X 
X 
2 
1 (±3) 
Anytime during visit 
X 
X 
Xe 
14 (-3) 
Anytime during visit 
X 
X 
3+ 
Any 
Anytime during visit 
Xe 
Abbreviations: CR: complete response; CxDx: Cycle x Day x; PK: pharmacokinetics 
a. Any changes to this sampling plan (e.g., reductions in the number of sample collections) will be provided in the study lab manual. 
b. In addition to the samples shown in this table, provide (if feasible) a sample of any colon biopsies taken for colitis or Grade ≥ 3 diarrhea 
c. PK sampling must occur on a dosing day. After a subjecthas had a dose reduction and received ≥ 10 consecutive days of the reduced dose (not including 
scheduled dose holidays), PK sa mpling as shown for C1D1 will be repea ted. 
d. On C1D14, C1D29 and C1D57, the morning dose of study medication will be administered in the clinic to accommodate PK a nd/or biomarker sampling. 
e. 
The C1D1 stool sample may be collected up to 7 days prior to C1D1. C2D1 stool samples may be collected up to 3 days prior to these visits. Stool samples 
may be collected either predoseor postdose. Obtain additional stool sample if subjecthas colitis or Grade ≥ 3 diarrhea. 


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2. 
INTRODUCTION 
Duvelisib (VS-0145) is a synthetic orally-active small molecule dual inhibitor of 
phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ that is being developed by Secura Bio, Inc. 
(Secura Bio; study Sponsor) for the treatment of follicular lymphoma (FL) and other indolent 
non-Hodgkin lymphomas (iNHLs), T-cell lymphoma and other hematological malignancies, and 
solid tumor malignancies. 
2.1. 
Study Rationale 
The registrational studies for duvelisib 25 mg twice daily (BID) in chronic lymphocytic leukemia 
(CLL)/small lymphocytic lymphoma (SLL; the DUO study) and for iNHL, including FL (the 
DYNAMO study), were positive with respect to their primary endpoints of progression-free 
survival (PFS; DUO) and overall response rate (ORR; DYNAMO) and included subjects who 
received at least 1 prior treatment regimen. Ultimately duvelisib (COPIKTRA®) 25 mg BID was 
approved by the United States (US) Food and Drug Administration (FDA) for the treatment of 
adult patients with relapsed or refractory (R/R) FL and SLL after ≥ 2 prior systemic therapies. 
The overall risk-benefit profile was greatest in the setting of ≥ 2 prior systemic therapies, which 
supported the approval in this specific subset of subjects. Although several other regimens (e.g., 
autologous transplantation for younger patients, repetition of the first-line treatment, 
bendamustine plus obinutuzumab or rituximab) are currently recommended by the European 
Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) 
guidelines in the second-line setting, relapses are common, and the unmet medical need remains 
high in this patient population (ESMO 2019, NCCN 2019). 
The post-hoc analysis of the DUO study showed that response to duvelisib was improved or 
maintained in most subjects who had ≥ 1 dose interruption (DI) for > 1 week (84%) or > 2 weeks 
(82%), then followed by ≥ 3 weeks on duvelisib. PFS was also similar between subjects with 
≥ 1 DI and those without DI for > 1 week or > 2 weeks within the first 3 months of therapy 
(median PFS: > 1 week, 17.8 vs 16.3 months; > 2 weeks, 17.8 vs 16.3 months) (Flinn 2019). 
These data support the hypothesis that prespecified 2-week DIs would not impact efficacy. 
This study (VS-0145-229) is a proof-of-concept study that will evaluate whether duvelisib 25 mg 
BID efficacy can be achieved and maintained, with acceptable or improved safety and 
tolerability, by inclusion of prespecified 2-week drug holidays in 2 different schedules in 
subjects with R/R iNHL after failure of at least 1 line of prior therapy. 
2.2. 
Background 
2.2.1. 
Non-Hodgkin Lymphoma 
Non-Hodgkin lymphoma (NHL) is one of the most common malignancies in the US, Europe, 
and Asia. It is expected that about 74,200 people will be diagnosed with NHL in the US in 2019 
with about 19,970 projected deaths from this disease (NCI-SEER 2019). Indolent NHL (iNHL) 
accounts for approximately one third of all NHL cases. Follicular lymphoma (FL) is the most 
common iNHL type, followed by SLL, and marginal zone B-cell lymphoma (MZL, that includes 


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nodal and splenic marginal zone), which occur in approximately 30%, 7%, and 4% of all NHL 
cases, respectively (Swerdlow 2016). 
The course of iNHL is variable. While some patients can remain asymptomatic for extended 
periods, others may require immediate intervention. Rituximab-based regimens are common 
front-line treatment choices in patients with FL and MZL, and ibrutinib or venetoclax in 
combination with obinutuzumab are preferred choices in patients with SLL (NCCN 2019). 
Although most patients with iNHL have durable responses to initial treatment with prolonged 
remission, relapses, requiring serial retreatment, are common. Almost all patients will eventually 
progress or have a disease recurrence, and advanced-stage iNHL remains incurable (Cheson 
1998, Hitz 2011, Sehn 2016). Recent data show that patients with FL who progress within 
2 years of initial diagnosis also have a lower 5-year overall survival (OS) rate (50%) than 
patients without early progression (90%) after front-line combination therapy with rituximab 
plus cyclophosphamide, doxorubicin, and prednisone (R-CHOP) (Casulo 2015). 
Despite the availability of several treatment options for relapsed iNHL, major challenges remain, 
which include cumulative toxicities from multiple therapies and resistance or transformation to 
aggressive or high-grade lymphomas (Coutre 2015, Federico 2000). While allogeneic stem cell 
transplantation could be potentially curative, only a small number of patients are eligible for this 
therapy, and there is unmet medical need for new therapies. 
2.2.2. 
PI3 Kinases 
PI3Ks catalyze the production of phosphatidylinositol (3, 4, 5)-trisphosphate, leading to 
activation of downstream effector pathways important for cellular survival, differentiation, and 
function. There are 4 mammalian isoforms of class 1 PI3Ks: PI3K-α, β, δ (class 1a), and PI3K-γ 
(class 1b) (Fruman 2017). 
PI3K-α and PI3K-β are widely expressed and are important mediators of signaling from cell 
surface receptors, while the PI3K-δ and PI3K-γ isoforms are more narrowly expressed in 
hematopoietic lineage cells, immune cells, and malignant hematopoietic cells. Pathways 
mediated by PI3K-δ and PI3K-γ are involved in diverse processes of cell growth, survival, 
proliferation, migration, differentiation, and metabolism. Since central regulatory roles for either 
or both enzymes have been demonstrated in B cells, T cells, macrophages/monocytes, mast cells, 
and natural killer (NK) cells, both PI3K-δ and PI3K-γ are believed to be important for the 
development and persistence of autoimmune disease and hematologic malignancies (Curran 
2014, Ortiz-Maldonado 2015, Steele 2014, Westin 2014). 
PI3K-δ, and PI3K-γ activity supports the growth and maintenance of cancer cells and the 
supportive tumor microenvironment. Data from nonclinical in vitro and in vivo studies show that 
inhibition of PI3K-δ, and PI3K-γ results in significant efficacy against hematologic malignancies 
and solid tumors. Duvelisib is being developed due to its ability to inhibit PI3K-δ and PI3K-γ 
and reduce their cancer-promoting effects. The direct effect of duvelisib on primary malignant 
hematologic tumor cells was demonstrated by duvelisib-mediated growth inhibition of both 
primary CLL cells and cell lines derived from transformed FL, diffuse large B-cell lymphoma 
(DLBCL), mantle cell lymphoma (MCL), multiple myeloma, and T-cell lymphoma/leukemia 
(Dong 2014, Faia 2015). 


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2.2.3. 
Duvelisib in Hematologic Malignancies 
Duvelisib has shown clinical activity in various hematologic malignancies, including CLL, 
iNHL, and cutaneous and peripheral T-cell lymphoma (CTCL and PTCL, respectively). In the 
Phase 1 study in hematologic malignancies, including iNHL (Flinn 2018), the recommended 
Phase 2 dose (RP2D) was determined to be 25 mg BID with maculopapular rash, alanine 
aminotransferase/aspartate aminotransferase (ALT/AST) elevation, neutropenia, and cellulitis 
observed as dose-limiting toxicities. 
As of 19 July 2018, approximately 1378 subjects have been exposed to duvelisib as monotherapy 
or in combination with another agent, including approximately 814 subjects with hematologic 
malignancies in Company- or Investigator-sponsored studies. Indications include NHL subtypes 
of mature B-cell lymphomas (e.g., FL, CLL/SLL, DLBCL, marginal zone lymphoma, MCL) and 
mature T-cell lymphomas (e.g., PTCL, CTCL), acute myeloid leukemia, and multiple myeloma. 
Studies have been conducted globally in countries including the US, Canada, the United 
Kingdom, Austria, France, Germany, Georgia, Hungary, Italy, Spain, Belarus, Belgium, 
Bulgaria, Czech Republic, and Australia. 
Duvelisib was approved by the FDA in September 2018 for the treatment of patients with R/R 
CLL/SLL after at least 2 prior therapies and received accelerated approval for R/R FL after at 
least 2 prior systemic therapies (COPIKTRA 2018). Please see the Duvelisib Investigator’s 
Brochure (IB) for detailed descriptions of nonclinical and clinical safety and efficacy results. 
These data, together with the available safety data, support the ongoing evaluation of duvelisib in 
subjects with hematologic malignancies. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
As of 19 July 2018, in 588 subjects treated with duvelisib monotherapy in hematologic 
malignancy studies (see Section 6.3.4.1.2 in the IB), the most frequent treatment-emergent 
adverse events (TEAEs) (≥ 20% of subjects) reported were diarrhea/colitis (49.0%), neutropenia 
(34.7%), rash (34.7%), fatigue (33.2%), pyrexia (30.3%), cough (26.7%), nausea (26.0%), 
transaminase elevation (22.8%), musculoskeletal pain (22.6%), anemia (22.4%), upper 
respiratory tract infection (22.3%), and pneumonia (21.6%). The most frequently reported 
TEAEs, diarrhea and neutropenia, are amenable to early recognition and intervention. These 
events infrequently resulted in treatment discontinuation with management, including dose 
modifications and supportive care. Many of the more severe TEAEs, such as infections and 
hematologic abnormalities, are commonly observed in subjects with advanced B-cell 
malignancies. Adverse events (AEs) of special interest (AESIs), such as diarrhea, colitis, 
pneumonitis, rash, and transaminase elevations, have been well-described with the use of PI3K-δ 
inhibitors and immuno-oncology therapies. The most commonly occurring AEs infrequently 
resulted in treatment discontinuation, representing a manageable safety profile in subjects with 
advanced hematologic malignancies. 
The identified risks for duvelisib treatment are infections, diarrhea/colitis, cutaneous reactions, 
pneumonitis, transaminase elevations, and neutropenia. Potential risks are hepatotoxicity and 
reproductive toxicity. Guidance on management of these AEs, including duvelisib dose 
interruptions and modifications, is provided in Section 6.6 and Section 6.7. Detailed information 


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about the known and expected risks and reasonably expected AEs of duvelisib may be found in 
the IB. 
2.3.2. 
Benefit Assessment 
Subjects may derive benefit due to improvements in symptoms and tumor control. Duvelisib 
treatment produced clinical activity in subjects with hematologic malignancies, including 
CLL/SLL, FL, and PTCL. In the pivotal CLL/SLL study (Study IPI-145-07), duvelisib 
monotherapy resulted in statistically significant improvement in PFS (16.4 months vs 9.1 
months) and ORR (78% vs 39%) compared to ofatumumab in subjects who had received at least 
2 prior therapies. Reductions in target lymph nodes were observed in Study IPI-145-07 in most 
subjects treated with duvelisib (85%), representing a statistically significant treatment effect over 
ofatumumab (16%). In subjects with FL in a Phase 2 study in iNHL (IPI-145-06), the ORR was 
42.2%, meeting the primary endpoint (p < 0.0001 against the null hypothesis that ORR was ≤ 
30% per Independent Review Committee [IRC]). In subjects with PTCL in a Phase 1 dose 
escalation study (IPI-145-02), the observed ORR was 53.3%. More detailed information about 
the clinical efficacy observed in duvelisib studies can be found in the IB. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Clinical study results to date support a favorable benefit-risk of duvelisib for subjects with 
hematologic malignancies. Efficacy has been seen in multiple studies, including significant 
improvements in ORR and PFS relative to the comparator in a pivotal study in R/R CLL/SLL 
(Study IPI-145-07) and positive ORR and duration of response (DOR) in a single-arm FL study 
(Study IPI-145-06). Important identified risks include infections, diarrhea/colitis, cutaneous 
reactions, pneumonitis, neutropenia, and ALT/AST elevations. The efficacy and safety profile of 
duvelisib, as detailed in the IB, indicates that the benefits of duvelisib therapy outweigh the risks. 
In addition, the alternative dosing schedules being evaluated in the current study may improve 
the safety profile while maintaining the efficacy benefit, potentially increasing the benefit:risk 
for subjects in this study. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 3: 
Objectives and Endpoints 
 
Objective 
Endpoint 
(see Section 9.4 for definitions) 
Primary 
Evaluate the efficacy of duvelisib administered 
with prescribed drug holidays in subjects with 
iNHL 
Overall Response Rate (ORR) according to the 
2007 revised International Working Group (IWG) 
Criteria (Cheson 2007) 
Secondary 
Evaluate supportive efficacy measures of 
duvelisib administered with prescribed drug 
holidays in subjects with iNHL 
• ORR according to 2014 Lugano criteria 
(Cheson 2014) 
Note: all additional secondary response 
endpoints, as well as progression-free survival 
(PFS), will be assessed separately using 2007 
revised IWG criteria (Cheson 2007) and 2014 
Lugano criteria (Cheson 2014) 
• ORR, at 6, 12, 18, and 24 months after first 
dose of study intervention 
• Progression-free Survival 
• Time to Treatment Failure (TTF) 
• Duration of Response (DOR) 
• Overall Survival (OS) 
• Lymph Node Response Rate (LNRR) 
• Time to the First Response (TTFR) 
Evaluate the safety and tolerability of duvelisib 
administered with prescribed drug holidays in 
subjects with iNHL 
Adverse events (AEs), serious AEs (SAEs), vital 
signs, physical examinations, and abnormal 
laboratory values 
Characterize the pharmacokinetics (PK) of 
duvelisib and metabolite IPI-656 when duvelisib 
is administered with prescribed drug holidays in 
subjects with iNHL 
PK parameters for duvelisib and metabolite IPI- 
656 
Exploratory 
Evaluate Quality of Life (QoL) in subjects treated 
with duvelisib with prescribed drug holidays 
• ECOG Performance Score 
• EQ-5D-3L questionnaire responses 
Evaluate potential biomarkers of clinical efficacy 
and/or safety of duvelisib administered with 
prescribed drug holidays in subjects with iNHL 
• Blood assessments of immune cell 
populations, chemokines, cytokines, proteins 
and/or circulating tumor (ctDNA) 


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• Assessments of protein, DNA, and or RNA in 
fecal microbiota 
• Tumor biopsy evaluation of biomarkers such 
as gene and copy number variation, RNA 
expression, protein expression, and/or immune 
cell content 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, randomized, open-label, 2-arm study designed to evaluate the efficacy and 
safety of alternative dosing schedules of duvelisib treatment in subjects with R/R iNHL who 
have received at least 1 prior systemic therapy. This is a multi-site global study. 
Subjects will be stratified by number of prior therapies (1 or > 1), bulky disease status (longest 
diameter of baseline lesion < 5 cm or ≥ 5 cm) and time since last recurrence (≥ 24 months or 
< 24 months). 
Subjects will be randomized to Arm 1 or Arm 2 in a 1:1 fashion. 
• Arm 1: duvelisib 25 mg BID for one 10-week cycle followed by 25 mg BID on 
Weeks 3 and 4 of each subsequent 4-week cycles until disease progression, 
unacceptable toxicity, or withdrawal. 
• Arm 2: duvelisib 25 mg BID on Weeks 1, 2, 5, 6, 9 and 10 of one 10-week cycle, then 
on Weeks 3 and 4 of each subsequent 4-week cycles until disease progression, 
unacceptable toxicity, or withdrawal. 
The study has a 2-stage design (see Figure 2). For each arm: in the first stage, 15 subjects will be 
enrolled. Responses will be assessed by the Investigator according to the 2007 revised IWG 
criteria (Cheson 2007) (primary endpoint) and the 2014 Lugano criteria (Cheson 2014). The 
evaluation of the first stage will take place after the enrolled subjects have been followed for a 
minimum of 3 cycles. If there are fewer than 6 responders (partial response [PR] or complete 
response [CR]) among the first 15 subjects per arm, consideration may be given to stopping that 
arm. Otherwise, approximately 36 additional subjects will be enrolled for a total of 51 per arm. 
Enrollment will be continuous between Stage 1 and Stage 2. If fewer than 22 (43%) responders 
(PR or CR) are observed in 51 subjects, consideration may be given to concluding that the 
treatment schedule does not warrant further study in this population. 
It is anticipated that study enrollment will occur over approximately 2 years. The last subject 
visit will occur 2 years after the last subject is randomized. 
4.2. 
Scientific Rationale for Study Design 
Dosing with duvelisib 25 mg BID has been shown to be efficacious in multiple Phase 1-3 studies 
including subjects with iNHL. Data from the pivotal Phase 3 CLL/SLL study (DUO) and Phase 2 
FL study (DYNAMO) showed that most tumor responses occurred by the end of Cycle 4 of 
duvelisib 25 mg BID treatment, and the majority of DIs for toxicity occurred primarily after 4 
cycles. The post-hoc analysis of the DUO study showed that response to duvelisib was improved 
or maintained in most subjects who had ≥ 1 DI for > 1 week (84%) or > 2 weeks (82%), then 
followed by ≥ 3 weeks on duvelisib. PFS was also similar between subjects with ≥ 1 DI and 
those without DI for > 1 week or > 2 weeks within the first 3 months of therapy (median PFS: > 
1 week, 17.8 vs 16.3 months; > 2 weeks, 17.8 vs 16.3 months) (Flinn 2019). These data support 
the hypothesis that prespecified 2-week drug holidays used in this study would not impact 
efficacy. Based on these results, the VS-0145-229 study will examine the effects of prespecified 
2-week dose holidays on tumor responses (i.e., is uninterrupted dosing required in early cycles to 


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achieve responses, or can comparable tumor responses be achieved starting with alternating 
2-week periods of dosing and holidays?) and safety/tolerability (i.e., will the holidays reduce the 
frequency, severity, and/or duration of AEs, allowing subjects to stay on treatment longer?). 
4.3. 
Justification for Dose 
The duvelisib 25 mg BID dose was selected as the current Recommended Phase 2 Dose (RP2D) 
based on the pharmacokinetics (PK), pharmacodynamics, clinical activity, and safety observed in 
a Phase 1 dose escalation study (IPI-145-02) in subjects with hematologic malignancies, 
including iNHL. The efficacy, safety, and tolerability of this RP2D was confirmed in a Phase 2 
study (IPI-145-06) in subjects with iNHL and is currently the approved label dose for CLL/SLL 
and FL patients. Please see the IB for detailed descriptions of duvelisib clinical study results and 
the selection of the RP2D. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed the last scheduled 
procedure shown in the Schedule of Activities (SoA) (Section 1.3). 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
(Section 1.3) for the last subject in the study globally. This will occur 2 years after the last 
subject is randomized. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Subjects may be eligible for inclusion in the study if they meet the following criteria: 
1. Male or female subjects ≥ 18 years of age 
2. Histologically confirmed diagnosis of iNHL. Histologic subtypes include FL Grades 1 to 
3a, marginal zone lymphoma (splenic, nodal, or extranodal), or SLL 
3. Must have received at least 1 prior systemic regimen for iNHL 
4. Must have documented radiologic evidence of disease progression, at least 
1 bidimensionally measurable lesion ≥ 1.5 cm (which has not been previously irradiated), 
according to 2007 revised IWG criteria (Cheson 2007), and be a candidate for a 
subsequent line of therapy 
5. Must have adequate organ function defined by the following laboratory parameters: 
a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L 
b. Platelet count ≥ 75 × 109/L 
c. Hemoglobin ≥ 8 g/dL 
d. Estimated creatinine clearance (eCCr) ≥ 60 mL/min, as determined by the Cockcroft- 
Gault method (Cockcroft 1976) 
e. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (exception: subjects with 
Gilbert's Syndrome may have a bilirubin > 1.5 × ULN) 
f. Aspartate transaminase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and 
alanine aminotransferase (ALT)/serum pyruvic transaminase (SGPT) ≤ 3.0 × ULN 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
7. Male and female subjects of reproductive potential (i.e., not surgically sterile or female 
subjects who are not postmenopausal) must be willing to use highly effective methods of 
contraception (see Section 10.4) for the duration of the study intervention and for 
3 months after the last dose of duvelisib 
8. Negative serum human chorionic gonadotropin (hCG) pregnancy test within 7 days 
before first dose of study intervention if the subject is a woman of childbearing potential 
(WCBP) (defined in Section 10.4) 
9. Signed and dated institutional review board (IRB)/independent ethics committee 
(IEC)-approved informed consent form before any study specific-screening procedures 
are performed 
5.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 


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1. Anticancer treatment, major surgery, or use of any investigational drug within 28 days 
before the start of study intervention; palliative radiation therapy is allowed if > 7 days 
before planned first dose of study interventions and any toxicity is Grade ≤ 1 
2. Clinical or histological evidence of transformation to a more aggressive subtype of 
lymphoma or grade 3b FL or Richter’s transformation or CLL 
3. Received prior allogeneic hematopoietic stem cell transplant (HSCT) 
4. Previous treatment with a PI3K inhibitor 
5. Known hypersensitivity to duvelisib and/or its excipients 
6. History or concurrent condition of interstitial lung disease of any severity and/or severely 
impaired lung function 
7. Prior history of drug-induced colitis or drug-induced pneumonitis 
8. History of tuberculosis treatment within the 2 years prior to randomization 
9. Administration of a live or live attenuated vaccine within 6 weeks of randomization 
10. Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic 
steroids > 20 mg of prednisone (or equivalent) per day 
11. Ongoing treatment for systemic bacterial, fungal, or viral infection at screening 
• Note: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not 
specifically excluded if all other inclusion/exclusion criteria are met 
12. Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjects with 
detectable viral load) 
13. Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), 
or herpes zoster (VZV) at screening 
14. Infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) 
• Subjects with a positive hepatitis B surface antigen [HBsAg] or hepatitis C antibody 
[HCV Ab] will be excluded 
• Subjects with a positive hepatitis B core antibody (HBcAb) must have negative 
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) to be eligible and must be 
periodically monitored for HBV reactivation by institutional guidelines 
• Investigators who strongly believe that a positive HBcAb is false due to passive 
immunization from previous immunoglobulin infusion therapy should discuss the 
potential to defer HBV prophylaxis with the Medical Monitor 
15. Concurrent administration of medications or foods that are strong inhibitors or inducers 
of cytochrome P450 3A (CYP3A). No prior use within 2 weeks before the start of study 
intervention. 
16. Subjects with clinically significant medical condition of malabsorption, inflammatory 
bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, 
vomiting, or any other condition that will interfere significantly with drug absorption 


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17. Central nervous system non-Hodgkin lymphoma (NHL); lumbar puncture not required 
unless central nervous system involvement is clinically suspected 
18. Baseline QTcF > 500 ms (average of triplicate readings). NOTE: This criterion does not 
apply to subjects with a right or left bundle branch block. 
19. Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ 
of the cervix, bladder cancer, or prostate cancer not requiring treatment. Subjects with 
previous malignancies are eligible if they have been disease-free for 2 years or more. 
20. History of chronic liver disease, veno-occlusive disease/sinusoidal obstruction syndrome, 
alcohol abuse, or illicit drug use 
21. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months prior to first dose of 
study intervention 
22. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, 
unstable pulmonary condition). Any important medical illness or abnormal laboratory 
finding that would, in the Investigator’s judgment, increase the subject’s risk to 
participating in this study. 
23. Female subjects who are pregnant or breastfeeding 
5.3. 
Lifestyle Considerations 
• Male and female subjects of reproductive potential (i.e., not surgically sterile or 
female subjects who are not postmenopausal) must use highly effective contraception 
for the duration of the study intervention and for at least 3 months after the last dose 
of duvelisib. Please see Section 10.4 for detailed contraceptive requirements. 
• Subjects should be advised to use appropriate protective measures to minimize 
exposure to direct sunlight or ultraviolet light sources during the treatment period and 
for at least 30 days after the last dose of duvelisib. Please see the IB for additional 
details on the potential for phototoxicity. 
• Refrain from consumption of grapefruit juice and St. John’s Wort, and other foods 
and herbal products that are strong inhibitors or inducers of CYP3A during treatment 
with duvelisib. Please see Section 6.6.3 for additional information on restrictions on 
the use of CYP 3A inhibitors, inducers, and substrates, and Section 10.2 for lists of 
CYP3A inhibitors, inducers, and substrates. The IB contains additional details on 
potential interactions with foods. 
5.4. 
Definition of Enrolled 
"Enrolled" means a subject's agreement to participate in a clinical study following completion of 
the informed consent process. Potential subjects who are pre-screened for the purpose of 
determining eligibility for the study but do not sign an informed consent form (ICF) are not 
considered enrolled. 


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5.5. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. A subject who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date. Please note that repeating of clinical 
laboratory assessments during screening does not constitute rescreening. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
Table 4: 
Study Intervention Arms 
 
Arm 1 
Arm 2 
Intervention Name 
Duvelisib 
Type 
Investigational Drug 
Drug Substance Description 
White to off-white crystalline powder 
Dose Formulation 
Capsule 
Unit Dose Strength(s) 
25 mg 
15 mg (dose reductions only) 
Formulation Excipients 
Excipients (diluent, glidant, disintegrant, and lubricant) that are listed in 
the United States (US) Food and Drug Administration (FDA) Inactive 
Ingredients Database for approved drug products and/or Generally 
Regarded as Safe (GRAS). 
Dosage Level(s) and 
Frequency 
25 mg BID for one 10-week cycle 
followed by 25 mg BID on Weeks 
3 and 4 of each subsequent 4-week 
cycles until disease progression, 
unacceptable toxicity, or 
withdrawal 
25 mg BID on Weeks 1, 2, 5, 6, 9 
and 10 of one 10-week cycle, then 
on Weeks 3 and 4 of each 
subsequent 4-week cycles until 
disease progression, unacceptable 
toxicity, or withdrawal 
Route of Administration 
Oral 
Use 
Experimental 
Investigational Medicinal 
Product (IMP) or Non- 
Investigational Medicinal 
Product (NIMP) 
IMP 
Sourcing 
Provided by the Sponsor 
Packaging and Labeling 
Packaging and labeling will be prepared to meet all regulatory 
requirements. 
Current/Former Name(s) or 
Alias(es) 
VS-0145, IPI-145 
6.2. 
Administration 
Duvelisib should be swallowed whole with a glass of water (approximately 8 ounces or 240 mL). 
Advise subjects not to open, break, or chew the capsules. Duvelisib may be administered without 
regard to meals, however, subjects must avoid grapefruit and grapefruit juice while on duvelisib. 


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Refer to the Pharmacy Manual for additional instructions regarding study intervention 
administration. 
6.3. 
Preparation/Handling/Storage/Accountability 
Dispensing and storage instructions for duvelisib will be provided in the Pharmacy Manual. On 
receipt at the investigative site, duvelisib should remain in the packaging as provided until use or 
dispensation. The packaged product should be stored at the investigative site at 20° to 25°C (68° 
to 77°F), with excursions permitted at 15° to 30°C (59° to 86°F). Temperature excursion 
procedures are provided in the Pharmacy Manual. Expired drug is not to be dispensed. 
Only subjects enrolled in the study may receive study intervention and only authorized site staff 
may supply or administer study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label randomized study. Subjects will be stratified by number of prior therapies 
(1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm) and time 
since last recurrence (≥ 24 months or < 24 months). 
Subjects will be assigned a unique number in ascending numerical order at each study site. This 
is an open-label study; however, the specific arm for a subject will be assigned using an 
interactive web response system (IWRS). The site will contact the IWRS prior to the start of 
study intervention administration for each subject. The site will record the arm assignment on the 
applicable case report form (CRF). Potential bias will be reduced by central randomization. 
6.5. 
Study Intervention Compliance 
When subjects are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. The 
dose of study intervention and study subject identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. 
When subjects self-administer study intervention at home, compliance with study intervention 
will be assessed at each visit. Compliance will be assessed by reviewing subject diaries (first 
year on treatment only) and counting returned capsules during the site visits and documented in 
the source documents and CRF. Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF. 


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A record of the number of duvelisib capsules dispensed to and taken by each subject must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded in 
the CRF. 
6.6. 
Concomitant Therapy 
Any other medication (e.g., supportive care) that is considered necessary for the subject’s 
welfare and is not expected to interfere with the evaluation of duvelisib may be given at the 
discretion of the Investigator. 
Any medication that the subject is receiving at the time of enrollment or receives during the 
study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6.1. 
Required and Recommended Prophylaxis 
6.6.1.1. 
Antimicrobial and Antiviral Prophylaxis 
Based on the duvelisib clinical experience to date the following are required or recommended: 
• Subjects are required to receive pneumocystis prophylaxis concomitant with study 
intervention treatment per institutional guidelines. Following completion of duvelisib 
treatment, continue prophylaxis until the absolute CD4+ T-cell count is greater than 
200 cells/μL. 
• HSV and VZV infections have been observed with duvelisib; therefore, herpes 
(HSV/VZV) prophylaxis concomitant with treatment is recommended, per 
Investigator discretion according to institutional guidelines. 
• Subjects with a history of CMV infection/reactivation or viremia should be monitored 
for reactivation by polymerase chain reaction (PCR) or antigen test at least monthly. 
Prophylactic treatment per institutional guidelines is recommended for subjects 
considered by Investigators to be at high risk for CMV reactivation. 
• Antimicrobial prophylaxis and pneumococcal pneumonia vaccine are recommended 
for subjects with history of or considered at high risk for infections and during 
periods of severe neutropenia. Choice of antimicrobial agent (antifungal, antibiotic, 
antiviral) is per Investigator discretion, but the restrictions on the use of CYP3A 
inducers, inhibitors, and substrates should be considered (see Section 6.6.3). 
6.6.2. 
Supportive Care and Management of Toxicities 
Supportive care should be provided as clinically indicated. Granulocyte colony-stimulating 
factor (G-CSF) may be used according to the American Society of Clinical Oncology (ASCO) 


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guidelines (Smith 2015). Transfusions may be used at any time as clinically indicated, and 
according to ASCO guidelines. Subjects on a stable dose of erythropoietin to treat baseline 
anemia may continue this therapy at this dose. 
Recommendations for the management of non-hematologic and hematologic AEs with 
supportive care, treatment hold, dose reduction, or discontinuation of duvelisib are found in 
Table 5. Additional information regarding management of toxicities can be found in the 
Summary of Data and Guidance to the Investigator section of the IB. 
Table 5: 
Recommendations for the Management of Toxicities 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
Non-hematologic Adverse Reactions 
Infections 
Grade 3 or higher infection 
• 
Withhold duvelisib until resolved 
• 
Resume at the same or reduced dose (see Table 8) 
Clinica l CMV infection or 
viremia (positive PCR or 
antigen test) 
• 
Withhold duvelisib until resolved 
• 
Resume at the same or reduced dose (see Table 8) 
• 
If duvelisib is resumed, monitor subjects for CMV 
reactivation (by PCR or antigen test) at least monthly 
PJP 
• 
For suspected PJP, withhold duvelisib until evaluated 
• 
For confirmed PJP, discontinue duvelisib 
Non-infectious 
Dia rrhea or colitis 
Mild/moderate dia rrhea 
(Gra de 1-2, up to 6 stools per 
day over baseline) and 
responsive to antidiarrheal 
agents, 
OR 
Asymptomatic (Gra de 1) 
colitis 
• 
No change in dose 
• 
Initiate supportive therapy with antidiarrheal agents 
as appropriate 
• 
Monitor at lea st weekly until resolved 
Mild/moderate dia rrhea 
(Gra de 1-2, up to 6 stools per 
day over baseline) and 
unresponsive to antidiarrheal 
agents 
• 
Withhold duvelisib until resolved 
• 
Initiate supportive therapy with enteric acting 
steroids (e.g., budesonide) 
• 
Monitor at lea st weekly until resolved 
• 
Resume at a reduced dose (see Table 8) 
Abdominal pain, stool with 
mucus or blood, change in 
bowel habits, peritoneal 
signs, 
OR 
Severe dia rrhea (Gra de 3, 
> 6 stools per day over 
baseline) 
• 
Withhold duvelisib until resolved 
• 
Initiate supportive therapy with enteric acting 
steroids (e.g., budesonide) or systemic steroids 
• 
Monitor at lea st weekly until resolved 
• 
Resume at a reduced dose (see Table 8) 
• 
For recurrent Gra de 3 dia rrhea or recurrent colitis of 
any grade, discontinue duvelisib 
Life-threatening 
• 
Discontinue duvelisib 


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Toxicity 
Adverse Reaction Grade 
Recommended Management 
Cutaneous reactions 
Gra de 1-2 
• 
No change in dose 
• 
Initia te supportive care with emollients, anti- 
histamines (for pruritus), or topical steroids 
• 
Monitor closely 
Gra de 3 
• 
Withhold duvelisib until resolved 
• 
Initia te supportive care with emollients, anti- 
histamines (for pruritus), or topical steroids 
• 
Monitor at lea st weekly until resolved 
• 
Resume at reduced dose (see Table 8) 
• 
If severe cutaneous reaction does not improve, 
worsens, or recurs, discontinue duvelisib 
Life-threatening 
• 
Discontinue duvelisib 
SJS, TEN, DRESS (any 
grade) 
• 
Discontinue duvelisib 
Pneumonitis without 
suspected infectious 
cause 
Moderate (Gra de 2) 
symptomatic pneumonitis 
• 
Withhold duvelisib 
• 
Treat with systemic steroid therapy 
• 
If pneumonitis recovers to Grade 0 or 1, duvelisib 
may be resumed at reduced dose (see Table 8) 
• 
If non-infectious pneumonitis recurs or subject does 
not respond to steroid therapy, discontinue duvelisib 
Severe (Gra de 3) or life- 
threatening pneumonitis 
• 
Discontinue duvelisib 
• 
Treat with systemic steroid therapy 
ALT/AST eleva tion 
3 to 5 × ULN (Grade 2) 
• 
Maintain duvelisib dose 
• 
Monitor at least weekly until return to 
< 3 × ULN 
> 5 to 20 × ULN (Grade 3) 
• 
Withhold duvelisib and monitor at lea st weekly until 
return to < 3 × ULN 
• 
Resume duvelisib at same dose (first occurrence) or 
at a reduced dose for subsequent occurrence (see 
Table 8) 
> 20 × ULN (Gra de 4) 
• 
Discontinue duvelisib 
Hematologic Adverse Reactions 
Febrile neutropenia 
Gra de 3-4 
• 
Interrupt duvelisib until afebrile and resolution of 
Grade 3 or Grade 4 neutropenia to Grade ≤2 
Neutropenia 
ANC 0.5 to 1.0 Gi/L 
• 
Maintain duvelisib dose 
• 
Monitor ANC at least weekly 
ANC less than 0.5 Gi/L 
• 
Withhold duvelisib 
• 
Monitor ANC until > 0.5 Gi/L 
• 
Resume duvelisib at same dose (first occurrence) or 
at a reduced dose for subsequent occurrence 
(see Table 8) 


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Toxicity 
Adverse Reaction Grade 
Recommended Management 
Thrombocytopenia 
Platelet count 25 to 
< 50 Gi/L (Gra de 3) with 
Grade 1 bleeding 
• 
No change in dose 
• 
Monitor platelet counts at least weekly 
Platelet count 25 to 
< 50 Gi/L (Gra de 3) with 
Grade 2 bleeding 
or 
Pla telet count < 25 Gi/L 
(Gra de 4) 
• 
Withhold duvelisib 
• 
Monitor platelet counts until ≥ 25 Gi/L and 
resolution of bleeding (if applicable) 
• 
Resume duvelisib at same dose (first occurrence) or 
resume at a reduced dose for subsequent occurrence 
(see Table 8) 
Abbrevia tions: ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: aspartate transaminase; 
CMV: cytomegalovirus; DRESS: drug reaction with eosinophilia and systemic symptoms; Gi:1 x 109; PCR: 
polymerase chain reaction; PJP: Pneumocystis jiroveci pneumonia; SJS: Stevens-Johnson syndrome; TEN: toxic 
epidermal necrolysis; ULN: upper limit of normal. 
6.6.3. 
Concomitant Therapies Restrictions 
Table 6:  
Prohibited Concomitant Therapies 
Prohibited Concomitant 
Therapy 
Guidance 
Use of Vaccines 
For all subjects, the use of live or live attenuated vaccines is prohibited 
within 6 weeks prior to C1D1, during the treatment with duvelisib, and for 
3 months after the last dose of study drug. 
The use of inactivated (or killed) vaccines (such as pneumococcal 
pneumonia vaccine) is allowed during the study, however subjects and their 
physicians should be aware that the effectiveness of any vaccine 
administered concomitantly with duvelisib may be diminished. The ability to 
generate an immune response to any vaccine following the administration of 
duvelisib has not been studied. 
Immunosuppressants 
Subjects are not to receive ongoing treatment with chronic 
immunosuppressants (e.g., cyclosporine) or systemic steroids for > 1 week at 
doses > the equivalent of 20 mg prednisone QD. 
Note: Acute treatment for underlying autoimmune disorders (e.g., reactive 
airway disease, rheumatoid arthritis, etc.) with corticosteroid doses > 20 mg 
prednisone or equivalent QD for ≤ 1 week is permitted during the study. 
Corticosteroid doses of ≤ 20 mg prednisone or equivalent QD are permitted 
during the study for physiological replacement or chronic treatment for 
underlying autoimmune disorders (e.g., reactive airway disease, rheumatoid 
arthritis, etc.). 
Other Anticancer Therapy 
or Investigational Agents 
During study intervention period, subjects are not to receive any additional 
anticancer therapy or other investigational agents not outlined in the 
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Prohibited Concomitant 
Therapy 
Guidance 
Medications or Foods that 
Strongly Inhibit or Induce 
CYP3A4 
Use of a strong CYP3A inhibitor or inducer is prohibited. Co-administration 
with a strong CYP3A inhibitor increases duvelisib exposure which may 
increase the risk of duvelisib toxicities. Co-administration with a strong 
CYP3A inducer decreases duvelisib exposure which may reduce duvelisib 
efficacy. 
Section 10.2 provides a list of medications and foods known to inhibit 
(Table 15) or induce (Table 16) CYP3A. Please note that these tables do not 
provide a comprehensive list of all medications which may modulate CYP3A 
activity. 
Abbreviations: CYP3A: cytochrome P450 3A; QD: once daily. 
Table 7: 
Concomitant Therapies: Use with Caution 
 
Concomitant Therapy: 
Use with Caution 
Guidance 
Medications or Foods that 
Weakly or Moderately 
Inhibit or Induce 
CYP3A4 
Please discuss use of weak or moderate CYP3A inhibitors and inducers with 
the Medical Monitor. 
Section 10.2 provides a list of medications and foods known to inhibit 
(Table 15) or induce (Table 16) CYP3A. Please note that these tables do not 
provide a comprehensive list of all medications which may modulate CYP3A 
activity. 
Medications that are 
Substrates of CYP3A 
Co-administration with duvelisib decreases AUC of a sensitive CYP3A4 
substrate which may decrease the efficacy of these drugs. Consider finding 
an alternative drug that is not a substrate of CYP3A4. Table 17 in 
Section 10.2 provides a list of medications known to be substrates of 
CYP3A. Please note that Table 17 is not a comprehensive list of all 
medications which may be substrates of CYP3A. The Sponsor should be 
contacted with any questions regarding concomitant use of medications that 
are CYP3A substrates. 
Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A; QD: once daily. 
6.6.4. 
Contraception and Pregnancy 
The effects of duvelisib on conception, pregnancy, and lactation are unknown. 
At Screening, all male and female subjects of reproductive potential (i.e., not surgically sterile or 
female subjects who are not postmenopausal) must be willing to use highly effective methods of 
contraception for the duration of the study intervention and for 3 months after the last dose of 
duvelisib. See Section 10.4 (Appendix 4) for Contraceptive Guidance including examples of 
highly effective contraceptive methods. Pregnancy testing will be performed throughout the 
study as shown in SoA (Table 1). 
6.6.5. 
COVID-19 Vaccines 
Subjects who have received, or receive while active in the trial, a regulatory-approved COVID- 
19 vaccine may participate in the study with no restrictions. Any vaccine-related AEs reported 
by study subjects will be recorded on the appropriate CRF. 


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6.7. 
Dose Modification 
For dose modifications and dose level recommendations refer to Table 8. Duvelisib may be held 
up to 42 days for toxicity. Doses held for > 42 days due to treatment-related toxicity will result in 
permanent discontinuation from duvelisib. Any subject who requires a dose level reduction to 
below 15 mg BID due to treatment-related toxicities will be permanently discontinued from 
duvelisib treatment. 
If duvelisib treatment is permanently discontinued due to an AE, subjects should be followed for 
disease response and survival as outlined in the SoA (Table 1). 
Dosing levels for duvelisib are shown in Table 8. 
Table 8: 
Duvelisib Dosing Levels 
 
Dose Level 
Duvelisib Dosing Levels 
1 
25 mg BID 
-1 
15 mg BID 
-2 
Discontinue duvelisib if subject is unable to tolerate 15 mg BID 
Abbrevia tions: BID: twice daily 
Subjects who have a dose reduction due to a toxicity will not be eligible for a dose re-escalation. 
6.8. 
Intervention after the End of the Study 
If the study is ended prior to all subjects discontinuing treatment, any subject continuing to 
receive benefit will be provided the opportunity to continue to receive duvelisib. Long-term 
continued treatment may be provided via an expanded access program consistent with local 
regulations, such as the Secura Bio NPP. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Duvelisib will be discontinued for any of the following reasons: 
• Subject withdrawal of informed consent 
• Protocol-specified disease progression 
• Clinical deterioration (at the discretion of the Investigator) 
• Study intervention interruption for > 42 days due to duvelisib-related toxicity (unless 
approved by study Medical Monitor) 
• Unacceptable toxicity 
• Pregnancy 
• Termination of the study by the Sponsor 
• Death 
• Other reasons, including major protocol violation or noncompliance 
The Investigator must determine the primary reason for a duvelisib discontinuation and record 
this information on the CRF. 
See the SoA for data to be collected at the time of discontinuation of study intervention and for 
any further evaluations that need to be completed. 
7.2. 
Subject Withdrawal from the Study 
• A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. 
• At the time of withdrawing from the study, if possible, an End of Treatment (EoT) 
Visit should be conducted, as shown in the SoA. See SoA (Table 1) for data to be 
collected at the EoT Visit and follow-up, and for any further evaluations that need to 
be completed. Additional visits may be conducted as necessary for any abnormal 
findings that require medical follow-up. 
• The subject will be permanently discontinued from the study intervention and 
withdrawn from the study at that time. 
• If the subject withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 


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7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject. These contact attempts (e.g., 3 phone 
calls followed by a certified letter) should be documented in the subject’s medical 
record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are described in Section 10.6.8. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1 and Table 2). 
Protocol waivers or exemptions are not allowed. 
• Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. Repeat lab assessments during the screening 
period do not constitute rescreening. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screen failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• The maximum amount of blood collected from each subject over the duration of the 
study, including any extra assessments that may be required, will be described in the 
ICF. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
Assessment of disease response and progression status in all subjects will be evaluated by the 
Investigator using 2007 IWG criteria (Cheson 2007) and 2014 Lugano criteria (Cheson 2014). 
Response and progression will be evaluated using the following procedures, as indicated in the 
SoA (Table 1). 
• Focused physical examination (PE) (including assessment of liver and spleen and 
review of disease-related constitutional symptoms) (see Section 8.2.1.2) 
• Imaging scans of chest, abdomen, and pelvis (see Section 8.1.1) 
• Bone marrow biopsy/aspirate (see Section 8.1.2) 
These evaluations will be done until progressive disease (PD) is documented, other anticancer 
therapy is initiated, or death occurs. For subjects who discontinue study intervention for reasons 
other than radiologic disease progression, response assessments will be performed during long- 
term follow-up (Section 8.1.4). 
8.1.1. 
Imaging Scans 
All subjects require CT or 18Fluoro-2-deoxy-d-glucose (FDG) positron emission tomography 
(PET)-CT (PET-CT) scans of the chest, abdomen, and pelvis. Magnetic resonance imaging 
(MRI) may be used instead of CT scans if CT cannot be done, but the same method must be used 


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throughout the study. Other scans may be performed (e.g., neck/head) if clinically indicated or if 
the area is a site of known disease. Any new abnormal findings outside disease measurements 
should be captured as an AE. 
8.1.2. 
Bone Marrow Biopsy/Aspirate 
If a bone marrow/aspirate is performed within 60 days before C1D1 as part of standard of care, 
the pathology report will be provided to the Sponsor. If a radiologic CR according to 2007 
revised IWG criteria (Cheson 2007) is observed during the course of the study, then a bone 
marrow biopsy should be done to confirm a CR. The pathology report will be provided to the 
Sponsor. 
8.1.3. 
Investigator Assessment of Response and Progression Status 
Assessment of response and progression status will be evaluated by the Investigator at each 
scheduled disease response assessment as outlined in the SoA (Table 1). Assessment of response 
and progression status in all subjects will be evaluated using the definitions from the 2007 
revised IWG criteria (Cheson 2007) for clinical decision-making and assessment of response. 
Secondarily, response will also be assessed using the 2014 Lugano criteria (Cheson 2014). 
Please see Section 10.1 for detailed descriptions of these response criteria. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1). Additional 
visits may be conducted as necessary for any abnormal findings that require medical follow-up. 
8.2.1. 
Physical Examinations and Vital Signs 
8.2.1.1. 
Full Physical Examination 
The full PE will include assessment of liver/spleen size, clinical assessment of tumor masses (if 
evaluable by PE), review of disease-related constitutional symptoms (B symptoms: symptoms of 
fever [i.e., temperature > 38°C/100.4°F] without evidence of infection, weight loss, and 
drenching night sweats without evidence of infection), neurologic exam, height, and weight. 
Any pre-existing PE abnormality deemed clinically significant by the Investigator during 
Screening will be reported as medical history. Any PE abnormality that emerges or has worsened 
after signing of the ICF and that is assessed as clinically significant by the Investigator will be 
reported as an AE. 
8.2.1.2. 
Focused Physical Examination 
Each focused PE is to include assessment of liver and spleen size, clinical assessment of tumor 
masses and evaluation for the presence of disease-related constitutional symptoms (B symptoms: 
symptoms of fever [i.e., temperature > 38°C/100.4°F] without evidence of infection, weight loss, 
and drenching night sweats without evidence of infection). 
Results from the focused PEs and assessments of ECOG performance status (Section 8.4.1) will 
be used for assessment of disease response and safety. Additionally, any new or ongoing 
abnormal findings will be assessed. Any new clinically significant abnormality from baseline 
should be recorded as an AE. 


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8.2.1.3. 
Vital Signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. 
8.2.2. 
Electrocardiogram and Echocardiogram/Multi-gated Acquisition Scan 
At Screening, a standard 12-lead electrocardiogram (ECG) will be conducted following an 
approximate 10-minute rest period. QTc measurements (as measured by triplicate readings) will 
use the Fridericia’s correction method (QTcF). 
To measure left ventricular ejection fraction (LVEF), an echocardiogram (ECHO) or multi-gated 
acquisition (MUGA) scan will be administered at the Screening Visit. 
Additional ECGs and ECHO/MUGA scans may be performed as clinically indicated per 
Investigator’s judgment. 
8.2.3. 
Concomitant Medication and Procedures 
Concomitant medications and procedures will be assessed and recorded in the CRF during 
Screening (including those occurring within 30 days prior to randomization) and at each visit. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Table 18 for the list of clinical laboratory tests to be performed and the SoA 
(Table 1) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the subject's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or the Medical Monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Table 18, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 1). 
o If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the Investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the CRF. 


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8.3. 
Adverse Event Management 
8.3.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product that 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 related to the study (investigational) product. This includes an exacerbation of 
pre-existing conditions or events, concurrent illnesses, drug interaction, or the significant 
worsening of the indication under investigation. Anticipated fluctuations of pre-existing 
conditions, including the disease under study that does not represent a clinically significant 
exacerbation or worsening, need not be considered AEs. 
Symptoms of the disease under study/lack of efficacy/disease progression should not be 
classified as an AE if they are within the normal day-to-day fluctuation or expected progression 
of the disease. 
It is the responsibility of the Investigator to document all AEs that occur during the study. AEs 
should be reported on the appropriate CRF. 
8.3.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence at any dose (including after the ICF is signed and 
prior to dosing) that: 
• Results in death 
• Is life-threatening (subject is at immediate risk of death from the event as it occurred) 
• Requires inpatient or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, are not immediately life-threatening, or do 
not require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
For SAE reporting purposes, hospitalization is defined as inpatient hospital stay. Hospitalizations 
for elective surgery or other medical procedures that are not related to a TEAE are not 
considered SAEs. Hospitalization, which in the opinion of the Investigator, is unrelated to the 
study intervention, and due to purely non-medical circumstances (e.g., respite care, lack of a 
caretaker at home, lack of transportation home) are also not considered to be SAEs. PD under 
study (including signs and symptoms of progression) if documented by use of appropriate 
methods, should not be reported as an SAE unless the outcome of the PD is fatal during the study 
or within the safety reporting period (see Section 8.3.3, Reporting of Adverse Events and Serious 


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Adverse Events). If the malignancy has a fatal outcome during the study or within the safety 
reporting period, then the event should be reported using the term "disease progression" with a 
Common Terminology Criteria for Adverse Events (CTCAE) severity of Grade 5. 
Death should not be reported as an SAE. The primary reason for a subject’s death should be 
reported as an SAE, with death reported as the outcome. 
8.3.3. 
Reporting of Adverse Events and Serious Adverse Events 
The AE reporting period begins from the time that the subject signs the ICF through and 
including 30 calendar days after the last study intervention dose. All subjects with treatment- 
related AEs/SAEs should be observed until resolution or stabilization. Any SAE occurring after 
the reporting period must be promptly reported if a causal relationship to the investigational drug 
is suspected. If the subject begins a new anticancer therapy, the safety reporting period ends at 
the time the new treatment is started, however, death must always be reported if it occurs during 
the AE reporting period irrespective of intervening treatment. 
Elective or previously scheduled hospitalizations for pre-existing conditions that have not 
worsened after initiation of treatment should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE. 
All AEs should be recorded individually unless, in the opinion of the Investigator or designated 
physician, the AEs constitute components of a recognized condition, disease, or syndrome. In the 
latter case, the condition, disease, or syndrome should be reported rather than each individual 
sign or symptom. If a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded as an AE or SAE as appropriate on the relevant form(s) (SAE Report Form and/or AE 
CRF). If a diagnosis is subsequently established, it should be reported as follow-up information 
becomes available. If a diagnosis is determined after the reporting of the constellation of 
symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
Each AE will be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug. The action taken with study intervention and the outcome must also be 
recorded. 
All SAEs, regardless of relationship to the study intervention, must be reported immediately 
(within 24 hours of awareness of event by Investigator) to the Sponsor and Contract Research 
Organization (CRO) pharmacovigilance group. Initial SAE notification should be made by e- 
mailing or faxing the SAE report form to the e-mail or fax number provided on the SAE report 
form. 
An initial SAE Report may be sent without the Investigator’s signature but must be followed by 
a report signed by the Investigator within 48 hours of becoming aware of the event. Follow-up 
SAE reports must be submitted by the Investigator as new information becomes available. 
The Medical Monitors for this study may be contacted for advice or assistance. Contact details 
will be provided in the study contact list. 


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8.3.4. 
Severity of Adverse Events 
The severity of the AE will be graded according to the National Cancer Institute (NCI) CTCAE, 
version 5.0 (see web page 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 for details). 
AEs not listed in the CTCAE should be graded as summarized in Table 9. 
Table 9: 
CTCAE AE Grading 
 
CTC Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although this 
could improve the overall well-being or symptoms of the 
subject 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated to improve the overall 
well-being or symptoms; delaying the onset of treatment is 
not putting the survival of the subject at direct risk 
Grade 4 
Life-threatening/ 
disabling 
An immediate threat to life or leading to a permanent mental 
or physical condition that prevents work or performing 
normal daily activities; treatment or medical intervention is 
required to maintain survival 
Grade 5 
Death 
AE resulting in death 
Abbreviations: AE: adverse event, CTC: Common Terminology Criteria; CTCAE: Common Terminology 
Criteria for Adverse Events. 
 
8.3.5. 
Relationship of Adverse Events to Study Intervention 
The Investigator will make a judgment regarding whether or not the AE was related to study 
intervention, as outlined below: 
• Definitely related: This category applies when, after careful medical consideration, 
there is almost no consideration of other causation. 
• Probably related: There is a clinically plausible time sequence between onset of the 
AE and study intervention administration. The AE is unlikely to be caused by a 
concurrent or underlying illness, other drugs, or procedures. If applicable, the AE 
follows a clinically consistent resolution pattern upon withdrawal of study 
intervention. 
• Possibly related: There is a clinically plausible time sequence between onset of the 
AE and study intervention administration, but the AE could also have been caused by 
the concurrent or underlying illness, other drugs, or procedures. Information 
regarding study intervention withdrawal may be lacking or unclear. "Possible" should 
be used when study intervention administration is one of several biologically 
plausible causes of the AE. 


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• Unlikely related: The AE is most likely due to a cause not related to study 
intervention administration. However, association with the study intervention cannot 
be completely ruled out. 
• Unrelated: Another cause of the AE is most plausible, and a clinically plausible 
temporal sequence is inconsistent with the onset of the AE and study intervention 
administration and/or a causal relationship is considered biologically implausible. 
For the purpose of regulatory reporting requirements, causal relationships of definite, probable, 
and possible will be considered treatment-related, while unlikely and unrelated will be 
considered not treatment-related. 
8.3.6. 
Clinical Laboratory Adverse Events 
A clinical laboratory AE is any laboratory value that is deemed clinically significant by the 
Investigator. The Investigator should decide, based upon the AE criteria and the clinical 
condition of the subject, whether a change in a laboratory parameter is clinically significant and 
therefore represents an AE. 
The following items may be considered when determining clinical significance: 
• Severity of the laboratory abnormality (i.e., greater than Grade 2 in severity) 
• Laboratory abnormality requires a medical intervention 
• Laboratory abnormality requires a change or suspension of study intervention 
• Laboratory abnormality is accompanied by clinical symptoms 
Laboratory abnormalities that are not considered clinically significant should not be recorded as 
AEs and will be captured and reported in the laboratory section of the clinical study report. If a 
medical intervention occurs, it should be recorded as a treatment with the abnormal laboratory 
finding as the AE (e.g., anemia with treatment required and blood transfusion recorded as a 
procedure, hyperglycemia with treatment required and change in insulin dose recorded on 
concomitant medications). 
If, at the end of the treatment phase with the study intervention, there are pathological laboratory 
values which were not present at Baseline, further clinical or laboratory investigations should be 
performed until the values return to within reference range or until a plausible explanation (i.e., 
concomitant disease) is found for the pathological laboratory values. 
8.3.7. 
Regulatory Aspects of Adverse Event Reporting 
The Sponsor is responsible for submitting reports of SAEs associated with the use of the study 
intervention to the appropriate Regulatory Authority (e.g., the US FDA), Investigators, and 
IRB/IEC/Central Ethics Committee (CEC) in accordance with all applicable regulations and 
guidelines. 
It is the responsibility of the Investigator to notify the IRB of all SAEs that occur at his or her 
site. Investigators will be notified of all suspected, unexpected serious adverse reactions 
(SUSARs; 7 / 15 Day Safety Reports) that occur during any clinical studies that are using the 
investigative compound. Each site is responsible for notifying their IRB/IEC/CEC of these 
additional SUSARs in accordance with local regulations. 


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8.3.8. 
Overdose 
In the case of overdose, clinic staff should be notified immediately, and supportive care should 
be given if needed and as indicated. Subjects should be informed to contact their doctor 
immediately if they have taken an overdose and should stop taking duvelisib. 
For this study, overdose is defined as a daily dose of duvelisib higher than the prescribed daily 
dose. Overdoses will not be considered SAEs unless the outcome of the overdose meets 
seriousness criteria as defined in Section 8.3.2. In the event of an overdose that causes an SAE, 
the Sponsor should be notified within 24 hours of Investigator’s knowledge. The subject should 
be carefully monitored for potential adverse reactions and symptomatic treatment instituted as 
per institutional standards of care. The Investigator will determine if and when dosing should 
resume. 
8.3.9. 
Pregnancy 
Any pregnancy must be reported to the Sponsor or designee within 24 hours of the Investigator’s 
knowledge of the pregnancy using a Pregnancy Report Form. 
Pregnancy per se is not considered an AE unless there is cause to believe that the study 
intervention may have interfered with the effectiveness of a contraceptive medication or if the 
outcome of the pregnancy meets SAE criteria (miscarriage or congenital anomaly/birth defect, 
etc.), in which case it should be reported in the same manner and timelines as an SAE. In 
addition, any infant death or congenital anomaly occurring after 30 days that the Investigator 
suspects is related to the in-utero exposure to the study intervention should also be reported as an 
SAE. Hospitalization for normal delivery of a healthy newborn is not an SAE. 
Since duvelisib has not been evaluated in pregnant or nursing women, the treatment of pregnant 
women or WCBP who are not using highly effective contraception is contraindicated (see 
Table 18 and Section 10.4 for instructions on pregnancy testing and contraception). 
Pregnancies occurring in subjects or partners of male subjects during the study intervention 
period until 30 days after the subject’s last dose of study intervention are considered immediately 
reportable events. If a pregnancy occurs in a subject, study intervention must be discontinued 
immediately. The pregnant woman should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling. The Investigator will 
observe the pregnant woman until completion of the pregnancy and must notify the Sponsor of 
the outcome within 24 hours of the Investigator’s knowledge of the pregnancy outcome using a 
Pregnancy Outcome Form. This notification includes pregnancies resulting in live, “normal” 
births. 
8.4. 
Quality of Life Assessments 
8.4.1. 
ECOG Performance Status 
ECOG Performance Status will be assessed at Screening. If the ECOG Performance Status 
assessed at Screening is performed within 7 days of Cycle 1 Day 1, the Screening assessment can 
be used and does not need to be repeated at Cycle 1 Day 1 (predose). Please see SoA Table 1 for 
the schedule of ECOG Performance Status during study treatment and follow-up. 


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8.4.2. 
Subject Self-reported Health-related Quality of Life 
Subject self-reported health-related quality of life (QοL) will be assessed at Screening, during 
study treatment, and, when possible, upon treatment discontinuation for any reason. Subject- 
reported health-related QoL will be assessed using the EQ-5D-3L questionnaire. Questionnaire 
should be administered predose and prior to other procedures during treatment visits. 
8.5. 
Pharmacokinetics 
• Blood samples will be collected to evaluate the PK of duvelisib and metabolite IPI- 
656 at the visits and timepoints defined in SoA Table 2. 
• Predose samples are preferred, therefore on the days that include PK assessments the 
morning dose of duvelisib should be administered in the clinic to facilitate collection 
of samples prior to dosing. However, the sample should still be collected even if the 
morning dose of duvelisib has already been taken. The date and time of the sample 
collection and date and time of the previous duvelisib dose must be recorded for all 
collected samples. 
• Additional PK samples beyond those listed in SoA (Table 2) may be requested (when 
feasible) for any unusual safety event. (i.e., an AE different in type and severity from 
that which is expected in the setting of duvelisib use). 
• Specific instructions on sample collection and handling will be provided in a separate 
Laboratory Manual. 
• Retained duplicate PK samples may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
• Genetic analyses will not be performed on these PK samples. 
• Subject confidentiality will be maintained. 
8.6. 
Pharmacodynamics 
Pharmacodynamic biomarkers will be assessed using blood samples collected at sampling 
timepoints in the SoA (Table 2) and are described under Biomarkers (Section 8.8). 
8.7. 
Genetics 
Normal germline genetic studies are not evaluated in this study. Tumor genomic studies may be 
conducted as part of exploratory biomarker research (Section 8.8). 
8.8. 
Biomarkers 
Biomarker samples will be collected according to the SoA (Table 2) and assessments may be 
conducted to evaluate potential biomarkers as described in Table 10. 


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Table 10:   Biomarker Samples and Assessments 
 
Sample 
Assessments 
Blood for pharmacodynamics 
Pharmacodynamic assays evaluate phosphorylated 
protein levels in several cell types. 
Serum and plasma for biomarker analysis 
Protein (e.g., cytokines, chemokines) and/or ctDNA 
Blood for immunophenotyping 
Immune cell population profiling (e.g., B T- funcDNA, 
and/or RNA analysis) 
Stool for biomarker analysis 
Protein, DNA, and/or RNA analysis to evaluate 
correlations with gastrointestinal toxicities 
Archival tumor tissue (if available) 
Tumor markers that may predict clinical response to 
duvelisib. 
PI3K pathway and/or disease-specific biomarkers (e.g. 
PTEN, PI3K isoforms) by immunohistochemistry 
and/or in situ hybridization. 
Tumor genomic studies may be performed (e.g. DNA 
sequencing, DNA copy number analysis, RNA 
expression profiling) to explore whether specific 
genomic features correlate with response or resistance 
to duvelisib in iNHL. 
Colon biopsies taken as standard of care to 
assess colitis (if available) 
Pharmacodynamic analysis, immune cell and immune 
cell function, protein and genomics analyses 
Abbrevia tions: ctDNA: circulating tumor deoxyribonucleic acid; iNHL: indolent non-Hodgkin lymphoma; PI3K: 
phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; RNA: ribonucleic acid 
In addition, C-reactive protein levels in blood (a clinical safety laboratory assessment) will be 
evaluated as a potential biomarker and will be assessed at Screening and whenever Grade ≥ 2 
diarrhea or any colitis occurs. 
8.9. 
Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 


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9. 
STATISTICAL METHODOLOGY 
A detailed description of the statistical methodology for this study can be found in the Statistical 
Analysis Plan (SAP). Deviations from the statistical analyses outlined in this protocol will be 
indicated in the SAP; any further modifications will be noted in the final clinical study report. 
9.1. 
Statistical Hypotheses 
This study will test the null hypothesis that the ORR for each arm is ≤ 30% against the 
alternative that ORR is ≥ 55%. 
9.2. 
Sample Size Determination 
The sample size for each arm was calculated using a 2-stage approach. 
For each arm: in the first stage, 15 subjects will be randomized. The evaluation of the first stage 
will take place after the 15 enrolled subjects have been followed for a minimum of 3 cycles 
(18 weeks). 
If there are fewer than 6 responders (PR or CR) among the first 15 subjects, consideration may 
be given to terminating the treatment arm. The decision to proceed to Stage 2 will be based on 
the totality of data observed, including types of responses, safety data, and discontinuation rates. 
The treatment arm may also not proceed to the second stage if the totality of the data is viewed 
as compelling; such scenarios could include (but are not limited to) accumulating enough data in 
Stage 1 to conclude the ORR exceeds 30%. If the treatment arm proceeds to the second stage, up 
to 36 additional subjects will be enrolled for a total of 51. If fewer than 22 (43%) responders (PR 
or CR) are observed in 51 subjects, consideration may be given to concluding that the treatment 
schedule does not warrant further study in this population. The final evaluation of each schedule 
will be based on the totality of data observed, including types of responses, safety data, and 
discontinuation rates. This design yields 90% power under the assumptions described above; the 
alpha level (type I error rate) for the study will be controlled at 0.025. 
Subjects will be stratified by number of prior therapies (1 or > 1), bulky disease status (longest 
diameter of baseline lesion < 5 cm or ≥ 5 cm) and time since last recurrence (≥ 24 months or 
< 24 months). 
9.3. 
Populations for Analyses 
The modified intent-to-treat (mITT) analysis set will include all subjects who receive at least 
1 dose of duvelisib. The mITT analysis set will serve as the primary analysis set for all endpoints 
and baseline characteristics. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to database lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints, including 
primary and secondary endpoints. 


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9.4.1. 
General Considerations 
Each treatment arm will be evaluated separately; no formal comparisons between treatment arms 
are planned. Hypothesis testing will be used for the primary efficacy endpoint of ORR for each 
treatment arm. No formal hypothesis testing will be used for any other endpoints or other study 
data, such as demographics and safety data. 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy, and 
safety parameters. For categorical variables, summary tabulations of the number and percentage 
of subjects within each category (with a category for missing data) of the parameter will be 
presented, as well as 2-sided 95% CIs, unless stated otherwise. For continuous variables, the 
number of subjects, mean, median, standard deviation, minimum, and maximum values will be 
presented. Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 
25th, 50th (median), and 75th percentiles with associated 2-sided 95% CIs, as well as number 
and percentage of censored observations. 
The Investigator’s assessments of disease response will be used as the basis for the evaluation of 
the primary and secondary efficacy endpoints. 
9.4.1.1. 
Procedures for Handling Missing, Unused, and Spurious Data 
All available efficacy and safety data will be included in data listings and tabulations. In general, 
missing data will be treated as missing and no data imputation will be applied, unless otherwise 
specified. Data that are potentially spurious or erroneous will be examined according to standard 
data management operating procedures. Details of procedures for handling missing, unused or 
spurious data can be found in the SAP. 
9.4.2. 
Primary Endpoint Efficacy Analysis 
The ORR (proportion of subjects achieving a CR or PR) will be estimated, along with the 
2-sided 95% exact CI. Responses for the primary ORR analysis will be assessed using the 2007 
revised IWG criteria (Cheson 2007). Missing data will be imputed by assuming that any subjects 
not exhibiting a response (CR or PR) are non-responders. 
9.4.3. 
Secondary Efficacy Endpoints Analyses 
• ORR according to 2014 Lugano criteria (Cheson 2014) 
Note: all additional secondary response endpoints will be assessed separately using 2007 
revised IWG criteria (Cheson 2007) and 2014 Lugano criteria (Cheson 2014) 
• ORR, at 6, 12, 18, and 24 months after first dose of study intervention, defined as the 
proportion of subjects achieving CR or PR at each of these time points. 
• PFS will be assessed using KM methods from time of first dose of study intervention 
to PD or death. 
• TTF will be calculated as the time from first dose of study intervention until 
discontinuation for any reason and will be summarized using KM methods. 
• DOR will be calculated for those subjects with a CR or PR from the time of first 
response to PD using KM methods. 


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• OS will be assessed using KM methods from time of first dose of study intervention 
to death. 
• LNRR will be calculated as the proportion of subjects achieving ≥ 50% decrease in 
the sum of the product of the diameters (SPD) of target lymph nodes. 
• TTFR will be calculated for those subjects with a CR or PR from the time of first 
dose of study intervention to time of first CR or PR. 
9.4.4. 
Secondary Safety Endpoints Analyses 
• Safety analyses will be performed on the mITT population, and safety endpoints will 
be tabulated and presented. 
• AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
for purposes of summarization. All AEs occurring during the study will be included 
in by-subject data listings and tabulated by MedDRA system organ class and 
preferred term, and in selected cases, High Level Group Term and High Level Terms. 
AEs will be summarized overall, by relationship and by severity. Events leading to 
death, SAEs, and events resulting in treatment discontinuation will be listed and, if 
warranted by the data, tabulated. 
• AEs of special interest (AESI) will be defined for analysis purposes in the SAP and 
will be summarized using the methods as described in the above bullet. 
• Exposure to duvelisib, including the proportion of expected doses received, will be 
tabulated. 
• Changes from baseline over time for vital sign measurements (including diastolic and 
systolic blood pressure) will be summarized. By-subject listings of vital sign 
measurements will be prepared. 
• Individual subject laboratory parameter values and summary statistics over time will 
be prepared using descriptive statistics. Severity of select clinical laboratory measures 
will be determined using NCI CTCAE criteria and Grade 3 or 4 laboratory values will 
be presented in a separate table and listing. 
• The use of concomitant medications, coded using World Health Organization Drug 
Dictionary, will be tabulated and included in a by-subject listing. 
• Additional safety analyses may be performed to more clearly enumerate rates of 
toxicities and to further define the safety profile of duvelisib. 
9.4.5. 
Secondary PK Endpoints Analyses 
• PK analyses will be conducted on the mITT population. 
• Blood samples will be taken for the analyses of duvelisib and metabolite IPI-656 in 
plasma at the time points defined in the SoA (Table 2). The relevant PK parameters 
will be determined using bioanalytical data. The PK data will be summarized using 
descriptive statistics and will be listed and summarized in tabular and/or graphical 
form. 


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• A separate PK analysis plan may be developed. 
9.4.6. 
Exploratory QoL Endpoints Analyses 
• Changes from baseline over time for ECOG performance status will be summarized. 
A by-subject listing of ECOG performance status data will be prepared. 
• Changes from baseline over time for EQ-5D-3L scores will be summarized. 
By-subject listings of EQ-5D-3L will be prepared. 
9.4.7. 
Exploratory Pharmacodynamic and Biomarker Endpoints Analyses 
• Pharmacodynamic analyses will be conducted on the mITT population. 
• Prognostic markers such as genetic variation, ctDNA, immunophenotype, functional 
immune assays, gene expression, and circulating protein, will be evaluated relative to 
baseline levels and change to baseline levels. 
• Additional exploratory analyses identified by the Sponsor also may be performed. 
• Listing of individual subject and summary statistics for duvelisib effects on 
biomarkers and graphs of changes versus time will be prepared. 
• Biomarker effects will be summarized using descriptive statistics and associations 
with clinical efficacy and/or safety outcomes may be explored. 
9.5. 
Interim Analyses 
There is no formal interim analysis. Study data for each arm will be evaluated at the end of 
Stage 1 to determine whether a study arm should be terminated or continued to Stage 2. Please 
see additional details of the 2-stage design in Section 9.2. 
9.6. 
Data Monitoring Committee (DMC) 
This study will not use a DMC. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS: APPENDICES 
 
Table 11: 
Appendices 
 
Appendix 
Title 
Section 
1 
Overview of Disease Response Criteria 
10.1 
2 
CYP3A Inhibitors, Inducers, and Substrates 
10.2 
3 
Clinical Laboratory Tests 
10.3 
4 
Contraceptive Guidance 
10.4 
5 
ECOG Performance Status 
10.5 
6 
Regulatory, Ethical, and Study Oversight Considerations 
10.6 
7 
Abbreviations 
10.7 
8 
Protocol Summary of Changes and Version History 
10.8 


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10.1. 
Appendix 1: Overview of Disease Response Criteria 
10.1.1. 
2007 Revised IWG Criteria 
Table 12: 
Revised Response Criteria for Malignant Lymphoma (Cheson 2007) 
 
Response Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disea se 
(a) FDG-avid or PET positive 
prior to therapy; mass of any 
size permitted if PET negative 
(b) Va ria bly FDG-avid or PET 
negative; regression to normal 
size on CT 
Not palpable, 
nodules disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up 
to 6 largest dominant masses; 
no increase in size of other 
nodes 
(a) FDG-avid or PET positive 
prior to therapy; 1 or more 
PET positive at previously 
involved site 
(b) Va ria bly FDG-avid or PET 
negative; regression on CT 
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
dia meter); no 
increase in size of 
liver or spleen 
Irreleva nt if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Fa ilure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET positive 
at prior sites of disease and no 
new sites on CT or PET 
(b) Va ria bly FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
Relapsed 
disease or 
PD 
Any new lesion 
or increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appea rance of a new lesion(s) 
> 1.5 cm in any axis, ≥ 50% 
increase in SPD of more than 
1 node, or ≥ 50% increase in 
longest diameter of a 
previously identified node 
> 1 cm in short axis 
Lesions PET positive if FDG- 
avid lymphoma or PET 
positive prior to therapy 
> 50% increase 
from nadir in the 
SPD of any previous 
lesions 
New or recurrent 
involvement 
Abbrevia tions: CR: complete remission; CT: computed tomography; FDG: [18F] fluorodeoxyglucose; PD: 
progressive disease; PET: positron emission tomography; PR: partial remission; SD: stable disease; SPD: sum of the 
product of the diameters. 
10.1.2. 
2014 Lugano Response Criteria 
PET-CT images will be assessed using the 5-point scale (5PS) (Table 13), a semi-quantitative 
analysis that is a pragmatic yet robust predictor of subject outcome, then disease response will be 
assessed using the Lugano response criteria (Table 14). 


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Table 13: 
5-Point Scale for Positron Emission Tomography Assessment (Barrington 
2014) 
 
Score 
Criterion 
1 
No uptake above background 
2 
Uptake ≤ mediastinum 
3 
Uptake > mediastinum, but ≤ liver 
4 
Uptake moderately > liver* 
5 
Uptake markedly higher than liver and/or new lesions* 
X 
(New) areas of uptake unlikely to be related to lymphoma 
*It is suggested according to published data that score 4 be applied to uptake greater than the maximum standardized 
uptake value (SUV) in a large region of normal liver and score 5 to uptake 2× to 3× greater than the maximum SUV 
in the liver. 
Table 14:   Lugano Response Criteria for Malignant Lymphoma (Cheson 2014) 
 
Response and Site 
PET-CT-based Response 
CT-based Response 
Complete Response 
Complete metabolic response 
Complete radiologic response 
(requires all of the following) 
Lymph nodes and extralymphatic 
sites 
Score of 1, 2, or 3* with or without 
a residual masson 5PS (Table 13) 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic 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, complete 
metabolic response may be inferred 
if uptake at sites of initia l 
involvement is no greater than 
surrounding normal tissue even if 
the tissue has high physiologic 
uptake 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
No extralymphatic sites of disease 
Non-measured lesions 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease 
in bone marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial Response 
Partial metabolic response 
Partial remission 
(all of the following) 
Lymph nodes and extralymphatic 
sites 
5PS score 4 or 5 with reduced 
uptake compared with baseline and 
residua l mass(es) of any size 
During treatment, these findings 
suggest responding disease 
At EoT, these findings indicate 
residua l disease 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extra nodal sites 
When a lesion is too small to 
measure on CT, assign 5 mm × 
5 mm as the default value 
When no longer visible, 0 × 0 mm 


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Response and Site 
PET-CT-based Response 
CT-based Response 
For a node × 5 mm × 5 mm, but 
sma ller than normal, use actual 
measurement for calculation 
Non-measured lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by 
≥ 50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changesin 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 
Stable disease (no response) 
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
5PS 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 a nd extranodal 
sites; no criteria for 
progressive disease 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 Disease 
Progressive metabolic disease 
Progressive disease requires at 
least 1 of the following: 
Individual target nodes/nodal 
ma sses 
5PS score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
PPD progression 
Extranodal lesions 
New FDG-a vid foci consistent with 
lymphoma at interim or EoT 
a ssessment 
An individual node/lesion 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 
ba seline 
New or recurrent splenomegaly 


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Response and Site 
PET-CT-based Response 
CT-based Response 
Non-measured lesions 
None 
New or clear progression of 
pre-existing non-measured lesions 
New lesions 
New FDG-a vid foci consistent with 
lymphoma rather than another 
etiology (e.g., infection, 
infla mmation). If uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be a ttributable to lymphoma 
Assessa ble disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS: 5-point scale; CT: computed tomography; EoT: endof treatment; FDG: fluorodeoxyglucose; 
IHC: immunohistochemistry; LDi: longest transverse diameter of a lesion; MRI: magnetic resonance imaging; PET: 
positron emission tomography; PPD: cross product of the LDi and perpendicular diameter; SDi: shortest axis 
perpendicular to the LDi; SPD: sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in studies involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to 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), 
gastrointestinal (GI) involvement, cutaneous lesions, or 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 or measurable or that do 
not meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer’s ring or in extra nodal sites (e.g., GI tra ct, liver, bone marrow), 
FDG uptake may be greater than in the mediastinum with complete metabolic response but should be no higher than 
surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth 
factors). 


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10.2. 
Appendix 2: CYP3A Inhibitors, Inducers, and Substrates 
10.2.1. 
Medications or Foods Known to Inhibit CYP3A 
The following list provides medications or foods known to induce or inhibit CYP3A activity. 
Note that this is not a comprehensive list of all medications or foods which may modulate 
CYP3A activity. Additional information can be found at: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl 
abeling/ucm093664.htm 
Note: Subjects receiving duvelisib are prohibited from concomitant use of medications or 
foods that are known to be strong inhibitors or inducers of CYP3A. 
 
Table 15: 
Classification of In Vivo Inhibitors of CYP3A 
 
Strong Inhibitors1 
Moderate inhibitors2 
Weak inhibitors3 
Boceprevir, 
cla rithromycin, conivaptan, 
grapefruit juice4, indinavir, 
itraconazole, ketoconazole, 
lopina vir/ritonavir, 
mibefradil5 
nefazodone, nelfinavir, 
posaconazole, ritonavir, 
saquinavir, 
tela previr, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltia zem, 
erythromycin, fluconazole, 
fosamprenavir, gra pefruit juice4, 
ima tinib, verapamil 
Alpra zolam, amiodarone, 
amlodipine, atorvastatin, 
bica lutamide, cilostazol, cimetidine, 
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo6, goldenseal6, 
isonia zid, nilotinib, 
oral contraceptives, ranitidine, 
ranolazine, 
tipra navir/ritonavir, zileuton 
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that 
CYP by ≥ 5-fold, or results in a > 80% decrease in CL. 
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by < 5-fold but ≥2-fold or results in a 50-80% decrease in CL. 
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by < 2-fold but ≥1.25-fold or results in a 20-50% decrease in CL. 
4. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation- 
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
prepa ration was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
prepa ration was used (e.g., low dose, single strength). 
5. Withdrawn from the United States market because of safety reasons. 
6. Herbal product. 


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10.2.2. 
Medications Known to Induce CYP3A 
Table 16: 
Classification of In Vivo Inducers of CYP3A 
 
Strong Inducers ≥ 80% decrease 
in AUC 
Moderate Inducers 
50-80% decrease in AUC 
Weak Inducers 
20-50% decrease in AUC 
Avasimibe1, carbamazepine, 
phenytoin, rifampin, St. John’s 
Wort2,3 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
Amprenavir, aprepitant, 
armodafinil, Echinacea3 
pioglitazone, prednisone, 
rufina mide 
Abbrevia tions: AUC: area under the curve; CYP3A: cytochrome P450 3A. 
1. Not a marketed drug. 
2. The effect of St. John’s Wort varies widely and is preparation-dependent. 
3. Herbal product. 
10.2.3. 
Medications Known to Be CYP3A Substrates 
Known sensitive CYP3A substrates and CYP3A substrates with a narrow therapeutic range are 
listed in Table 17. Drugs or foods that are substrates of CYP3A should only be used if medically 
necessary and therapeutic alternatives do not exist. 
Additional information can be found at: 
• https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/drugi 
nteractionslabeling/ucm093664.htm 
Table 17: 
Cytochrome P450 3A (CYP3A) Substrates 
 
Sensitive CYP3A Substrates 
budesonide 
mida zolam 
buspirone 
saquinavir 
eplerenone 
sildena fil 
eletripta n 
simva statin 
felodipine 
tria zolam 
flutica sone 
va rdenafil 
lova statin 
CYP3A Substrates with a Narrow Therapeutic Range 
a lfentanil 
fentanyl 
astemizole 
pimozide 
cisa pride 
quinidine 
cyclosporine 
sirolimus 
diergota mine 
tacrolimus 
ergotamine 
terfenadine 


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10.3. 
Appendix 3: Clinical Laboratory Tests 
• The tests detailed in Table 18 will be performed by the local laboratory. The timing 
and frequency are detailed in SoA Table 1. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
• The results of each test must be entered in the CRF. 
Table 18: 
Protocol-required Safety Laboratory Assessments 
 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Indices: 
Mean corpuscular 
volume (MCV) 
White blood cell 
(WBC) count with 
Differential: 
Red blood cell (RBC) Count 
Hemoglobin 
Mean corpuscular 
hemoglobin (MCH) 
Neutrophils 
Lymphocytes 
Hematocrit 
% Reticulocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry1 
Blood urea 
nitrogen 
(BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
Total Protein 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Glucose (non- 
fasting) 
Calcium 
Alkaline phosphatase 
(ALP) 
Lactate 
dehydrogenase 
(LDH) 
Quantitative 
serum 
immunoglobulins 
(Ig) 
IgA, IgG, IgM 


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Laboratory 
Assessments 
Parameters 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• 
Microscopic examination (if dipstick is abnormal) 
Pregnancy 
• 
Highly sensitive serum human chorionic gonadotropin (hCG) pregnancy test 
(as needed for women of childbearing potential)2 
Other Screening 
Tests 
• 
Viral screening: serology (hepatitis B surface antigen [HBsAg], hepatitis B 
core antibody [HBcAb], hepatitis C virus antibody [HVC Ab], Epstein-Barr 
virus [EBV] antibody, human immunodeficiency virus [HIV] antibody); 
cytomegalovirus (CMV) via serology or viral load detection via polymerase 
chain reaction (PCR). Subjects with a negative HBsAg and positive HBcAb 
require an undetectable/negative hepatitis B DNA test (e.g., PCR test) to be 
enrolled. 
o HIV testing is required for subjects without documentation of a prior 
negative test result from within the last 9 months. Results will be 
analyzed locally and will not be captured in the study database. Only 
subjects with negative results will be eligible to enroll. 
• 
Coagulation tests: prothrombin time (PT), partial thromboplastin time (PTT) 
and international normalized ratio (INR) 
• 
C-reactive protein 
• 
Endocrine function tests: Free thyroxine (T4) and thyroid-stimulating 
hormone (TSH) 
• 
Human leukocyte antigen (HLA) typing: types A, B, C, DRB1, and DQB1 
NOTES: 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments 
after liver stopping or monitoring event are provided in Table 5. All liver-related SAEs must be 
reported as described in Section 8.3.3. 
2. A serum pregnancy test must be performed within 7 days of C1D1. At subsequent time points, 
serum testing is preferred but urine testing is allowed if a blood draw for other assessments is 
not performed. A positive urine test must be confirmed by a serum test. 


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10.4. 
Appendix 4: Contraception Guidance 
The effects of duvelisib on conception, pregnancy, and lactation are unknown. Every woman of 
childbearing potential (WCBP) and male subjects with a partner who is a WCBP must use highly 
effective methods of contraception as described below in Section 10.4.1. A woman is considered 
to be a WCBP following menarche and until becoming postmenopausal (i.e., > 55 years and 
postmenopausal for at least 1 year), unless permanently sterile. 
At Screening, all male and female subjects of reproductive potential (i.e., not surgically sterile or 
female subjects who are not postmenopausal) must agree to use highly effective methods of 
contraception for the duration of the study intervention, and for at least 3 months after the last 
dose of duvelisib. Male subjects must also refrain from donating sperm during their participation 
in the study and for at least 3 months after the last dose of duvelisib. 
The use of contraceptive methods is not required if the male subject or the male partner (of the 
female subject) has a documented history of a vasectomy or if the female subject or the female 
partner (of the male subject) has a documented history of bilateral oophorectomy, hysterectomy, 
or tubal ligation, or if she is > 55 years of age and postmenopausal for at least 1 year. 
Section 8.3.9 for requirements for pregnancy reporting. 
10.4.1. 
Highly Effective Methods of Contraception 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation1: 
o oral 
o injectable 
o implantable2 
• intrauterine device (IUD)2 
• intrauterine hormone-releasing system (IUS)2 
• bilateral tubal occlusion2 
• vasectomized partner2,3 
• sexual abstinence4 
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method. 
2Contraception methods that are considered to have low user dependency 


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3Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WCBP study participant and that the vasectomized partner has received medical assessment 
of the surgica l success. 
4Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient. 


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10.5. 
Appendix 5: Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on a ny self-care. Totally confined to bed or chair 
5 
Dea d 
Source: (Oken 1982). 


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10.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight 
Considerations 
10.6.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.6.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.6.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject and answer all questions regarding the study. 
• Subjects must be informed that their participation is voluntary. Subjects will be 
required to sign a statement of informed consent that meets the requirements of 21 


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CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements (where applicable), and the IRB/IEC or 
study site. 
• Subjects who are detained by administrative or judicial order will be excluded from 
participating in the study. 
• The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the subject. 
• A subject who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date. 
10.6.4. 
Subject Data Protection 
• Subjects will be assigned a unique identifier during screening. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information that would make the subject identifiable will not be 
transferred. 
• The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject who will be required to give consent for their data to 
be used as described in the informed consent. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.6.5. 
Dissemination of Clinical Study Data 
The Sponsor will comply with current regulatory requirements for disclosure and submission of 
study results. The Sponsor’s policy on publication of study results is described in Section 10.6.9. 
10.6.6. 
Data Quality Assurance 
• All subject data relating to the study will be recorded in the electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 


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• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk- 
Based Monitoring), methods, responsibilities, and requirements (including handling 
of noncompliance issues and monitoring techniques [central, remote, or on-site 
monitoring]) are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
CROs). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 2 years after study completion, for a 
period of 2 years after a marketing application is approved for duvelisib in the study 
population, until 2 years after shipment and delivery of the drug for investigational 
use is discontinued, or as long as required by local regulations, whichever is longer. 
No records may be destroyed during the retention period without the written approval 
of the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor. 
10.6.7. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
site. 
• Data reported on the CRF or entered in the CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in ICH guidance for industry 
E6 GCP: Consolidated Guidance. 
10.6.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
The first act of recruitment is the first site open and will be the study start date. 


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The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason (e.g., as necessary for patient safety) at the sole discretion of the Sponsor. 
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
Circumstances that may warrant premature termination of the entire study by the Sponsor 
include but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects, including: 
− the occurrence of AEs with character, severity, or frequency that are new in 
comparison to the existing risk profile 
− data derived from other clinical studies or toxicological studies that negatively 
influence the risk/benefit assessment 
• Failure to enter subjects at an acceptable rate 
• Plans to modify, suspend, or discontinue the development of the study intervention 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the subject and should assure appropriate subject therapy 
and/or follow-up. 
10.6.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings with 
prior approval of the Sponsor. The Investigator agrees to submit all manuscripts or 
abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multi-site studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement between the Sponsor and the Investigators. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.7. 
Appendix 7: Abbreviations 
Table 19: 
List of Abbreviations and Definitions 
 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
CEC 
Central Ethics Committee 
CI 
Confidence interval 
CxDx 
Cycle x Day x 
CLL 
Chronic lymphocytic leukemia 
CMV 
Cytomegalovirus 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organization 
CTCL 
Cutaneous T-cell lymphoma 
CYP3A 
Cytochrome P450 3A 
DI 
Dose interruption 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
EBV 
Epstein-Barr virus 
eCCr 
Estimated creatinine clearance 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ESMO 
European Society for Medical Oncology 
FDA 
Food and Drug Administration 
FDG 
18fluoro-2-deoxy-d-glucose 
FFPE 
Formalin-fixed paraffin-embedded 


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Abbreviation 
Definition 
FL 
Follicular lymphoma 
GCP 
Good Clinical Practice 
Gi 
Giga (1 x 109) or 1 billion 
HBcAb 
Hepatitis B core antibody 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus; 
HLA 
Human leukocyte antigen 
HSV 
Herpes simplex virus 
IHC 
Immunohistochemistry 
iNHL 
indolent non-Hodgkin lymphoma 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IWG 
International Working Group 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
L 
Liter 
LDH 
Lactate dehydrogenase 
LNRR 
Lymph node response rate 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
Modified intent-to-treat 
MUGA 
Multi-gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPP 
Named Patient Program 
ORR 
Overall response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 


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Abbreviation 
Definition 
PD 
Progressive disease 
PE 
Physical examination 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI3K 
Phosphoinositide 3-kinase 
PJP 
Pneumocystis jiroveci pneumonia 
PK 
Pharmacokinetics 
PR 
Partial response 
PTCL 
Peripheral T-cell lymphoma 
PTEN: 
Phosphatase and tensin homolog 
QD 
Once daily 
QTcF 
QT interval corrected with Fridericia’s method 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
R/R 
Relapsed or refractory 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum pyruvic transaminase 
SJS 
Stevens Johnson syndrome; 
SLL 
Small lymphocytic lymphoma 
SoA 
Schedule of Activities 
SPD 
Sum of the product of the diameters 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic epidermal necrolysis 
TTF 
Time to treatment failure 
TTFR 
Time to the first response 
ULN 
Upper limit of normal 
VZV 
Herpes zoster 
WBC 
White blood cell 
WCBP 
Woman of childbearing potential 


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10.8. 
Appendix 8: Protocol Summary of Changes and Version History 
10.8.1. 
Protocol Version 4.0 (Amendment 5), 18 May 2021 
10.8.1.1. 
Amendment Rationale and Summary of Changes 
The primary purpose for this amendment was to remove the Long-Term and Survival F/U visits, 
while continuing to provide the opportunity for patients experiencing long term benefit to receive 
study drug. Changes were made in the Schedule of Assessments and in the body text. 
Additionally, the study duration was modified to end 2 years after the last subject is randomized. 
COVID-19 vaccine information was also added. 
Minor language and format corrections were also done throughout the document. 
The revised protocol, Version 4.0, dated 18 May 2021 will be submitted by the Investigator(s) to 
all applicable IRBs, IECs, or CECs, and by Secura Bio, Inc. (or designee) to all applicable 
Regulatory Authorities. 
Table 20: 
Summary of Changes for Version 4.0 
 
Section(s) 
Description of Change 
Rationale for the Change 
Global 
Updated the version number and date of 
protocol from Version 3.2 dated 08 
December 2020 to Version 4.0 dated 18 May 
2021 
Administrative change 
Global 
Minor corrections to grammar/spelling 
Administrative changes 
Synopsis 
Section 1.3 
Section 4.1 
Section 4.4 
Section 6.8 
Section 7.1 
Removed Long-Term and Survival F/U 
visits, and revised study end date to be 2 
years after last subject randomized 
Removed the Long-Term and 
Survival F/U visits, which 
required a revision to the study 
end date 
Table 2 
Removed all PD/Biomarker sampling after 
Cycle 2 
Re-evaluated need for additional 
sample collection after Cycle 2 
Section 6.6.5 
Added COVID-19 vaccines as allowed 
Concomitant Medications 
Global rollout of COVID-19 
vaccines addressed with this 
addition 
Section 8.4 
Section removed as part of Long-Term and 
Survival F/U removal 
Harmonizing protocol with prior 
removal of the Long-Term and 
Survival F/U visits 


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10.8.2. 
Protocol Version 3.2 (Amendment 4), 08 December 2020 
10.8.2.1. 
Amendment Rationale and Summary of Changes 
Secura Bio, Inc. acquired the global rights in Oncology for the Investigational Medicinal Product 
(IMP), duvelisib (also referred to as Copiktra®) from Verastem. Updates were made in this 
document in all sections, as applicable, to reflect that Secura Bio is now the Sponsor for this 
study. This is an administrative change that does not affect the planned study. 
In addition, minor language and format corrections were also done throughout the document. 
The revised protocol, Version 3.2, dated 08 December 2020 will be submitted by the 
Investigator(s) to all applicable IRBs, IECs, or CECs, and by Secura Bio, Inc. to all applicable 
Regulatory Authorities. 
10.8.3. 
Protocol Version 3.1 (Amendment 3), 25 February 2020 
10.8.3.1. 
Amendment Rationale and Summary of Changes 
The primary purpose for this amendment was to make minor administrative changes to the 
protocol. Specifically, to provide a consistent and correct date of the amendment throughout the 
document. In Version 3.0, the date of the amendment was not correct in some footers and text 
(28 January 2019 instead of 28 January 2020). In addition, a minor change to the ECG note in 
the Schedule of Assessments and Section 8.2.2 was made to indicate that “QTc measurements 
will be as measured by triplicate readings” for consistency with the text of Exclusion Criterion 
#18. 
10.8.4. 
Protocol Version 3.0 (Amendment 2), 28 January 2020 
10.8.4.1. 
Amendment Rationale 
The primary purpose for this amendment was to incorporate changes made in 3 country-specific 
amendments to address requests from Regulatory Authorities after their review of Version 1.0. 
The revised protocol, Version 3.0, dated 28 January 2020 will be submitted by the Investigator(s) 
to all applicable IRBs, IECs, or CECs, and by Secura Bio, Inc. to all applicable Regulatory 
Authorities. 
A summary of key changes that were made to protocol Version 1.0, including the rationales for 
these changes, is provided in Table 20. 
Table 21: 
Summary of Changes for Version 3.0 
 
Section(s) 
Description of Change 
Rationale for the Change 
Global 
Updated the version number and date of 
protocol from Version 1.0 dated 04 April 
2019 to Version 3.0 dated 28 January 2020 
Administrative change 
Global 
Minor corrections to grammar/spelling 
Administrative changes 
Synopsis 
Section 3 
Specified the metabolite of duvelisib as 
IPI-656 
To clarify that the only metabolite 
analyzed in PK data analysis is PI- 
656 


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Section(s) 
Description of Change 
Rationale for the Change 
Section 8.5 
Section 9.4.5 
Section 1.2 
Legend for Figure #1 revised to provide 
correct disease response frequency to be 
consistent with Table 1 (Schedule of 
Assessments) 
Correction of error 
Section 1.3 
Minor corrections/clarifications and 
reorganizations to Table 1 (Schedule of 
Assessments) 
Correction of errors (incorrect or 
missing information), addition of 
clarifications, and elimination of 
sub-header rows 
Section 1.3 
Added an optional tumor biopsy at Screening 
To allow the Investigator, at their 
discretion, to perform a tumor 
biopsy during Screening to 
confirm diagnosis if they suspect 
transformation to a more 
aggressive lymphoma. 
Section 1.3 
Added details (e.g., “Day 1” and “Window” 
to describe timing of CT assessment 
Clarification 
Section 1.3 
Merge cells for Bone Marrow Biopsy and/or 
Aspirate 
To correct omission, as biopsy 
may be required at any visit during 
the course of the study, including 
LTFU, to confirm CR 
Section 1.3 
Added guidance text to indicate that 
additional ECGs and echocardiograms may 
be conducted at the Investigator’s discretion 
as clinically indicated 
For consistency with body of the 
protocol (existing guidance text in 
Section 8.2.4) 
Section 1.3 
Add C1D43 visit, with Hematology, 
Conmeds, focused PE, vitals, AEs, drug 
diary, and self-admin of drug 
To provide for additional 
neutrophil count monitoring 
consistent with US Prescribing 
Information and ensure safety 
monitoring at this visit 
Section 1.3 
Added note to Clinical Chemistry, 
Hematology, and Urinalysis assessments that 
tests must be conducted, and results 
available, within 7 days prior to the first dose 
of duvelisib 
To ensure that key laboratory 
parameters are assessed within a 
short time frame before first dose 
of study drug 
Section 1.3 
Section 5.2 
Section 10.3 
Removal of human T-lymphotrophic virus 
type 1 (HTLV-1) testing at Screening and 
from exclusion criterion #14 
This testing is not relevant for this 
clinical study 
Section 1.3 
Section 8.1.1 
Modified text describing requirements for 
imaging scans 
To clarify that CT or PET-CT is 
required but MRI may be used 
instead of CT if CT cannot be 
done 


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Section(s) 
Description of Change 
Rationale for the Change 
Section 1.3 
Section 8.1.2 
(Section 8.1.3 in 
prior version) 
Changed bone marrow biopsy guidance for 
submission of available pathology reports 
from “most recent” to “within 60 days before 
C1D1” 
If a patient had bone marrow 
biopsy/aspirate prior to the first 
dose of the study drug as a part of 
standard of care; the pathology 
report data within 60 days of 
C1D1 are more medically relevant 
than results from an earlier time 
point 
Section 1.3 
Section 8.2.1 
Modified schedule of assessments to include 
Full Physical Examination (PE) at C1D1, 
and Focused PE and Vital Signs at every 
visit. Re-ordered SoA rows and text sections 
to present full PE, focused PE, and Vital 
Sign assessments sequentially. Align SoA 
notes and text descriptions. 
To increase frequency of vital 
signs measurements and provide 
additional safety monitoring. Re- 
ordering and text alignment was 
done for clarity 
Section 1.3 
Section 10.3 
Removed cortisol testing at Screening 
Not needed for this clinical study 
Section 1.3 
Section 10.3 
Added description of HLA types included in 
the HLA assessment at Screening 
To provide additional assessment 
details for clarity 
Section 2.1 
Section 2.2 
Section 4.2 
Section 11 
Added information to Rationale, 
Background, and Scientific Rationale 
sections, with supporting references 
To provide justification for study 
design and population, as well as 
additional information on 
indication and available therapies 
Section 5.1 
Modified inclusion criterion #4 to indicate 
that subjects are required to be candidates for 
a subsequent line of therapy 
To clarify eligibility requirements 
Section 5.1 
Modified inclusion criterion #5 to indicate 
that subjects must have hemoglobin level 
≥ 8 g/dL 
To clarify the eligibility based on 
hemoglobin levels 
Section 5.1 
Section 11 
Modified inclusion criterion #5 to indicate 
that renal function will be measured by 
estimated creatinine clearance rather than 
serum creatinine level 
To more accurately assess 
eligibility based on renal function 
Section 5.1 
Section 5.3 
Section 6.6.4 
Section 8.3.9 
Section 10.4 
Modified inclusion criterion #7 and 
contraception guidance to indicate that 
highly effective methods of contraception 
must be used 
To align contraception guidance 
with the Clinical Trials Facilitation 
Group (CFTG) guidance 
Section 5.2 
Modified exclusion criterion #14 to remove 
requirement for HBV viral prophylaxis with 
entecavir (or equivalent) concomitant with 
Monitoring for reactivation of 
HBV is a sufficient precaution 
against active HBV infection for 


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Section(s) 
Description of Change 
Rationale for the Change 
duvelisib treatment for subjects who have 
positive HBcAB and negative DNA 
subjects who have positive 
HBcAB and negative DNA 
Section 5.4 (new) 
Moved definition of enrolled from the 
Sample Size Determination section 
(Section 9.2) to a new section (Definition of 
Enrolled) 
To improve clarity 
Section 5.5 
Deleted text stating that rescreened subjects 
should be assigned the same subject number 
as for the initial screening 
To align with current practice 
Section 6.6.2 
Section 10.7 
Added definition for the term “Gi” as 1 X 
109 (1 billion cells or giga) 
To clearly distinguish the “Gi” 
abbreviation from the “GI” 
abbreviation 
Section 6.6.3 
Modified text to indicate that, in addition to 
during treatment, live vaccines are prohibited 
within 6 weeks of C1D1 and for 3 months 
after last dose of study drug 
To provide additional safety 
protection for study subjects after 
treatment discontinuation 
Section 6.8 
Added the following statement: “Long-term 
continued treatment will be provided either 
in a separate clinical study or expanded 
access program consistent with local 
regulations” 
To clarify how subjects who are 
still receiving treatment at the end 
of the study will access duvelisib 
after the end of the study 
Section 8 
Section 8.2.1 
Deleted text describing timing of Screening 
activities, including the following statement: 
“A full PE will be conducted at Screening.” 
To align with the protocol 
template by limiting descriptions 
for the timing of assessments to 
the SoA 
Section 8.1.1 
(Section 8.1.2 in 
prior version) 
Modified text describing PET-CT 
To align with SoA 
Section 8.3.6 
Modified Clinical Laboratory Adverse Event 
section to remove language that restricts the 
constitution of abnormal laboratory values as 
AEs 
To align with ICH Guideline 
E.2.A 
Section 8.3.8 
Clarified that only cases of overdose that 
cause an SAE are required to be reported 
within 24 hours, and that Investigator will 
determine if and when dosing should resume 
To clarify and expand overdose 
guidance 
Section 5.4 (new, 
statement was 
moved from 
Section 9.2 in 
prior version) 
Section 10.6.3 
Deleted references to subject’s legal 
representative 
To address request by regulatory 
authorities to limit participation to 
subjects who are capable of 
providing informed consent 


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Section(s) 
Description of Change 
Rationale for the Change 
Section 9.2 
Reworded the power statement in terms of 
significance level alpha 
To clarify the significance level 
Section 10.1.2 
Corrected PET to PET-CT and deleted 
“(PET)” from title of Table 13 
To align with nomenclature in 
published response criteria 
Section 10.2.1 
Footnote 3: corrected the definition of a 
weak CYP inhibitor based on FDA definition 
To correct a textual error 
Section 10.6.3 
Clarified that patients who are detained by 
administrative or judicial order will be 
excluded from participating in the study 
To provide information regarding 
the eligibility of patients who are 
detained by administrative or 
judicial order 
Section 10.6.8 
Provided additional details regarding study 
termination criteria, particularly termination 
due to safety concerns 
To clarify criteria for premature 
termination of the study 
Section 10.7 
Updated Abbreviations list 
To reflect updated protocol 
Section 10.8.1 
Added Summary of Changes made in 
Version 3.0 
Administrative change 
Section 10.8.2 
Updated version history 
Administrative change 
10.8.5. 
Version History 
Table 22: 
Primary Reason for Each Version 
 
Version 
Primary Reason for Version 
4.0 
To revise study assessments/sample collection and incorporate COVID-19 
vaccine approvals 
3.2 
Administrative amendment to update the Sponsor contact information and to 
correct minor errors in Version 3.1 
3.1 
Administrative amendment to correct minor errors in Version 3.0 
3.0 
To incorporate Version 2.0 country-specific changes into a global amendment 
2.0 (3 country-specific 
amendments) 
To address country-specific requests from Czech Republic/Italian, German, and 
United Kingdom regula tory authorities after their review of global Version 1.0. 
There was no global Version 2.0. 
1.0 
Origina l version 


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SAP_001.pdf: 
P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1  of  3 5  
P are xel  I nter n ati o n al 
Sec ura  Bi o,  I nc. 
V S -0 1 4 5 -2 2 9  
A  P h ase  2,  R a n d o mize d,  O pe n -l a bel, 2 -Ar m  St u d y  C o m p ari n g  2  I nter mitte nt D osi n g 
Sc he d ules of D u velisi b i n S u bjects wit h I n d ole nt N o n -H o d g ki n L y m p h o m a (i N H L)  
St atistic al  A n al ysis  Pl a n  
Versi o n:  3. 0  
P are xel  P r oject  N u m ber:  2 4 3 6 6 1  
N C T # : N C T 0 4 0 3 8 3 5 9


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2  of  3 5  
 
 
 
S P O N S O R  SI G N A T U R E  P A G E  
 
 
 
A p pr o ve d b y:  
 
 
Date  
 (I nteri m) 
Sec ura Bi o, I nc.  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3  of  3 5  
 
 
 
P A R E X E L  SI G N A T U R E  P A G E  
 
Si g nat ure(s)  bel o w  c o nfir m  t hat t he Statistical  A nal ysis  Pla n  was  de vel o p e d  i n ac c or da nce  wit h 
S O P -G D O -W W -0 1 9 a n d t hat it is a p pr o ve d f or release.  
T his  d oc u me nt  h as  bee n  a p pr o ve d  a n d  si g ne d electr o nic all y  o n  t he fi n al p a ge  b y  t he 
f oll o wi n g: 
 
 
 
Si g n at or y  
A ut h or  
 
 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  4  of  3 5  
 
 
T A B L E  O F  C O N T E N T S  
1  
I N T R O D U C TI O N ......................................................................................................1 0  
2  
S T U D Y  O BJ E C TI V E S ...............................................................................................1 1  
2. 1  
Pri mar y  O bjecti ve(s)  ...............................................................................................1 1  
2. 2  
Sec o n dar y  O bjecti ve(s)  ...........................................................................................1 1  
2. 3  
E x pl orat or y  O bjecti ve(s)  ........................................................................................1 1  
3  
I N V E S TI G A TI O N A L P L A N  .....................................................................................1 1  
3. 1  
O verall  St u d y  Desi g n  a n d Pla n  ...............................................................................1 1  
3. 2  
E n d p oi nts  ................................................................................................................1 3  
3. 2. 1  
Effica c y  Varia bles  ................................................................................................1 3  
3. 2. 2  
Safet y  Varia bles  ................................................................................................... 1 4  
3. 3  
E x pl orat or y  Varia bles  .............................................................................................1 4  
4  
S T A TI S TI C A L  M E T H O D S  .......................................................................................1 5  
4. 1  
Data  Q ualit y  Ass ura nce  ..........................................................................................1 5  
4. 2  
Ge ner al  Prese nt ati o n  C o nsi derati o ns  ...................................................................... 1 5  
4. 3  
Ge ner al  C o nsi derati o ns  ...........................................................................................1 6  
4. 3. 1  
Missi n g Data  ........................................................................................................ 1 6  
4. 3. 1. 1  
I m p utati o n of  Partial  Dates.  ............................................................................... 1 6  
4. 3. 1. 2  
Ha n dli n g  Missi n g  Dates/ M o nt hs/ Years  f or Deter mi n ati o n  of  T E A Es  .............. 1 7  
4. 3. 1. 3  
Ha n dli n g  Missi n g  Dates/ M o nt hs/ Years  f or C o nc o mit a nt  Me dicati o ns  ............. 1 7  
4. 3. 1. 4  
Ha n dli n g  Missi n g  Dates/ M o nt hs/ Years  f or Disease  Hist or y  ............................. 1 7  
4. 3. 2  
Sta n dar d  Dicti o nari es  f or C o di n g  ........................................................................1 7  
4. 4  
S oft ware  ..................................................................................................................1 8  
4. 5  
A nal ysis  Sets  .......................................................................................................... 1 8  
4. 6  
St u d y  S u bjects  ........................................................................................................1 9  
4. 6. 1  
Dis p ositi o n  of  S u bjects  ........................................................................................ 1 9  
4. 6. 2  
Pr ot oc ol  De viati o ns  ..............................................................................................2 0  
4. 7  
De m o gra p hic  a n d  Ot her  Baseli ne  C haracteristics  .................................................. 2 0  
4. 8  
Pri or  a n d C o nc o mita nt  Me dicati o n .........................................................................2 1  
4. 9  
Me dical  Hist or y  ...................................................................................................... 2 2  
4. 1 0  
Effica c y  E val uati o n  ................................................................................................2 2  
4. 1 0. 1  A nal ysis  a n d Data  C o n ve nti o ns  ........................................................................... 2 2  
4. 1 0. 1. 1  M ulti -ce nter  St u dies ........................................................................................... 2 2  
4. 1 0. 1. 2  A dj ust me nts  f or C o variates  ............................................................................... 2 2  
4. 1 0. 1. 3  Ha n dli n g  of  Dr o p o uts  or Missi n g Data  .............................................................2 2  
4. 1 0. 1. 4  M ulti ple  C o m paris o ns/ M ulti plicit y  ....................................................................2 2  
4. 1 0. 1. 5  I nteri m A nal yses  ................................................................................................2 2  
4. 1 0. 1. 6  E xa mi n ati o n  of  S u b gr o u ps  ................................................................................2 3  
4. 1 0. 2  Pri mar y  Effica c y  Varia bl e  –  O R R  .......................................................................2 3  
4. 1 0. 3  Sec o n dar y  Effica c y  Varia bles  ..............................................................................2 3  
4. 1 1  
Safet y  E val uati o n  .................................................................................................... 2 5  
4. 1 1. 1  E xte nt  of  E x p os ure  ...............................................................................................2 5  
4. 1 1. 2  A d verse  E ve nts  .................................................................................................... 2 6  
4. 1 1. 2. 1  Ot her  A d verse  E ve nts  of  I nterest ....................................................................... 2 8  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  5  of  3 5  
 
 
4. 1 1. 3  Deat hs,  Seri o us  A d verse  E ve nts,  a n d Ot her  Si g nific a nt  A d verse  E ve nts  ............2 9  
4. 1 1. 4  Cli nic al  L a b orat or y  E val uati o n  ............................................................................2 9  
4. 1 1. 5  Vital  Si g ns,  P h ysical  Fi n di n gs  a n d Ot her  O bser vati o ns  Relate d  t o Safet y.  ......... 3 1  
4. 1 1. 5. 1  Vital  Si g ns  3 1  
4. 1 1. 5. 2  E C G,  E C H O/ M U G A,  a n d P h ysical  E xa mi nati o ns  ............................................3 2  
4. 1 1. 6  Safet y  M o nit ori n g  ................................................................................................ 3 2  
4. 1 2  
Ot her  A nal yses  .......................................................................................................3 2  
4. 1 2. 1  P har mac o ki netics  .................................................................................................3 2  
4. 1 2. 2  Q ualit y  of  Life  ( Q o L) ...........................................................................................3 3  
4. 1 2. 2. 1  E C O G  Perf or ma n ce  Stat us  ................................................................................3 3  
4. 1 2. 2. 2  E Q -5 D -3 L  Sc ores  ..............................................................................................3 3  
4. 1 2. 3  Ot her  E x pl orat or y  A nal yses  ................................................................................. 3 3  
4. 1 3  
Deter mi n ati o n  of  Sa m ple Size  ................................................................................3 3  
4. 1 4  
C ha n ges  i n t he C o n d uct  of  t he St u d y  or  Pla n ne d A nal ysis  .................................... 3 4  
5  
R E F E R E N C E S  ...........................................................................................................3 4  
6  
A P P E N DI X .................................................................................................................3 5  
A p pe n di x  1:  List  of  Preferre d  Ter ms  f or A d verse E ve nts  of  S pecial  I nterest....................3 5  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  6  of  3 5  
 
 
R E VI SI O N  HI S T O R Y  
 
 
Versi o n  N o.  
Effecti ve  Date  
S u m mar y  of  C ha n ge(s)  
0. 1  
2 9  Ma y 2 0 1 9  
Ne w  d oc u me nt  
0. 2  
1 2  A u g ust 2 0 1 9  
I nc or p orate i nter nal re vie wer’s c o m me nts 
1. 0  
2 2  A u g ust 2 0 1 9  
I nc or p orate fi nal c o m m e nts, fi n ali ze f or si g nat ures 
1. 1  
2 6  A u g ust 2 0 2 1  
U p dates  per  pr ot oc ol  v 4. 0,  d oc u m e nt  s p o ns or c ha n ge  fr o m 
Veraste m t o Se c ura Bi o., a d d s u m mari es f or C O VI D -1 9 
relat e d pr ot oc ol de viati o ns 
2. 0  
3 1 A u g ust  2 0 2 1  
I nc or p orate all c ha n ges,  fi naliz e f or si g nat ures. 
2. 1  
1 9 Ma y  2 0 2 3  
U p dates  per  dr y  r u n c o m me nts: 
A d d  Ka pla n  Meier  a n d F or est  pl ots  f or effic ac y  a nal yses 
A d d A E SI f or C O VI D -1 9  
C ha n ge  T E A E  s u m mari es c urre ntl y  b y  S O C,  H L G T,  a n d 
P T t o b y S O C a n d P T 
3. 0  
0 9  A u g ust 2 0 2 3  
I nc or p orate fi nal c o m me nts,  fi nali ze f or si g nat ures. 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  7  of  3 5  
 
 
LI S T O F  A B B R E VI A TI O N S  
 
 
 A b bre vi ati o n /  Acr o n y m  
 Defi niti o n  / E x p a nsi o n  
 
A E  
A d verse  e ve nt 
A L T  
Ala ni ne  a mi n otra nsferase 
A S T  
As partate  a mi n otra nsferase 
A T  
All -treate d 
A T C  
A nat o mic al  T h era pe utic  C he mical  
BI D  
T wice  dail y  
B L Q  
Bel o w  t he li mit of q ua ntificati o n  
B MI  
B o d y  mass i n de x 
B P  
Bl o o d press ure  
CI  
C o nfi de nce  i nter val 
C L L  
C hr o nic  l y m p h oc ytic le u ke mia 
C R  
C o m plet e  res p o nse 
C S  
Cli nic all y  si g nifica nt 
C T C A E  
C o m m o n  T er mi n ol o g y  Criteria  f or A d verse  E ve nts  
ct D N A 
circ ul ati n g  t u m or D N A  
D N A  
De o x yri b o n ucleic  aci d 
D O R  
D urati o n  of  res p o nse 
E C G  
Electr ocar di o gra ms  
E C H O  
Ec h ocar di o gra m  
E C O G  
Easter n  C o o p erati ve  O nc ol o g y  Gr o u p  
e C R F 
Electr o nic  case r e p ort f or m 
E Q -5 D -3 L  
E ur o Q o L  5 -di m e nsi o ns  3 -le vel 
F L  
F ollic ul ar  l y m p h o ma 
H L G T  
Hi g h -le vel gr o u p  ter m 
I C F 
I nf or me d c o nse nt f or m 
i N H L 
I n d ole nt N o n -H o d g ki n’s  L y m p h o ma  
I W G 
I nter nati o nal W or ki n g  Gr o u p  
K M  
Ka pla n -Meier  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  8  of  3 5  
 
 
 
 A b bre vi ati o n /  Acr o n y m  
 Defi niti o n  / E x p a nsi o n  
 
L L Q  
L o wer  li mit of  q ua ntitati o n  
L N R R  
L y m p h  n o de  res p o nse rate 
Me d D R A  
Me dical  Dicti o nar y f or  R e g ulat or y  Acti vities  
mI T T  
M o difie d  i nte nt-t o-treat 
M U G A  
M ulti gat e d  ac q uisiti o n 
M Z L  
Mar gi nal  z o n e l y m p h o ma 
N CI  
Nati o nal  Ca nc er  I nstit ute 
N C S  
N ot  cli nic all y  si g nifica nt 
O R R  
O verall  r es p o nse rate 
O S  
O verall  s ur vi val 
P D  
Pr o gressi ve  disease  
P E  
P h ysical  e xa mi nati o n 
P F S  
Pr o gressi o n -free s ur vi val 
P K  
P har mac o ki netics  
P P  
Per -pr ot oc ol  
P R  
Partial  res p o nse 
P T  
Preferre d  Ter m  
Q o L  
Q ualit y  of  Life  
R B C  
Re d  bl o o d cell 
R N A  
ri b o n ucleic aci d 
R/ R  
Rela pse d  or  refract or y 
S A E  
Seri o us  a d verse e ve nt 
S A P  
Statisti cal  a nal ysis  pla n  
S D  
Sta n dar d  de viati o n  
SI  
I nter nati o nal S yste m  of  U nits  
S L L  
S mall  l y m p h o c yti c l y m p h o ma 
S o A  
Sc he d ule  of  assess me nts 
S O C  
S yste m  or ga n  class  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt 
T T F  
Ti me  t o tre at m e nt fail ure 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  9  of  3 5  
 
 
 
 A b bre vi ati o n /  Acr o n y m  
 Defi niti o n  / E x p a nsi o n  
 
T T F R  
Ti me  t o t he first res p o nse 
V A S  
Vis ual  A nal o g  Scale  
W H O Dr u g  
W orl d  Healt h  Or ga niz ati o n  - Dr u g  Dicti o nar y  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 0  of  3 5  
 
 
 
1  
I N T R O D U C TI O N 
 
D osi n g wit h d u velisi b 2 5 m g t wice d ail y ( BI D) has b ee n s h o w n t o be effi caci o us i n m ulti ple 
P hase 1 -3 st u dies i ncl u di n g s u bjects wit h i n d ol e nt n o n -H o d g ki n l y m p h o ma (i N H L). T he 
effica c y, safet y a n d t oler a bilit y of t his d ose s u p p orte d t he U. S. a p pr o val of d u velisi b f or t h e 
treat me nt of a d ult s u bj ects wit h rela pse d or refr act or y ( R/ R) c hr o nic l y m p h oc ytic le u ke mia 
( C L L)/s mall l y m p h oc ytic l y m p h o ma ( S L L) after at l east 2 pri or t h era pi es a n d acc eler ate d 
a p pr o val i n a d ult s u bj ects wit h R/ R f ollic ul ar l y m p h o ma ( F L) aft er at least 2 pri or s yste mic 
t hera pi es. T he  c urre nt  st u d y will  e val uat e w het her  efficac y  ca n b e  a c hie v e d  a n d mai ntai ne d,  wit h 
acce pta bl e or i m pr o ve d saf et y a n d t oler a bilit y, b y i n cl usi o n of pre -s pecifie d 2-wee k dr u g 
h oli da ys i n 2 diff ere nt 2 5 m g BI D sc he d ules i n s u bje cts wit h R/ R i N H L.  
 
T his  statistic al a nal ysis  pla n  ( S A P) pr o vi des  a detaile d  descri pti o n  of  t he statisti cal met h o ds  a n d 
a nal yses t o be carrie d o ut i n s u p p ort f or st u d y V S -0 1 4 5 -2 2 9.  
 
T he  f oll o wi n g will  be  c oll ecte d  b ut  n ot  e nter e d  i nt o t he cli ni cal st u d y data base:  
 
• P har mac o ki n eti c  data  ( P R A Healt h  Scie nces)  
• P har mac o d y na mic  dat a  ( Pri mit y Bi o)  
• E x pl orat or y  bi o mar k ers  ( C o va nce) 
 
T he  a n al yses  descri be d  i n t his S A P  are base d  u p o n  t he f oll o wi n g st u d y d oc u me nts:  
• St u d y  Pr ot oc ol,  Versi o n  1. 0  ( A pril 4,  2 0 1 9)  
• St u d y  Pr ot oc ol,  Versi o n  4. 0  ( Ma y 1 9,  2 0 2 1)  
• electr o nic  Case  Re p ort  F or m  (e C R F), Versi o n  1. 0  ( A u g ust, 2 1,  2 0 1 9)  
• electr o nic  Case  Re p ort  F or m  (e C R F), Versi o n  9. 0 ( 2 3  Se p  2 0 2 2)  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 1  of  3 5  
 
 
2  
S T U D Y  O B J E C TI V E S  
 
2. 1  Pri m ar y  O bjecti ve(s)  
 
E val uate  t h e effi cac y  of  d u velisi b  a d mi nistere d  wit h  prescri be d  dr u g  h oli da ys  i n s u bje cts wit h 
i N H L. 
 
2. 2  Sec o n d ar y  O bjecti ve(s)  
 
• E val uate  s u p p orti ve effic ac y  m eas ures  of  d u velisi b  a d mi nister e d  wit h  pr escri be d  dr u g 
h oli da ys i n s u bje cts wit h i N H L.  
• E val uate  t he saf et y a n d  t ol era bilit y of  d u v elisi b  a d mi nistere d  wit h  prescri b e d  dr u g 
h oli da ys i n s u bje cts wit h i N H L.  
• C haract erize  t he p har mac o ki netics  ( P K) of  d u velisi b  meta b olit e(s)  a n d d u velisi b  w he n 
d u velisi b is a d mi nist ere d wit h pr escri be d dr u g h oli da ys i n s u bjects wit h i N H L.  
 
2. 3  E x pl or at or y  O bjecti ve(s)  
 
• E val uate  Q ualit y  of  Life  ( Q o L) i n s u bjects treate d wit h  d u velisi b  wit h  pr escri be d  dr u g 
h oli da ys.  
• E val uate  p ote ntial  bi o m ar kers  of  cli ni cal effica c y  a n d/ or safet y of  d u velisi b  a d mi nist ere d 
wit h prescri be d dr u g h oli da ys i n s u bj ects wit h i N H L.  
 
 
3  
I N V E S TI G A TI O N A L P L A N  
 
3. 1  O ver all  St u d y  Desi g n  a n d  Pl a n  
 
T his is a P hase 2, ra n d o mize d, o p e n -la bel, m ultic e nt er, i nter n ati o n al 2-ar m st u d y d esi g ne d t o 
e val uate t h e effica c y  a n d safet y of  alt er nati ve d osi n g  sc he d ules of  d u v elisi b  tre at m e nt i n s u bje cts 
wit h R/ R i N H L w h o ha ve re cei v e d at l east 1 pri or s yste mic t hera p y.  
S u bjects will b e stratifie d b y t he n u m b er of pri or t her a pies ( 1 or > 1), b ul k y dise ase stat us 
(l o n gest dia m eter  of  baseli ne  lesi o n <  5  c m or  ≥ 5 c m)  a n d ti m e si nc e l ast rec urre nc e ( ≥ 2 4 
m o nt hs or < 2 4 m o nt hs).  
S u bjects  will  be  ra n d o mize d t o Ar m  1 or  Ar m  2 i n  a 1: 1 fas hi o n. 
• Ar m  1:  d u velisi b  2 5  m g  BI D  f or o ne  1 0 -wee k  c y cle f oll o we d b y  2 5  m g  BI D  o n 
Wee ks 3 a n d 4 of ea c h s u bse q ue nt 4 -wee k c ycl es u ntil disease pr o gr essi o n, 
u nacce pta bl e t o xicit y, or wit h dr a wal.  
• Ar m  2:  d u velisi b  2 5  m g  BI D  o n  Wee ks  1,  2,  5,  6, 9  a n d 1 0  of  o ne  1 0 -we e k  c ycl e,  t he n 
o n Wee ks 3 a n d 4 of ea c h s u bse q ue nt 4 -wee k c ycl es u ntil dise ase pr o gressi o n, 
u nacce pta bl e t o xicit y, or wit h dr a wal (Fi g ure 1 ). 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 2  of  3 5  
 
 
 
 
Fi g ure  1:  
Tre at me nt  Sc he me  
 
 
S oli d  s ecti o ns: d u velisi b  2 5  m g  BI D;  has he d  s ecti o ns: dr u g  h oli da y.  S u bjects  will  be  ra n d o mize d 1: 1  t o Ar ms  1  a n d 
2.  S u bjects  will  be  assesse d  f or dis eas e  res p o ns e o n  Da y  1  of  C ycles  2,  4,  6,  9,  1 3,  1 7  a n d e ver y  f o urt h c ycle 
t hereafter u ntil dis eas e pr o gressi o n, u nacce pta ble t o xicit y or wit h dra wal. 
A b bre viati o ns:  BI D:  t wice dail y.  
 
 
T he st u d y has a 2 -sta g e desi g n. F or eac h ar m: i n t he first sta ge, 1 5 s u bje cts will b e e nr olle d. 
Res p o nses will be assesse d b y t he I n vesti gat or a cc or di n g t o t he 2 0 0 7 r e vise d I W G criteri a 
(C hes o n 2 0 0 7 ) ( pri mar y e n d p oi nt) a n d t he 2 0 1 4 L u g a n o crit eria (C h es o n 2 0 1 4 ). T he e val uati o n 
of  t he first sta ge will ta k e pla ce  aft er t he e nr olle d s u bjects ha v e bee n f oll o we d f or  a mi ni m u m of 
3 c ycles. If t h ere are f e wer t ha n 6 r es p o n ders ( partial res p o nse ( P R) or c o m plet e res p o nse ( C R)) 
a m o n g t he first 1 5 s u bjects per ar m, c o nsi d erati o n m a y be gi ve n t o st o p pi n g t h at ar m. A 
treat me nt ar m m a y als o n ot pr oc ee d t o t he sec o n d st a ge if t he t otalit y of t he data is c o m p elli n g 
(e. g., acc u m ulati n g e n o u g h data i n St a ge 1 t o c o ncl u de t he o ver all r es p o nse rate ( O R R) e xc ee ds 
3 0 %).  Ot her wise,  a p pr o xi mat el y  3 6  a d diti o nal s u bje cts will  be  e nr oll e d  f or a t otal of  5 1  per ar m. 
E nr oll m e nt will be c o nti n u o us bet we e n Sta ge 1 a n d Sta ge 2. If fe wer t ha n 2 2 ( 4 3 %) r es p o n ders 
( P R or C R) are o bser ve d i n 5 1 s u bje cts, c o nsi derati o n ma y be gi v e n t o c o n cl u di n g t hat t he 
treat me nt sc he d ul e d oes n ot  warr a nt  f urt her st u d y i n t his p o p ulati o n.  Ea c h  ar m will  be  e val u ate d 
se paratel y. 
It is a ntici pat e d  t h at st u d y e nr oll me nt will  o cc ur  o v er  a p pr o xi m atel y  2  y ears.  T h e  l ast s u bj ect visit 
will occ ur 2 y ears after t he l ast s u bject is ra n d o mize d. If t he st u d y e n ds pri or t o all s u bj ects 
disc o nti n ui n g treat me nt, a n y s u bje ct c o nti n ui n g t o r e cei ve b e nefit will be pr o vi de d t h e 
o p p ort u nit y t o c o nti n u e t o re cei ve d u v elisi b. L o n g -ter m c o nti n u e d tre at m e nt ma y b e pr o vi de d via 
a n e x pa n d e d  a ccess  pr o gra m  c o nsist e nt wit h  l o cal re g ulati o ns, s uc h as  t h e Sec ura  Bi o  N P P.  St u d y 
pr oce d ures a n d t h eir ti mi n g ar e s u m marize d i n t he sc he d ule of assess me nts ( S o A) ( Pr ot oc ol 
Secti o n 1. 3)  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 3  of  3 5  
 
 
3. 2  E n d p oi nts 
Pri m ar y  E n d p oi nt  
O verall  Res p o nse  R ate  ( O R R) a cc or di n g  t o t h e 2 0 0 7  re vise d I nter n ati o n al W or ki n g Gr o u p  (I W G) 
Criteri a  ( C hes o n 2 0 0 7)  
Sec o n d ar y  E n d p oi nts  
• O R R  acc or di n g  t o 2 0 1 4  L u ga n o  criteria (C h es o n  2 0 1 4 ) 
N ote: wit h t he e xce pti o n of ti me t o tre at me nt f ail ure, all a d diti o n al sec o n d ary res p o nse 
e n d p oi nts list e d bel o w as well as pr o gressi o n -free s urviv al ( P F S), will be assesse d se p ar ately 
usi n g 2 0 0 7 revise d I W G criteri a ( C h es o n 2 0 0 7 ; referre d t o as "revise d I W G criteri a" f or 
s u bse q ue nt refere n ces i n t his d oc u me nt  ) a n d  2 0 1 4  L u g a n o  criteri a  (C hes o n  2 0 1 4 ; referre d t o as 
" L u g a n o criteri a" f or s u bse q ue nt refere nc es i n t his d oc u me nt).  
• O R R,  at 6, 1 2,  1 8, a n d  2 4 m o nt hs  aft er  first d ose  of  st u d y i nter ve nti o n 
• P F S  
• Ti me  t o tre at m e nt fail ur e ( T T F) 
• D urati o n  of  res p o nse ( D O R) 
• O verall  s ur vi v al ( O S) 
• L y m p h  n o de  res p o nse rate ( L N R R) 
• Ti me  t o t h e first res p o nse ( T T F R) 
• A d verse  e ve nts  ( A Es), seri o us A Es  ( S A Es), vit al  si g ns, p h ysical  e x a mi n ati o ns,  a n d  cli nic al 
la b orat or y v al ues 
• P K  para met ers  f or d u velisi b  a n d meta b olite(s)  
 
E x pl or at or y  E n d p oi nts  
• Easter n  C o o per ati v e  O nc ol o g y  Gr o u p  ( E C O G) Perf or ma nce  Sc ore  
• E ur o Q o L  5  di me nsi o ns  3 -le vel (E Q -5 D -3 L)  q uesti o n naire  res p o nses 
• Bl o o d  assess me nts  of  i m m u ne cell p o p ulati o ns,  c h e m o ki nes,  c yt o ki n es,  pr otei ns  a n d/ or 
circ ul ati n g t u m or (ct D N A)  
• Assess me nts  of  pr otei n,  D N A  a n d or  R N A  i n fecal micr o bi ota  
• T u m or  bi o ps y  e val u ati o n  of  bi o m ar kers  s uc h as  ge ne  a n d c o p y  vari ati o n,  R N A  e x pressi o n, 
pr otei n e x pr essi o n, a n d/ or i m m u ne c ell c o nte nt  
 
 
3. 2. 1  Effic ac y  V ari a bles  
Assess me nt of disease res p o nse a n d pr o gressi o n stat us i n all s u bje cts will b e e val uat e d b y t he 
I n vesti gat or usi n g 2 0 0 7 r e vise d I W G criteri a (C hes o n 2 0 0 7 ) a n d 2 0 1 4 L u ga n o criteria (C hes o n  
2 0 1 4 ). Res p o nse a n d pr o gressi o n will be e val uate d usi n g t he f oll o wi n g pr o ce d ures, o n Da y 1 of 
C ycles  2,  4,  6,  9,  1 3,  1 7  a n d e ver y f o urt h c ycle t here after, as  s h o w n i n t he S o A  ( Pr ot oc ol Secti o n  
1. 3).  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 4  of  3 5  
 
 
• F oc use d  p h ysi cal  e xa mi nati o n  ( P E) (i ncl u di n g assess me nt  of  li ver a n d  s plee n a n d 
re vie w of disease-relat e d c o nstit uti o n al s y m pt o ms) 
• I ma gi n g sca ns of c hest,  a b d o me n,  a n d pel vis  
• B o ne  marr o w  bi o ps y/as pir ate  (as necessar y  t o c o nfir m C R)  
T hese e val uati o ns will be d o ne u ntil pr o gressi ve dise ase ( P D) is d oc u me nte d, ot her a ntica n cer 
t hera p y is i nitiate d, or  deat h  oc c urs. F or  s u bje cts w h o  disc o nti n u e  st u d y i nter ve nti o n f or reas o ns 
ot her t ha n r a di ol o gic disease pr o gr essi o n, res p o nse assess me nts will be perf or m e d d uri n g 
pr ot oc ol -s pecifie d l o n g-ter m f oll o w-u p.  
3. 2. 2  S afet y  V ari a bles  
 
• P h ysical e xa mi nati o ns, i ncl u di n g assess me nt of li ver/s plee n siz e, cli nic al assess me nt of 
t u m or masses  (if e val ua bl e b y  P E),  re vi e w of  disease -relat e d c o nstit uti o nal  s y m pt o ms ( B 
s y m pt o ms: s y m pt o ms of fe v er [i.e., te m p erat ure > 3 8° C/ 1 0 0. 4° F] wit h o ut e vi de nc e of 
i nfecti o n, wei g ht l oss, a n d dre nc hi n g ni g ht s weats wit h o ut e vi d e nce of i nfecti o n), 
ne ur ol o gic e xa mi nati o n, hei g ht  
• Vital  si g ns (se mi-s u pi ne s yst oli c a n d diast olic  bl o o d  press ure  [ B P] a n d p ulse, 
te m per at ure, res pirat or y rate) 
• 1 2 -lea d electr ocar di o gra ms  ( E C Gs): P R  i nter val, Q R S  i nter val, R R  i nter val, Q T  i nt er val 
a n d Fri d ericia’s c orrecti o n [ Q Tc F])  
• Ec h ocar di o gra m  ( E C H O)/ m ulti g ate d a c q uisiti o n  ( M U G A) sca ns ( ma y be  perf or me d  as 
cli ni call y i n di cat e d per I n vesti g at or’s j u d ge me nt)  
• Cli nic al  l a b orat or y tests ( he mat ol o g y, cli ni cal c he mistr y,  uri nal ysis  a n d i m m u n o gl o b uli ns 
para meters)  
• A d verse  e ve nt ( A E) assess me nts 
• C o nc o mit a nt  me di cati o n  assess me nts 
 
3. 3  E x pl or at or y  V ari a bles  
 
• E C O G  Perf or ma n ce  Stat us  
• E Q -5 D -3 L  q uesti o n naire  ( S u bject Self -re p orte d Healt h -relate d Q o L)  
• Bl o o d  assess me nts  of  i m m u ne c ell  p o p ulati o ns,  c he m o ki nes,  c yt o ki n es,  pr otei ns  a n d/ or 
circ ul ati n g t u m or (ct D N A)  
• Assess me nts  of  pr otei n,  D N A,  a n d or  R N A  i n fecal micr o bi ota  
• T u m or  bi o ps y  e val u ati o n  of  bi o m ar kers  s uc h as  ge ne  a n d c o p y  n u m ber  v ariati o n,  R N A 
e x pressi o n, pr otei n e x pressi o n, a n d/ or i m m u ne cell c o nte nt  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 5  of  3 5  
 
 
4  
S T A TI S TI C A L  M E T H O D S  
 
4. 1  D at a  Q u alit y  Ass ur a nce  
 
All  ta bles, fi g ures a n d data  listi n gs t o be  i ncl u de d i n t he re p ort will  be  i n de p e n de ntl y c hec ke d  f or 
c o nsiste nc y, i nte grit y a n d i n acc or da n ce wit h st a n dar d Pare xel pr oc e d ures.  
 
4. 2  Ge ner al  Prese nt ati o n  C o nsi der ati o ns  
 
Baseli ne  is defi ne d  as  t he last a v aila ble pre -treat me nt assess me nt (sc he d ul e d or  u nsc he d ul e d). 
‘ Treat me nt Da y’ will be c alc ulat e d rel ati v e t o t h e dat e of ra n d o mi zati o n, i.e., Tr eat me nt 
Da y  =  Assess me nt  Date  - First  D ose  Date  +  1.  
T he  f oll o wi n g visit  wi n d o ws  will  be  defi ne d  f or t he p ur p oses  of  deter mi nati o n  of  O R R  per 
L u ga n o a n d re vise d I W G crit eria at 6, 1 2, 1 8 a n d 2 4 m o nt hs:  
Ti me p oi nt  
Visit  Wi n d o w  
M o nt h 6  
1 5 5  –  2 1 1  ( 1 8 3 ± 2 8 da ys)  fr o m first d ose  
M o nt h 1 2  
3 5 1  - 4 0 7  da ys  ( 3 7 9 ±  2 8  da ys)  fr o m first d ose  
M o nt h 1 8  
4 6 3  –  5 1 9  da ys  ( 4 9 1 ± 2 8 da ys)  fr o m first d ose  
M o nt h 2 4  
6 8 7  –  7 4 3  da ys ( 7 1 5  ±  2 8  da ys)  fr o m first d ose  
 
F or  ot h er  b y -visit  s u m maries, data  will  be  cat e g oriz e d  base d  o n  t he sc he d ule d visit  (i.e. c ycle) 
s pecifie d o n t he e C R F o n w hic h t he data were c olle cte d.  
 
C o nti n u o us data will be s u m mari ze d i n ter ms of t he mea n, sta n d ar d de vi ati o n ( S D), me di a n, 
mi ni m u m, ma xi m u m a n d n u m ber of o bser v ati o ns, u nless ot her wise stat e d. C o nti n u o us data t h at 
are e x pe cte d t o b e s ke we d will b e prese nt e d i n t er ms of t he ma xi m u m, u p p er q uartile, me dia n, 
l o wer q uartile, mi ni m u m a n d n u m b er of o bser vati o ns. T he mi ni m u m a n d ma xi m u m will be 
re p orte d t o t he sa m e n u m ber of de ci m al pl aces as t h e ra w data rec or d e d i n t h e dat a base. T h e 
mea n,  me di a n,  l o wer q uartile  a n d u p per  q uartile  will  be  re p orte d t o o ne  m ore  de ci m al  plac e  t ha n 
t he ra w data  re c or de d i n t h e data base.  T he  S D  will  b e  re p orte d t o t w o m ore de ci m al  pl aces  t ha n 
t he ra w dat a rec or de d i n t he d ata b ase. I n ge ner al, t he ma xi m u m n u m ber of d eci mal places 
re p orte d s hall be f o ur f or a n y s u m m ar y statistic. 
 
Cate g ori cal d ata will be s u m mariz e d i n t er ms of t he n u m ber of s u bjects pr o vi di n g data at t he 
rele va nt ti me p oi nt  ( n), fre q ue n c y c o u nts  a n d  perc e nt a ges.  A n y  pla n ne d  c oll a psi n g  of  cat e g ories 
will be detaile d i n t he S A P te xt a n d t he dat a dis pla ys.  
 
Perce nta g es will be prese nte d t o o n e deci mal pla ce. Perce nta g es will n ot b e prese nte d f or zer o 
c o u nts.  Perce nt a ges  will  be  c alc ulate d  usi n g  n  as  t he de n o mi nat or.  If sa m ple si zes are s mall, t he 
data dis pl a ys will s h o w t he per ce nta g es, b ut a n y t e xt ual re p ort will descri be fre q ue n cies o nl y.  
 
C ha n ges  fr o m baseli ne  i n c ate g orical  dat a  will  be  s u m mari ze d usi n g  s hift ta bles w here 
a p pr o priate. 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 6  of  3 5  
 
 
P -val ues  greater  t h a n or  e q ual t o 0. 0 0 1,  i n ge n eral,  will  b e  prese nte d  t o t hr ee deci mal  pla ces.  P - 
val ues less t ha n 0. 0 0 1 will be pr ese nte d as “ < 0. 0 0 1”.  
 
C o nfi de nce  i nter vals ( CIs) will  be  prese nte d  t o o ne  m ore  deci mal  pl ace  t ha n t he ra w data.  
 
Ti me -t o-e ve nt e n d p oi nts ( P F S, D O R, O S, T T F)  will be  esti mate d usi n g t h e  Ka pla n -Mei er  ( K M) 
met h o d. Descri pti ve st atistics f or a nal yses of s uc h e n d p oi nts will i n cl u de n u m ber of e v e nts, 
n u m ber  of  s u bje cts c e ns ore d,  esti mate d  2 5 %  q uartile,  esti m ate d  me dia n,  esti m ate d  7 5 %  q uartil e, 
a n d 9 5 % CI f or me di a n esti mate. Detaile d descri pti o ns of t he ti m e -t o-e v e nt a nal yses t o be 
perf or me d f or s ec o n dar y e n d p oi nts ar e descri b e d i n Secti o n 4. 1 0. 3 . 
 
4. 3  Ge ner al  C o nsi der ati o ns  
 
4. 3. 1  Missi n g  D at a  
I n ge neral,  ot h er  t h a n f or partial  dates,  missi n g  safet y data  will  n ot  b e  i m p ute d a n d will  b e  tre ate d 
as missi n g.  H o we ver, i n all dat a prese ntati o ns (e xc e pt listi n gs), safet y assess me nt val ues bel o w 
t he li mit of q u a ntitati o n ( B L Q) will b e i m p ute d as ‘l o wer li mit of q ua ntitati o n ( L L Q)’, w here 
L L Q will be r e pla ce d wit h t h e val u e f or t he l o wer li mit of q ua ntit ati o n.  I n listi n gs, B L Q val ues 
will be re p orte d as ‘ < L L Q’.  
4. 3. 1. 1  
I m p utati o n of  Partial  Dates  
 
F or  missi n g  me di cati o n  a n d A E  start dates,  t he f oll o wi n g will  be  a p plie d: 
• If year  is missi n g  ( or c o m pletel y  missi n g),  n o  i m p utati o n will  be  perf or me d.  
• If year  is prese nt  b ut  m o nt hs  a n d da y  are missi n g,  or  year  a n d da y are  prese nt  b ut  m o nt h 
is missi n g, t he missi n g da y/ m o nt h will b e i m p ute d as 0 1 Ja n uar y. 
• If year  a n d m o nt h  are pr ese nt  b ut  da y  is missi n g,  t he missi n g  da y  will  be  i m p ute d as  first 
da y of t he m o nt h.  
 
F or  missi n g  me di cati o ns  a n d A E  e n d dates,  t he f oll o wi n g will  be  a p plie d: 
• If year  is missi n g  ( or c o m pletel y  missi n g),  n o  i m p utati o n will  be  perf or me d.  
• If year  is prese nt  b ut  m o nt h  a n d da y  are missi n g,  or  year  a n d da y are  prese nt  b ut  m o nt h  is 
missi n g, t he missi n g da y/ m o nt h will b e i m p ute d as 3 1 Dece m ber.  
• If year  a n d m o nt h  are pr ese nt  b ut  da y  is missi n g,  t he missi n g  da y  will  be  i m p ute d as  last 
da y of t he m o nt h.  
• If a s u bject dies i n  t he sa m e m o nt h/ y ear  of  partial  st o p date, t he date  of  deat h  will be  use d.  
 
I n a d diti o n, f or A Es,  if f or a p arti al  start dat e,  t he A E  start dat e  c o ul d ( w he n  als o c o nsi deri n g  t he 
A E e n d date) p ote ntiall y be  o n t he first d ose of st u d y i nter ve nti o n date, t h e A E start date will be 
i m p ute d wit h  t he first d ose  of  st u d y i nter ve nti o n d ate  t o ass u me  a “ w orst case” sc e nari o; e. g.  A E 
fr o m U N K-J u n-2 0 1 7 t o 2 3 -J ul-2 0 1 7 wit h t he first d ose of st u d y i nter ve nti o n date 2 1 -J u n-2 0 1 7, 
t he n t he A E st art date will be i m p ute d t o 2 1-J u n-2 0 1 7.  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 7  of  3 5  
 
 
4. 3. 1. 2  
Ha n dli n g  Missi n g  Dates/ M o nt hs/ Years  f or Deter mi n ati o n  of  T E A Es  
 
A d verse  e ve nts  ( A Es) wit h  i nc o m plet e o nset  dates  will  b e  ha n dl e d  as  f oll o ws f or t h e p ur p ose  of 
deter mi ni n g tr eat me nt e mer ge n ce a cc or di n g t o t he d efi niti o n pr o vi de d i n Secti o n 4. 1 1. 2 . 
• If t he start/e n d date of a n A E is partiall y missi n g, t he date will be c o m pare d as a cc uratel y 
as  p ossi ble  wit h  t he first d ose  of  st u d y dr u g  a n d t he d ate  of  last d ose  of  st u d y dr u g  pl us  3 0 
da ys. T he  A E  will be  ass u me d t o be  treat me nt e m er g e nt if it ca n n ot b e defi niti vel y s h o w n 
t hat t h e A E di d n ot st art or w orse n d uri n g t he treat m e nt-e m er ge nt p eri o d.  
• If t he start dat e  is c o m pletel y  missi n g,  a n A E  will  b e  c o nsi dere d  treat me nt-e mer g e nt 
u nless t he st o p dat e is bef ore first d ose of st u d y dr u g.  
T he  ori gi n al  partial  or  missi n g  date will  b e  dis pla ye d  i n t he A E  listi n gs. 
 
4. 3. 1. 3  
Ha n dli n g  Missi n g  Dates/ M o nt hs/ Years  f or C o nc o mit a nt  Me dicati o ns  
 
Pri or  or  c o nc o mita nt m e dic ati o ns  wit h  i n c o m pl ete st art dates  will  be  h a n dle d  as  f oll o ws f or t he 
p ur p ose of deter mi ni n g w het h er a n o n -st u d y me dicati o n is a c o nc o mit a nt m e dic ati o n  
• If t he start/st o p dat e of a me dicati o n is partiall y missi n g, t he dat e will b e c o m p are d as 
acc uratel y  as  p ossi ble  wit h  t h e first d ose  d ate  of  st u d y dr u g  a n d t he last d ose  dat e  of  st u d y 
dr u g pl us 3 0 da ys. T he me dicati o n will be ass u me d t o be c o nc o mita nt if it ca n n ot be 
defi niti vel y s h o w n t hat t he st o p d ate is bef ore first d ose date of st u d y dr u g, or t h e start 
date is m or e t ha n 3 0 d a ys after t h e last d ose d ate of st u d y dr u g.  
• If t he start/st o p dat es  are  c o m plet el y  missi n g,  a m e di cati o n  will  b e  c o nsi der e d 
c o nc o mita nt. 
4. 3. 1. 4  
Ha n dli n g  Missi n g  Dates/ M o nt hs/ Years  f or Disease  Hist or y  
 
F or  t h e p ur p ose  of  calc ul ati n g  t he d ur ati o n  fr o m i niti al di a g n osis,  partial/ missi n g  d ates  f or 
dia g n osis will be i m p ut e d as f oll o ws:  
• If b ot h  da y  a n d m o nt h  are missi n g  a n d t he ye ar  is pri or t o t he y ear  of  scree ni n g, t he 
i m p ute d d ate will be 0 1 J ul y 
• If b ot h da y a n d m o nt h are missi n g a n d year is t he sa me as t he y ear of scree ni n g, t he 
i m p ute d dat e  will  be  t he mi d dl e  p oi nt  bet wee n  0 1  Ja n uar y of  t h e year  a n d  t he scr ee ni n g 
date. If  t he mi d dle  p oi nt falls bet wee n t w o  dates, t h e  first of t he t w o dat es will be use d.  
• If da y  is missi n g  a n d  t he m o nt h  a n d y ear  ar e pri or  t o t he m o nt h  a n d  year  of  scre e ni n g, t he 
i m p ute d d ate will be t he 1 5t h d a y of t he m o nt h. 
• If da y  is missi n g  a n d t he m o nt h  a n d ye ar  ar e t h e sa m e as  t he m o nt h  a n d year  of  scree ni n g, 
t he i m p ute d date will be t h e mi d dle p oi nt bet wee n t h e first da y of t h e m o nt h a n d t he 
scree ni n g date. If t he mi d dl e p oi nt f alls bet wee n t w o dates, t he first of t he t w o dates will 
be use d.  
• N o  i m p utati o n will  be  perf or me d  if t h e year  is missi n g.  
 
4. 3. 2  St a n d ar d  Dicti o n aries  f or C o di n g  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 8  of  3 5  
 
 
T he  f oll o wi n g dicti o naries  will  be  use d  t o c o de me di cal  v er bati m  ter ms f or t he cli nical data 
bel o w.  
T y pes  of D at a  
C o di n g  T o ols  a n d  L atest  Versi o n  
A d verse  e ve nts 
Me dical  Dicti o nar y  f or Re g ulat or y  Acti viti es  ( Me d D R A) 
Versi o n 2 4. 0  
Pri or  a n d c o nc o mita nt me dicati o ns  
W orl d  Healt h  Or ga ni zati o n  Dr u g  Dicti o nar y 
( W H O Dr u g) Marc h 2 0 2 1  
Pri or  s yste mic t hera pies 
W H O Dr u g  Marc h  2 0 2 1  
S u bse q ue nt  a nti ca nc er  t hera pies 
W H O Dr u g  Marc h  2 0 2 1  
Me dical  hist or y  
Me d D R A  Versi o n  2 4. 0  
 
 
4. 4  S oft w are  
 
All  re p ort o ut p uts  will  be  pr o d uc e d  usi n g  S A S ®  versi o n  9. 3  or  a later v ersi o n  i n a sec ure a n d 
vali date d e n vir o n me nt.  
 
4. 5  A n al ysis  Sets  
 
M o difie d  I nte nt-t o-tre at ( mI T T) A n al ysis  Set  
 
T he  m o difie d  i nte nt-t o-tr eat ( mI T T) a nal ysis  set will  i ncl u de all  s u bjects w h o  rec ei ve at  least o ne 
d ose of st u d y dr u g. T he mI T T a nal ysis set will ser ve as t he pri m ar y a nal ysis set f or all effic ac y 
e n d p oi nts a n d baseli ne c haracteristics.  
 
All -tre ate d ( A T) A n al ysis  Set  
 
T he  all-tre ate d ( A T) a nal ysis  set will  i ncl u de all s u bj ects w h o  recei ve d at l east o ne  d ose  of  st u d y 
dr u g. T he A T a nal ysis set will b e t he pri mar y a n al ysis set f or all safet y e n d p oi nts.  
 
Per -pr ot oc ol  ( P P) A n al ysis  Set  
 
T he per -pr ot o c ol ( P P) a nal ysis set i ncl u des all s u bje cts i n t he mI T T a n al ysis set w h o d o n ot 
vi olat e  t he pr ot oc ol  i n a wa y  t h at w o ul d  si g nifi ca ntl y affect  t he st u d y o ut c o me.  S u bjects  w h o 
meet a n y of t he f oll o wi n g criteri a ma y b e e xcl u de d fr o m t he P P a nal ysis set:  
• D o  n ot  ha ve  hist ol o gicall y  c o nfir me d  di a g n osis  of  i N H L: F L  Gra des  1  t o 3a, 
mar gi nal z o ne l y m p h o m a ( M Z L; s ple nic, n o dal, or e xtra n o dal), or S L L  
• Ha ve  n ot  rec ei ve d at le ast 1  pri or  s yste mic r e gi m e n f or i N H L 
• M ust ha ve at le ast o ne bi -di me nsi o nall y me as ura ble  lesi o n ≥ 1. 5 c m ( w hic h h as 
n ot  bee n  pre vi o usl y  irra diat e d) acc or di n g  t o 2 0 0 7  re vise d I W G res p o nse crit eria 
( C hes o n 2 0 0 7) 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  1 9  of  3 5  
 
 
• Cli nic al  or  hist ol o gic al  e vi de n ce of  tra nsf or m ati o n t o a m ore  a g gr essi ve  s u bt y pe 
of l y m p h o ma or Gra d e 3 b F L or Ric hter’s tra nsf or m ati o n or C L L  
• Ne ver  recei ve d st u d y dr u g  
• Recei v e d  c o nc o mita nt a nti ca nc er  t h era p y pri or  t o o bs er vati o n of  O R R  
S u bjects wit h m aj or pr ot o c ol de viati o ns n ot list e d a b o ve a n d wit h C O VI D -1 9 relate d pr ot oc ol 
de viati o ns  will  be  c o nsi der e d  f or re m o v al fr o m t he P P  a nal ysis  set o n  a case b y  case b asis.  T he 
P P  a nal ysis  set will  be  a  sec o n dar y a n al ysis  set f or t h e a nal ysis  of  O R R.  Fi nal  deter mi nati o n  of 
s u bjects t o be i ncl u d e d i n t h e P P a nal ysis set will be deter mi ne d pri or t o data b ase l oc k a n d 
u n bli n di n g of tr eat me nt assi g n me nt.  
 
 
4. 6  St u d y  S u bjects  
 
4. 6. 1  Dis p ositi o n of  S u bjects  
A  clear  ac c o u nti n g  of  t h e dis p ositi o n  of  all  s u bjects w h o  e nr oll i n t h e st u d y will  b e  pr o vi de d, 
fr o m scree ni n g t o st u d y c o m pleti o n. 
 
T he  dis p ositi o n  of  s u bj ects will  i ncl u d e t h e n u m b er  a n d perce nta ge  of  s u bjects f or t he f oll o wi n g 
cate g ories: t h e n u m ber ra n d o miz e d, t he n u m ber a n d perce nt a ge ra n d o mize d b ut n ot d ose d, a n d 
t he n u m ber a n d perce nta ge d ose d. T hese c ate g ories will be s u m m ariz e d f or eac h treat me nt ar m 
a n d f or t he t w o tr eat me nt ar ms c o m bi n e d (t ot al). T h e perce nt a ges will b e base d o n all 
ra n d o miz e d s u bjects. A n e n d-of -treat me nt dis p ositi o n (still o n tr eat me nt vs. disc o nti n ue d fr o m 
treat me nt) will be pr o vi de d f or ea c h tre at m e nt ar m a n d f or t he t w o tre at m e nt ar ms c o m bi ne d 
(t otal) b ase d o n t he A T a nal ysis set. T h e pri m ar y reas o n f or disc o nti n uati o n will b e i ncl u de d i n 
t he t a ble. A  listi n g of  t h ese s u bje cts will  als o be  pr o vi de d,  br o ke n  d o w n  b y ce nter  a n d treat me nt 
ar m. 
 
A n  e n d-of -st u d y dis p ositi o n  (still o n  st u d y vs.  disc o nti n ue d  fr o m st u d y) will  als o be  pr o vi de d  f or 
eac h tr eat me nt ar m a n d f or t h e t w o tre at m e nt ar ms c o m bi ne d (t otal) b ase d o n t he mI T T a n al ysis 
set. T he pri mar y reas o n f or st u d y disc o nti n uati o n will be i ncl u de d i n t he t a ble. A listi n g of t hese 
s u bjects will als o be pr o vi d e d, br o ke n d o w n b y ce nt er a n d treat me nt ar m.  
 
A s u m mar y of strata as ca pt ure d i n I R T will be prese nte d b y tre at m e nt ar m a n d f or t he t w o 
treat me nt ar ms  c o m bi n e d  (t otal) base d  o n  t h e mI T T  a nal ysis  set. A  s u m mar y ta bl e a n d  a listi n g of 
discre pa ncies i n data f or stratific ati o n f act ors bet wee n t h ose ca pt ur e d i n t h e I R T a n d t h ose 
re p orte d o n t h e e C R F will b e prese nte d. B ot h t he s u m mar y t a ble a n d listi n g will b e dis pla y e d b y 
treat me nt ar m. 
 
All  s u bjects i n t he mI T T  p o p ulati o n  will  als o  be  s u m mariz e d b y  site a n d b y  c o u ntr y. 
 
U p o n data base rel ease, pr ot o c ol de viati o n a n d a nal ysis set o ut p uts will be pr o d u ce d a n d will be 
se nt t o Se c ura  Bi o  f or re vie w. A n  a n al ysis  set cl assificati o n  m eeti n g  will  be  arr a n ge d  t o disc uss 
t he o ut p uts a n d t o deci de w hic h s u bj ects a n d/ or s u bj ect data will be e xcl u de d fr o m cert ai n 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 0  of  3 5  
 
 
a nal yses.  Decisi o ns  ma d e  re gar di n g t h e e xcl usi o n  of  s u bjects a n d/ or  s u bject d ata  fr o m a n al yses 
will be m a de pri or t o u n bli n di n g a n d will be d oc u m e nte d a n d a p pr o v e d b y Veraste m.  
 
T he  f oll o wi n g a nal ysis  set s u m maries will  be  pre pare d:  
• T he  n u m ber  a n d p erce nta ge  of  s u bjects e nt eri n g  a n d c o m pleti n g  eac h  p hase  of  t h e st u d y b y 
treat me nt gr o u p a n d o verall f or ea c h a nal ysis set ( A nal ysis set: mI T T). 
• A b y -s u bject listi n g of a nal ysis set det ails prese nt e d b y treat me nt gr o u p t hat will i n cl u de: 
ce nter, s u bj ect i de ntifi er, i ncl usi o n/ e xcl usi o n fla g f or eac h set a n d re as o n f or e xcl usi o n  fr o m 
eac h set.  All s u bjects scree ne d s h o ul d a p p ear o n t his listi n g.  
4. 6. 2  Pr ot oc ol  De vi ati o ns  
 
Maj or pr ot oc ol d e viati o ns are defi ne d as t h ose d e viati o ns fr o m t he pr ot o c ol li kel y t o ha ve a n 
i m pact o n  t he p ercei v e d  effi cac y  a n d/ or saf et y of  st u d y treat me nts. T he  i m pact of  maj or  pr ot oc ol 
de viati o ns  o n  t h e efficac y  a n d/ or  safet y res ults will  b e  i n vesti g ate d b y  assessi n g  t h e r o b ust ness of 
t he st u d y res ults a n d c o ncl usi o ns t o t he c h oice of a n al ysis set, b ot h i ncl u di n g a n d e xcl u di n g dat a 
p ote nti all y affecte d b y maj or pr ot oc ol de vi ati o ns, if a p plic a ble.  
 
Maj or  pr ot oc ol  de viati o ns  a n d a n y a cti o n  t o b e  t a ke n re gar di n g t he e x cl usi o n  of  s u bjects or 
affect e d data fr o m s pecific a n al yses are d efi ne d i n t h e Pr ot oc ol De vi ati o n S pe cifi cati o n.  
 
T he  f oll o wi n g s u m mari es will  be  prese nte d:  
 
• T he  n u m ber  a n d p erce nta ge  of  s u bjects wit h  a m aj or  pr ot oc ol  d e viati o n  b y  tre at m e nt gr o u p 
a n d o verall a n d b y t y p e of de viati o n ( A nal ysis set: mI T T).  
• T he  n u m ber  a n d p erce nta ge  of  s u bjects wit h  a n y C O VI D -1 9  relate d pr ot oc ol  d e viati o n  ( eit h er 
maj or or mi n or) b y tre at me nt gr o u p a n d o ver all a n d b y t y pe of de vi ati o n ( A nal ysis set: 
mI T T).  
• A  b y -s u bject listi n g of  m aj or  pr ot o c ol  de viati o ns  a n d C O VI D -1 9  relate d pr ot o c ol  de viati o ns 
will be pr o vi d e d.  
 
 
4. 7  De m o gr a p hic  a n d  Ot her  B aseli ne  C h ar acteristics  
 
De m o gra p hic  v aria bles  a n d ot her  b aseli ne  c har act eristics  will  b e  s u m marize d f or eac h  tre at me nt 
ar m base d o n all ra n d o mize d s u bj ects ( mI T T a n al ysis set) a n d f or t he t w o tr eat me nt ar ms 
c o m bi ne d (t otal). T he varia bl es t o be s u m m ariz e d will i ncl u de ( b ut will n ot b e li mit e d t o):  
• A ge  (c o nti n u o us varia ble)  
• A ge  gr o u p ( <  6 5 vs. ≥ 6 5)  
• Ge n der  
• Race  
• Et h nicit y  
• B o d y  mass  i n de x ( B MI), calc ulate d as wei g ht  ( k g)/( h ei g ht [ m] )2 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 1  of  3 5  
 
 
• Stratifi cati o n  fact ors use d  i n t he ra n d o mizati o n 
o  N u m ber  of  pri or  t hera pies ( 1 or  > 1)  
o  B ul k y  disease  stat us (l o n gest di a meter  of  baseli ne lesi o n  <  5  c m or  ≥ 5  c m) 
o  Ti me  si nc e last rec urre n ce ( ≥ 2 4  m o nt hs or  <  2 4 m o nt hs)  
• E C O G  perf or m a nce  stat us 
• N u m ber  of  pri or  t hera pi es ( < 3 or  ≥ 3)  
• M o nt hs  fr o m i nitial dia g n osis  t o ra n d o mizati o n ( cal c ulate d as  date  of  r a n d o mi zati o n –  
date of i niti al di a g n osis + 1)/( 3 6 5. 5/ 1 2)  
• M o nt hs  fr o m last rec urr e nce ( cal c ulate d as  date  of  ra n d o mizati o n –  dat e  l ast re c urre nc e + 
1)/( 3 6 5. 5/ 1 2)  
• i N H L s u bt y pe: F L,  S L L  or  M Z L;  f or M Z L  s u bj ects t y pe of  M Z L  will  als o be 
cate g orize d: s ple nic, n o d al, or e xtra n o dal  
• S pecific  pri or  t hera pies r ecei ve d (i. e., pri or  s ur ger y, ra di ot her a p y, c he m ot hera p y,  a n d 
ot her  s yste mic a nti ca nc er  t hera pies, i ncl u di n g ti m efr a me i n w hic h  t he y wer e  recei ve d, 
w here a p pli ca ble)  
 
A ge  will  b e  calc ul ate d  as  t he n u m b er  of  c o m plete ye ars  bet wee n  a  s u bject's birt h  year  a n d t he 
date of i nf or me d c o nse nt.  
 
 
4. 8  Pri or  a n d C o nc o mit a nt  Me dic ati o n  
 
T he  W orl d  Healt h  Or ga ni zati o n  - Dr u g  Dicti o nar y  ( W H O Dr u g) will  be  use d  f or c o nc o mit a nt a n d 
pri or me dic ati o ns c o di n g. Me di cati o ns will be c o nsi dere d as pri or if t he y st o p pe d bef ore t he d ate 
of  first d ose of  st u d y dr u g. Me dicati o ns will be c o nsi dere d c o nc o mita nt if  t he y were ta ke n at a n y 
ti me bet wee n t he first d ose of st u d y dr u g a n d 3 0 da ys after t he last d ose of st u d y dr u g, i ncl usi ve. 
If t he start d ate or e n d d ate of a me dicati o n is c o m pletel y or partiall y missi n g refer t o Secti o n  
4. 3. 1. 3  f or t he al g orit h m t o deter mi ne  w het her  a m e dicati o n  is c o nc o mita nt. 
 
Pri or me dic ati o ns a n d c o nc o mita nt me di cati o ns will be s u m mari ze d se paratel y. B ot h s u m maries 
will be base d o n t he A T a n al ysis set. Me dic ati o ns will be s u m m ariz e d b y A nat o mical 
T hera pe utic C h e mic al ( A T C) classific ati o n le vel 2, a n d preferre d dr u g na m e f or ea c h tre at m e nt 
ar m. T he s u m mar y will be s orte d al p ha betic all y b y A T C le vel 2 a n d t he n b y d ecreasi n g 
fre q ue nc y b y  preferr e d  dr u g  n a me.  A  s u bject t a ki n g t he sa me dr u g  m ulti pl e  ti mes will  b e  c o u nte d 
o nl y o nce.  
 
A listi n g will b e pr o vi de d f or all n o n -st u d y me di cati o ns ta ke n o n t he st u d y. A n i d e ntifier will be 
pr o vi de d t o s h o w if a m e dic ati o n is pri or or c o nc o mita nt. Me di cati o ns t hat st arte d m ore t ha n 3 0 
da ys  after t h e last d ose  of  st u d y dr u g  will  be  i d e ntifie d as  p ost -treat me nt. A d diti o nal  gr o u pi n gs  of 
me dic ati o ns will be defi ne d t o i de ntif y me di cati o ns a d mi nister e d t o tr eat A Es s pecific t o t he 
d u velisi b ris k pr ofile.  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 2  of  3 5  
 
 
4. 9  Me dic al  Hist or y  
 
Me dical  hist or y  will  b e  s u m m ariz e d a n d  base d  o n  t h e A T  a nal ysis  set. Me dical  hist or y  will  be 
s u m mariz e d b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T) usi n g t he n u m b er a n d 
perce nt a ge  of  s u bjects w h o ha d at le ast o ne occ urr e n ce  of  a S O C or  P T.  T he  s u m mar y will be 
s orte d al p ha b eti call y b y S O C a n d b y decreasi n g fr e q ue nc y of P T wit hi n a n S O C.  
 
4. 1 0  Effic ac y  E v al u ati o n  
 
4. 1 0. 1  A n al ysis  a n d  D at a C o n ve nti o ns  
 
T his  st u d y will  test t he n ull  h y p ot hesis  t hat t h e O R R  f or eac h ar m is ≤ 3 0 %  a gai nst t h e alter n ati v e 
t hat O R R is ≥ 5 5 %. E ac h tr eat me nt ar m will b e e val uate d se par atel y; n o f or mal c o m p aris o ns 
bet wee n tr eat me nt ar ms are pl a n ne d.  T h e O R R ( pr o p orti o n of s u bjects ac hi e vi n g a C R or P R) 
will be esti mate d, al o n g wit h t h e 2 -si de d 9 5 % e xa ct CI. 
4. 1 0. 1. 1  M ulti -ce nter  St u dies  
 
Statisti cal a nal yses will n ot c o ntr ol f or sit es; h o we ver, s u b gr o u p a nal yses f or re gi o n ( N ort h 
A merica  or  Rest  of  W orl d)  will  be  perf or me d  f or t he pri mar y  e n d p oi nt,  as  well  as  t h e sec o n dar y 
e n d p oi nt of O R R per L u g a n o criteria.  
4. 1 0. 1. 2  A dj ust me nts  f or C o variates  
 
A dj ust me nts  f or c o vari ates  will  n ot  be  perf or me d f or  t his st u d y 
 
4. 1 0. 1. 3  Ha n dli n g  of  Dr o p o uts  or  Missi n g Data  
 
I n ge neral,  val ues  f or missi n g  data  will  n ot  be  i m p ut e d u nless  met h o ds  f or ha n dli n g  missi n g  dat a 
are s pecifie d. F or a nal yses of O R R, s u bjects w h o d o n ot e x hi bit a res p o nse will be classifie d as 
n o n -res p o n ders. F or a nal yses of ti m e t o e ve nt e n d p oi nts, i ncl u di n g D O R, P F S, O S, a n d T T F, 
s u bjects f or w h o m t he e ve nt is n ot o bser ve d will b e c e ns ore d as descri be d i n Secti o n 4. 1 0. 3 . 
 
4. 1 0. 1. 4  M ulti ple  C o m paris o ns/ M ulti plicit y  
 
Eac h  treat me nt ar m will b e  a n al yz e d  se parat el y wit h  n o  a dj ust me nt f or m ulti plicit y.  
 
4. 1 0. 1. 5  I nteri m A nal yses  
 
N o f or mal i nt eri m a nal ysis is pl a n ne d. St u d y data f or eac h ar m will b e e val u ate d at t h e e n d of 
Sta ge  1  t o det er mi ne  w het her  a st u d y ar m s h o ul d be  t er mi nate d or  c o nti n u e d  t o Sta ge  2.  Please 
see a d diti o nal d etails of t he 2-sta g e desi g n i n Se cti o n 4. 1 3  bel o w.  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 3  of  3 5  
 
 
4. 1 0. 1. 6  E xa mi n ati o n  of  S u b gr o u ps  
 
T he  u nif or mit y  of  t he tr eat me nt effe ct f or O R R  ( usi n g b ot h  re vise d I W G a n d  L u ga n o  criteri a) 
will be e x a mi n e d f or t he f oll o wi n g s u b gr o u ps:  
 
1.  Stratifi cati o n  fact ors 
o  N u m ber  of  pri or  t hera pies ( 1 vs.  >  1)  
o  B ul k y  disease  stat us (l o n gest di a meter  of  baseli ne lesi o n  <  5  c m vs.  ≥ 5  c m) 
o  Ti me  si nc e last re c urre nce ( ≥ 2 4 m o nt hs  vs. <  2 4 m o nt hs)  
2.  Baseli ne  E C O G  sc ore ( 0 vs.  ≥ 1)  
3.  Re gi o n  of  w orl d  ( N ort h A meric a  vs.  Rest  of W orl d)  
4.  A d diti o nal  c hara cterizati o n  of  n u m b er  of  pri or  s yste mic re gi me ns ( 1, 2,  or ≥ 3)  
5.  i N H L s u bt y pe ( F L, M Z L, S L L)  
6.  Pri or  treat me nt wit h  rit u xi ma b ( yes vs.  n o)  
7.  Pri or  treat me nt wit h  be n da m usti ne  ( yes vs.  n o)  
8.  A ge  ( < 6 0  years, ≥ 6 0 years)  
9.  Se x  ( mal e, fe male) 
1 0.  Et h nic  ori gi n  ( Ca ucasi a n, n o n-Ca ucasia n)  
 
F orest  pl ots  will  be  use d  t o pl ot  res p o nse rat e b y  st u d y Ar m  f or eac h s u b gr o u p. 
4. 1 0. 2  Pri m ar y  Effic a c y  V ari a ble  –  O R R  
T he  O R R  ( pr o p orti o n of  s u bjects ac hi e vi n g  a C R or  P R  usi n g  t he n u m ber  of  s u bje cts i n t he mI T T 
a nal ysis set as t h e  de n o mi nat or)  will b e  esti mate d, al o n g wit h t he  2 -si de d 9 5 % e xa ct CI  usi n g t he 
Cl o p per -Pears o n e xa ct met h o d f or bi n o mial pr o p orti o ns. Res p o nses f or t he pri mar y O R R 
a nal ysis will b e assesse d usi n g t he 2 0 0 7 re vise d I W G criteri a ( C hes o n 2 0 0 7). Missi n g data will 
be i m p ut e d b y ass u mi n g t h at a n y s u bj ects n ot e x hi biti n g a res p o nse ( C R or P R) are  
n o n -res p o n ders. Res p o nses  occ urri n g  aft er  t he start of  s u bse q ue nt a ntica n cer  t hera p y will  n ot  b e 
i ncl u de d i n t he n u merat or. 
 
T he  pri m ar y  a n al ysis  of  O R R  will  be  perf or me d  1 2  m o nt hs  aft er t h e last s u bject is r a n d o mi ze d, 
usi n g t he ti me wi n d o ws s pecifi e d i n Secti o n 4. 2  as a p plica ble.  
 
A  b y -s u bject listi n g of  t he pri mar y  effica c y  data will  be  pr o vi de d.  
4. 1 0. 3  Sec o n d ar y  Effic ac y  V ari a bles  
T he  sec o n dar y effica c y  a nal yses  will  b e  c o n d u cte d  o n  t he mI T T  a n al ysis  set. 
 
• O R R  acc or di n g  t o 2 0 1 4  L u g a n o  criteria ( C hes o n 2 0 1 4)  will  b e  a nal yze d  i n t he sa m e 
fas hi o n as t he pri mar y e n d p oi nt 
 
N ote:  wit h  t h e exc e pti o n  of  T T F,  all  a d diti o n al  sec o n d ary res p o nse e n d p oi nts  ( d escri be d b el o w) 
as well as P F S will be assesse d se p ar atel y usi n g 2 0 0 7 revise d I W G criteri a ( C h es o n 2 0 0 7) a n d 
2 0 1 4 L u g a n o criteri a ( C hes o n 2 0 1 4)  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 4  of  3 5  
 
 
• O R R,  at 6,  1 2,  1 8,  a n d 2 4  m o nt hs  after first d ose  of  st u d y i nter v e nti o n, defi n e d  as  t he 
pr o p orti o n of s u bjects ac hi e vi n g C R or P R at eac h of t hese ti me p oi nts.  
 
• P F S  will  be  assesse d  usi n g  K M  met h o ds  fr o m ti m e of  first d ose  of  st u d y i nter ve nti o n 
t o P D  or  deat h.  Me dia n  P F S  will  b e  esti mate d,  al o n g  wit h  t h e 9 5 %  CI.  T he  6 -m o nt h  a n d 
1 2 -m o nt h P F S esti mat es will als o be prese nt e d. See Ta ble 1 f or e ve nt a n d ce ns ori n g 
defi niti o ns. Ka pla n -Mei er s ur vi val c ur v es b y ar m will be pr o d uce d.  
 
• T T F will be cal c ulate d as t he ti m e fr o m first d ose of st u d y i nter ve nti o n u ntil 
disc o nti n uati o n  f or a n y r eas o n a n d  will  be  s u m mariz e d usi n g  K M  m et h o ds.  Me dia n  T T F 
will  be  esti mat e d,  al o n g wit h  t he 9 5 %  CI.  T h e  6 -m o nt h  a n d 1 2 -m o nt h  T T F  esti mat es  will 
als o be prese nt e d. S u bjects w h o are still o n treat me nt at ti me of data c ut off will be 
ce ns ore d at t heir last d ose dat e. Ka pla n -Meier s ur vi v al c ur ves b y ar m will b e pr o d uce d.  
 
 
• D O R will be cal c ulate d f or t h ose s u bje cts wit h a C R or P R fr o m t he ti me of first 
res p o nse t o P D  usi n g  K M  met h o ds.  Me dia n  D O R  will  be  esti mate d,  al o n g wit h  t he 9 5 % 
CI. T he 6 -m o nt h a n d 1 2 -m o nt h D O R esti mat es will als o be prese nt e d. See Ta ble 1 f or 
e ve nt a n d ce ns ori n g defi niti o ns. Ka pl a n -Meier s ur vi val c ur ves b y ar m will b e pr o d uce d.  
 
 
• O S  will  be  assesse d  usi n g  K M  met h o ds  fr o m ti m e of  first d ose  of  st u d y i nter v e nti o n 
t o deat h. Me dia n O S will be esti m ate d, al o n g wit h t h e 9 5 % CI. T he 6 -m o nt h a n d  
1 2 -m o nt h  O S  esti m ates  will  als o be  prese nte d.  S u bj e cts  wit h o ut  d o c u me nte d  de at h  will  b e 
ce ns ore d at t heir last k n o w n ali v e dat e. Ka pla n -Meier s ur vi val c ur ves b y ar m will b e 
pr o d uce d.  
 
• L N R R  will  be  c alc ulat e d as  t he pr o p orti o n  of  s u bjects ac hie vi n g  ≥ 5 0 %  de crease  i n 
t he s u m of t he pr o d u ct of t h e dia meters of t ar get l y m p h n o des. A 2 -si de d 9 5 % e xact CI 
f or L N R R  will  als o be  esti mate d.  A  waterfall  pl ot  of  mi ni m u m  perce nt  c ha n ge i n t he s u m 
of t he pr o d uct of t he di a met ers b y ar m will be pr o d u ce d.  
 
• T T F R  will  be  cal c ulate d  f or t h ose s u bj ects wit h  a C R  or  P R  fr o m t he ti m e of  first 
d ose of st u d y i nter ve nti o n t o ti m e of first C R or P R.  T T F R will be s u m mari ze d  
descri pti v el y  ( m ea n, S D,  m e dia n,  r a n ge). Ka pla n -Meier  s ur vi val c ur ves  b y  ar m will  b e 
pr o d uce d.  
 
 
A  b y -s u bject listi n g of  D O R,  P F S  a n d O S  data  will  b e  pr o vi de d.  
 
T a ble  1:  Pri m ar y  P F S  Ce ns ori n g/ E ve nt  R ule  
 
Sit u ati o n  
D ate  of  E ve nt  or  Ce ns ori n g  
O utc o me  
N o  a de q uate baseli n e  dise ase  stat us assess me nt 
Date  of  r a n d o mi zati o n +  1  da y  
Ce ns ore d  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 5  of  3 5  
 
 
 
N o  a de q uat e p ost -baseli ne  disease  stat us assess me nt 
u nless deat h oc c urs pri or t o first sc he d ule d p ost - 
baseli ne assess me nt  
Date  of  r a n d o mi zati o n +  1  da y  
Ce ns ore d  
N o  d oc u me nte d  pr o gressi o n  or  deat h  
Date  of  last a de q uate disease 
stat us assess me nt 
Ce ns ore d  
D oc u me nte d  pr o gressi o n  wit h  ≤1  missi n g  sc he d ule d 
disease  stat us assess me nt  bef ore  pr o gressi o n  
Date  of  t he earliest assess me nt 
t hat res ults i n a fi n di n g of 
u ne q ui v ocal pr o gressi o n  
E ve nt  
Deat h  bef ore  pr o gr essi o n  bei n g  d oc u me nt e d  wit h  ≤1 
missi n g sc he d ule d disease stat us assess me nt bef ore 
deat h  
Date  of  deat h  
E ve nt  
D oc u me nte d  pr o gressi o n  or  d eat h  f oll o wi n g a ga p 
bet wee n a d e q uate disease stat us assess me nts 
e q ui val e nt t o 2 misse d visits  
Date of last a de q uate disease 
stat us assess me nt  bef ore  t he ga p  
Ce ns ore d  
Ne w  a ntic a ncer  tre at m e nt or  pr o ce d ure  starte d bef or e 
d oc u me nt e d pr o gressi o n  
Date of last a de q uate disease 
stat us assess me nt  pri or  t o st art of 
ne w a ntic a ncer t h era p y  
Ce ns ore d  
N ote:  Disease  stat us assess me nt  i ncl u des ra di ol o gic d oc u me ntati o n  ( C T, P E T/ C T,  M RI  sca ns) (c hest, a b d o me n  a n d pel vis,  ot hers  as 
cli nicall y  i n dicate d), b o ne  marr o w  bi o ps y/as pirate  ( ma y n ot  be  re q uire d of  all patie nts  at all sc he d ule d disease  stat us assess me nts), 
a n d f oc use d p h ysical  e xa mi nati o n ( disease relate d s y m pt o ms, li ver a n d s plee n assess me nt). A n a de q uate baseli ne  disease 
assess me nt  is a n y assess me nt  wit h  meas ura ble  tar get lesi o ns fr o m sca ns. A n  a de q uate  p ost -baseli ne  disease  stat us assess me nt  is a n y 
disease  stat us assess me nt f or w hic h a  disease  stat us of  C R,  P R,  S D  or  P D  is arri ve d per re vise d I nter nati o nal W or ki n g Gr o u p 
(I W G) res p o nse criteria f or mali g na nt l y m p h o ma2. 
 
 
4. 1 1  S afet y  E v al u ati o n  
 
All  safet y s u m maries a n d a nal yses  will  b e  base d  u p o n  t he A T  A nal ysis  Set  as  defi ne d  i n Secti o n 
4. 5 . 
4. 1 1. 1  E xte nt  of  E x p os ure  
E xte nt  of  e x p os ure will  be  s u m mari ze d f or eac h  tre at me nt ar m b ase d  o n  t he A T  a n al ysis  set. 
E xte nt of e x p os ure will b e s u m marize d f or t h e f oll o wi n g varia bl es:  
• D urati o n  ( m o nt hs): ( date of l ast d ose –  date  of first  d ose  +  1)  di vi de d  b y ( 3 6 5. 2 5/ 1 2). 
• N u m ber  of  c y cles  start e d (c o nti n u o us a n d cate g orical)  
• Relati ve d ose i nte nsit y ( o v erall a n d b y c ycle), defi ne d as 1 0 0 % × (t otal d ose 
recei v e d)/( pla n n e d c u m ulati ve d ose f or t h e d urati o n of treat me nt). T he pla n n e d 
c u m ulati ve d ose f or t he tre at m e nt d urati o n is defi ne d as 2 5 m g BI D × t otal n u m ber of 
da ys  o n  w hic h  d u v elisi b  is sc h e d ule d t o b e  a d mi nist ere d  d uri n g  t he i nter v al bet we e n  first 
d ose date a n d last d ose date.  T he treat me nt sc he m e is pr o vi de d i n Secti o n 3. 1 . 
• N u m ber  a n d perce nt a ge  of  s u bjects wit h  a d ose  re d ucti o n 
• Ti me  fr o m first d ose  t o first d ose re d ucti o n 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 6  of  3 5  
 
 
• T otal  da ys  s pe nt at  d ose  re d ucti o n: last date  of  d ose  r e d ucti o n –  first dat e  of  d ose 
re d ucti o n + 1 
• N u m ber  a n d per ce nt a ge  of  s u bjects wit h  a n u n pla n ne d  d ose  h ol d  ( e xcl u di n g t h e pla n n e d 
2 -wee k h oli da ys f or ea c h ar m)  
• N u m ber  a n d perce nt a ge of  s u bjects wit h  a n u n pl a n ne d  d ose  h ol d  <  7  da ys,  ≥ 7 da ys  
• Ti me  fr o m first d ose t o first u n pl a n ne d  d ose  re d ucti o n 
• N u m ber  a n d perc e nta g e  of  s u bje cts f or w h o m  st u d y dr u g  was  disc o nti n ue d 
A b y -s u bject listi n g will b e prese nt e d f or e x p os ure t o st u d y dr u g 
 
 
4. 1 1. 2  A d verse  E ve nts  
A d verse e ve nts will b e c o de d usi n g Me di cal Di cti o n ar y f or Re g ulat or y Acti vities ( Me d D R A) 
Versi o n  2 2  or  hi g h er.  T he  se verit y gra de  of  t he A E  will  b e  assesse d  b y  t he I n vesti g at or a cc or di n g 
t o t he Nati o nal C a ncer I nstit ute C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts 
( N CI-C T C A E, Versi o n 5. 0). If a n A E is n ot i ncl u de d i n t he N CI -C T C A E Versi o n 5. 0, t h e 
se verit y gr a de  of  t h e A E  will  be  assesse d  b y  t he I n vesti gat or a cc or di n g  t o t he st u d y pr ot oc ol.  
 
A  treat m e nt-e mer ge nt a d verse e v e nt ( T E A E) is defi n e d  as  a n y  A E  t h at e mer g es  or  w orse ns  i n t he 
peri o d fr o m t h e first d ose of d u velisi b t o 3 0 da ys after t he last d ose of d u v elisi b. T he o nset date 
of  a n A E will be  c o m par e d t o t h e  first d ose dat e a n d t he  last d ose date  pl us 3 0 da ys (i ncl usi ve)  t o 
deter mi ne w het h er t he A E is tr eat me nt -e mer g e nt or n ot. Refer t o Se cti o n 4. 3. 1. 2  f or t he 
al g orit h m t o deter mi ne w het her a n A E is tre at m e nt e mer ge nt if t he o nset date of a n A E is 
c o m pletel y or p arti all y missi n g.  
T E A Es will be s u m mari ze d f or ea c h tre at m e nt ar m b y Me d D R A S O C a n d P T, or P T o nl y, or 
S O C o nl y. F or s u m mar y t a bles b y S O C a n d P T, S O C will be s orte d al p ha b eti call y, a n d P T will 
be s orte d b y decr easi n g fre q ue n c y i n Ar m 1 wit hi n e ac h S O C. F or s u m mar y ta bl es b y P T o nl y, 
P T  will  b e  s orte d b y  decr easi n g  fr e q ue nc y. F or  sel ecte d s u m m aries (i n dic ate d i n t he list b el o w), 
T E A Es will be s u m mari ze d b y S O C, hi g h -le v el gr o u p ter m ( H L G T) a n d P T, s ort e d b y m ost 
fre q ue ntl y o cc urri n g S O C. 
 
If m ulti pl e  T E A Es  of  t he sa me P T  are re p ort e d f or a  s u bject, o nl y  t h e ma xi m u m  gra de  o bser ve d 
f or t his P T will be i ncl u d e d i n s u m m ar y of T E A Es b y gra de; t h e s u bject will b e c o u nte d o nl y 
o nce  i n t he n u m ber  of  s u bje cts f or t his P T  a n d o nl y  o nce  f or t he n u m ber  of  s u bj ects f or t he S O C 
t o w hic h t he P T is classifi e d. 
 
A n  o ver vie w  T E A E  s u m mar y ta ble will  b e  pr o vi de d  w hic h  will  i ncl u de t he n u m ber  of  s u bjects 
wit h A Es i n selecte d c ate g ori es. I n a d diti o n, T E A Es will be s u m m ariz e d f or t he f oll o wi n g 
cate g ories, a n d will be ta b ulat e d b y S O C a n d P T, u nl ess ot her wise s pecifi e d.  
• T E A Es  (all gra des,  all ca usalities) 
• Treat me nt -r elat e d T E A Es  (all gra des)  
• T E A Es  b y  ma xi m u m  gra d e  (all ca usalities) 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 7  of  3 5  
 
 
• Treat me nt -r elat e d T E A Es  b y  ma xi m u m  gra de  
• Gra de  3 or  hi g her  T E A Es  (all ca usalities) 
• Gra de  3  or  hi g her  tre at m e nt-relat e d T E A Es  
• Treat me nt -e mer ge nt S A Es  (all ca usalities) 
• T E A Es  res ulti n g i n disc o nti n u ati o n  of  st u d y dr u g  (all ca usalities) 
• T E A Es  res ulti n g i n d ose  h ol d  (all ca usalities) 
• T E A Es  res ulti n g i n d ose  re d ucti o n (all ca usalities) 
• T E A Es  res ulti n g i n d ose  h ol d  or  re d ucti o n (all ca usalities) 
• T E A Es  res ulti n g i n a n y d ose  m o dific ati o n  ( d ose h ol d,  d ose  re d ucti o n a n d/ or 
disc o nti n uati o n)  
• T E A Es  occ urri n g  d uri n g  t h e first 1 0  wee ks  of  treat me nt 
• Treat me nt -r elat e d T E A Es  res ulti n g i n disc o nti n uati o n  of  st u d y dr u g  
• T E A Es  b y  res ol uti o n stat us (res ol ve d/res ol ve d wit h  se q uela e vs.  n ot res ol ve d) 
• Gra de  3  a n d  or  hi g her  T E A Es  b y  r es ol uti o n st at us (res ol ve d/res ol ve d wit h  se q uelae vs. 
n ot res ol ve d)  
• Treat me nt -e mer ge nt S A Es  b y  res ol uti o n stat us (res ol ve d/res ol ve d wit h  se q uel ae vs.  n ot 
res ol ve d) 
• T E A Es  res ulti n g i n deat h  (all ca usalities) 
• Treat me nt -r elat e d T E A Es  res ulti n g i n deat h  
• T E A Es  re p orte d i n ≥ 2 0 %  of  all tre ate d s u bje cts b y P T  (all gra des,  all ca usalities) 
• Gra de  3  or  hi g her  tr eat me nt-e mer g e nt A Es  re p orte d i n ≥ 2 0 %  of  all treate d s u bj ects b y  P T  
(all ca usalities) 
• Treat me nt -e mer ge nt S A Es  re p orte d i n ≥ 2 %  of all  tre ate d s u bjects b y  P T  (all ca usalities) 
• T E A Es  re p orte d i n ≥ 5 % of  s u bjects a n d occ urre d  at ≥2 %  hi g her  i n ci de n ce i n s u bje cts o n  
Ar m  1  (all gra des,  all ca usalities) 
• Gra de  3  or  hi g her  T E A Es  re p orte d i n ≥ 5 %  of  s u bjects o n eit her  ar m (all ca usalities) 
A  b y -s u bject listi n g of  t he f oll o wi n g A E  cat e g ories  will  be  prese nte d.  
• All  A Es  ( T E A Es will  be fla g ge d) 
• All  S A Es  ( T E A Es will  be  fla g ge d) 
• All  S A E  re p orte d wit h  t he ter m dise ase  pr o gressi o n  
• T E A Es  res ulti n g i n d ose  h ol d  
• T E A Es  res ulti n g i n d ose  re d ucti o n 
• T E A Es  res ulti n g i n disc o nti n uati o n  of  st u d y dr u g  
• T E A Es  res ulti n g i n d eat h (see  Secti o n  4. 1 1. 3  f or f ull c haracteriz ati o n  of  deat hs)  
• T E A Es  res ol ve d or  res ol ve d wit h  se q uelae 
• T E A Es  n ot  res ol ve d 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 8  of  3 5  
 
 
4. 1 1. 2. 1  
Ot her  A d verse  E v e nts  of  I nterest 
Select e d Me d D R A P Ts will be c o m bi ne d t o creat e gr o u pe d P Ts or cate g ories t o f urt her 
c haracteriz e  ris ks ass ociate d  wit h  d u velisi b.  T he  f oll o wi n g ris ks will  be  s u m mari ze d as  A d verse 
E ve nt of S pecial I nterest:  
• Diarr hea/c olitis  
• I nfecti o ns 
o  All  i nfe cti o ns, e xcl u di n g P ne u m o nia  a n d C O VI D -1 9  i nfecti o ns 
o  P ne u m o nia  
o  C O VI D -1 9  i nfecti o ns 
• C uta ne o us  reacti o ns 
• N o n -i nfecti o us p ne u m o nitis  
• Ne utr o pe nia  
• He pat ot o xi cit y  (as defi ne d  b y  tra nsa mi nase ele vati o ns) 
T he  s pecifi c P Ts  t hat will  b e  c o m bi ne d  f or e ac h ris k are defi ne d  i n A p pe n di x  1 . 
F or  e ac h ris k, P Ts  will  be  s u m mari ze d at t h e gr o u pe d  P T  a n d i n di vi d ual P T  (a n d gr o u pe d  S O C  if 
a p plic a ble), at t he s u bject le vel:  
• T E A Es  (all gra des,  all ca usalities) 
• Treat me nt -r elat e d T E A Es  (all gra des)  
• Gra de  1  or  2 o nl y  T E A Es  (all ca usalities) 
• Gra de  3 or  hi g her  T E A Es  (all ca usalities) 
• Treat me nt -e mer ge nt S A Es  (all ca usalities) 
• T E A Es  res ulti n g i n d ose  h ol ds  
• T E A Es  res ulti n g i n d ose  re d ucti o ns 
• T E A Es  res ulti n g i n d ose  h ol ds  or re d ucti o ns 
• T E A Es  res ulti n g i n disc o nti n u ati o n  of  st u d y dr u g  (all ca usalities) 
• Ti me  t o i niti al o nset  ( defi ne d as  A E  start date  –  first d ose  date  +  1)  
I n a d diti o n,  t he f oll o wi n g s u m mari es will  be  create d  f or eac h gr o u p e d  P T  wit hi n  eac h  gr o u pe d 
S O C, at t he e ve nt le v el:  
• S u m mar y  of  d ose  m o dificati o ns  
o  N u m ber  of  e ve nts  res ulti n g i n d ose  h ol ds  
o  N u m ber  of  e ve nts  res ulti n g i n d ose  re d ucti o ns 
o  N u m ber  of  e ve nts res ulti n g  i n d ose  h ol ds  or  re d ucti o ns 
o  N u m ber  of  e ve nts  res ulti n g i n disc o nti n uati o n  of  st u d y dr u g  
• S u m mar y  of  o utc o me  
o  N u m ber  of  e ve nts  res ol ve d 
o  N u m ber  of  e ve nts  res ol ve d wit h  se q uelae 
o  N u m ber  of  e ve nts  res ol ve d or  res ol ve d wit h  se q uelae 
o  N u m ber  of  e ve nts  n ot res ol ve d 
• D urati o n  of  A E  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  2 9  of  3 5  
 
 
• C o nc o mit a nt  me dic ati o ns  use d  t o tr eat A Es  ( a s pecifi c list of  c o n c o mita nt me di cati o ns 
ass ociate d wit h ea c h ris k will be pr o vi de d)  
 
F or  ea c h s u bject a n d e ac h A E,  t he w orst  se verit y re c or de d will  be  attri b ute d  a n d use d  i n t h e b y - 
se verit y s u m mari es. Si mil arl y,  t he w orst  ca usalit y  ( m ost rel ate d t o tre at m e nt) will  be  attri b ute d 
a n d use d  i n t he b y -ca usalit y  s u m m aries. If ca usalit y is missi n g,  t he w orst  case will  be  ass u me d 
(relat e d t o tr eat m e nt). 
 
A b y -s u bject listi n g of all A Es (i ncl u di n g n o n-T E A Es) will be pr o vi de d.  T his listi n g will b e 
prese nte d  b y  tre at m e nt gr o u p  a n d will  i ncl u d e: ce nt er,  s u bject i de ntifi er, a ge, se x, rac e, A E  ( S O C, 
P T, a n d ver bati m t er m), date of o nset, date of res ol uti o n, d urati o n, se v erit y, seri o us ness, acti o n 
ta ke n, o ut c o me a n d ca usalit y. 
 
4. 1 1. 3  De at hs,  Seri o us  A d verse  E ve nts,  a n d  Ot her  Si g nific a nt  A d verse  E ve nts  
A  c o m plet e t a b ulati o n of all  deat hs  oc c urri n g  o n  st u d y will  be  pr o vi d e d,  w hic h  will  i ncl u de: 
• All  re p ort e d fatal A Es  
o  Treat me nt -e mer ge nt fatal A Es  b y  S O C  a n d P T  
▪ Deat hs  wit hi n  3 0  da ys  of d u velisi b  last d ose  b y  S O C  a n d P T  
▪ Deat hs  >  3 0 da ys  fr o m d u velisi b last  d ose  b y S O C  a n d P T  
o  Treat me nt -r elat e d treat me nt-e mer g e nt fat al A Es  b y  S O C  a n d P T  
▪ Deat hs  wit hi n  3 0  da ys  of d u velisi b  last d ose  b y  S O C  a n d P T  
▪ Deat hs  >  3 0 da ys  fr o m d u velisi b last  d ose  b y S O C  a n d P T  
o  Fat al  A Es  re p orte d t h at start >  3 0  da ys  p ost  d u velisi b  last d ose  b y  S O C  a n d P T  
T he  f oll o wi n g listi n gs will  als o be  prese nte d:  
• A b y -s u bject listi n g of all deat hs t hat o cc urre d d uri n g t he st u d y will b e prese nt e d a n d will 
disti n g uis h  bet wee n  d eat hs  o n  tre at m e nt (t hr o u g h 3 0  da ys  after  last d ose  of  d u velisi b),  fat al 
A Es o utsi de t he 3 0 da y wi n d o w, a n d d eat hs d uri n g s ur vi val f oll o w -u p  
• A  b y -s u bject listi n g of  all S A Es  
• A  b y -s u bject listi n g of  all A Es  lea di n g t o disc o nti n u ati o n  of  st u d y treat me nt 
• A  b y -s u bject listi n g of  all ot her  si g nifi ca nt A Es  
Listi n gs  will  f oll o w t he f or m at descri b e d f or  A Es  i n Secti o n  4. 1 1. 2,  if a p pr o priate. 
 
4. 1 1. 4  Cli nic al  L a b or at o r y  E v al u ati o n  
 
La b orat or y  tests will  be  re p ort e d se paratel y f or he mat ol o g y  a n d bl o o d  c he mistr y. 
F or  t he p ur p oses of  prese ntati o n i n b ot h ta bl es a n d listi n gs, t he  f oll o wi n g l a b orat or y test res ults 
will be c o n v erte d t o t he I nter nati o nal S yste m of U nits ( SI) bef ore prese ntati o n: s o di u m, 
p otassi u m,  c hl ori d e,  bicar b o nate  ( or C O 2), al b u mi n, t otal pr otei n,  creati ni ne,  uri c  aci d, cal ci u m, 
p h os p h or us,  ma g nesi u m,  gl u c ose,  t otal a n d dir ect  bilir u bi n,  al kali ne p h os p hatase,  re d bl o o d  c ell 
( R B C) c o u nt, he m o gl o bi n, he mat o crit, platelets, w hit e bl o o d cell c o u nt wit h 5-part differe ntial  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3 0  of  3 5  
 
 
perf or me d  m a n uall y  or  b y  fl o w c yt o metr y  (l y m p h oc ytes, ne utr o p hils,  m o n oc ytes,  bas o p hils,  a n d 
e osi n o p hils), a m ylase, li pase, ala ni ne a mi n otra nsferase ( A L T), a n d as partate a mi n otr a nsferase 
( A S T). La b orat or y t ests will be gra d e d ac c or di n g t o C T C A E Versi o n 5. 0 or hi g her. 
If a la b orat or y test val ue is re p orte d usi n g a n o n-n u m eric q ualifi er (e. g., less t ha n [ <] a certai n 
val ue  or  greater  t ha n [ >] a c ertai n  val ue),  t he gi ve n  n u meric  val u e  will  be  use d  i n t he s u m mar y 
statisti cs, i g n ori n g t h e n o n-n u meric q ualifier.  
F or  l a b orat or y tests gr a de d  b y  C T C A E,  t he f oll o wi n g s u m mar y ta bl es will  be  create d  b y 
treat me nt ar m: 
• S u m mar y  of  w orst  p ost -baseli ne  val ue  o n  tr eat me nt, re gar dless of  baseli ne  val u e 
acc or di n g t o t he f oll o wi n g cate g ori es:  
o  A n y  gra de  
o  Gra des  1 - 2  
o  Gra des  3 - 4  
o  Gra de  3  
o  Gra de  4  
• S u m mar y  of  w orst  p ost -baseli ne  val ue  o n  tr eat me nt t hat re prese nts a w orse ni n g  i n gra d e 
fr o m baseli n e acc or di n g t o t h e f oll o wi n g cat e g ories: 
o  A n y  gra de  
o  Gra des  1 - 2  
o  Gra des  3 - 4  
o  Gra de  3  
o  Gra de  4  
La b orat or y  tests wit h  bi -dire cti o n al  gr a des  (e. g., h y p er gl yce mia  a n d h y p o gl y ce mia)  will  be 
prese nte d se paratel y f or eac h directi o n wit hi n ea c h s u m mar y t a ble.  
F or  l a b orat or y tests n ot  gra d e d  b y  C T C A E,  t h e f oll o wi n g s u m mar y ta bl es will  be  create d  b y 
treat me nt ar m: 
• S u m mar y  of  w orst  p ost -baseli ne  val ue  o n  tr eat me nt, re gar dless of  baseli ne  val u e 
acc or di n g t o t he f oll o wi n g cate g ori es:  
o  L o w  (less t ha n l o wer li mit of  n or mal)  
o  N or mal  ( gre ater t ha n or  e q ual t o l o wer li mit of  n or m al  a n d  less t h a n or  e q ual  t o 
u p per li mit of n or m al)  
o  Hi g h  ( greater t ha n u p per  li mit of  n or mal)  
• S u m mar y  of  w orst  p ost -baseli ne  val ue  o n  tr eat me nt t hat re prese nts a w orse ni n g  fr o m 
baseli ne acc or di n g t o t he f oll o wi n g c ate g ories:  
o  L o w  (less t ha n l o wer li mit of  n or mal)  
o  N or mal  ( gre ater t ha n or  e q ual t o l o wer li mit of  n or m al  a n d  less t h a n or  e q ual  t o 
u p per li mit of n or m al)  
o  Hi g h  ( greater t ha n u p per  li mit of  n or mal)  
 
A  s u bject will  b e  defi n e d  as  ha vi n g  a treat me nt-e m er ge nt l a b orat or y a b n or m alit y  if a n y of  t he 
f oll o wi n g c o n diti o ns are satisfie d f or a s pe cifi c la b or at or y para met er: 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3 1  of  3 5  
 
 
 
• La b orat or y r es ult wit hi n t he n or mal ra n g e at b aseli n e a n d eit h er a res ult bel o w t he l o wer 
li mit of  t he n or mal  ra n ge or  a b o v e t he u p per  li mit of  t he n or m al  ra n ge at a n y p ost -baseli ne 
ti me p oi nt o n or bef or e 3 0 da ys after t he l ast d ose of d u velisi b. 
• La b orat or y r es ult bel o w t he l o wer li mit of t he n or mal ra n ge at baseli ne a n d a la b orat or y 
res ult a b o ve t h e u p per  li mit of  t he n or mal  ra n ge at a n y p ost -baseli ne  ti m e p oi nt  o n  or  bef ore 
3 0 da ys after t h e last d ose of d u velisi b.  
• La b orat or y r es ult a b o ve t he u p per li mit of t h e n or mal ra n ge at baseli ne a n d a la b orat or y 
res ult bel o w  t h e l o wer li mit of  t he n or mal  ra n ge at a n y p ost -baseli ne  ti me p oi nt  o n  or  bef ore 
3 0 da ys after t h e last d ose of d u velisi b.  
A b y -s u bject listi n g of all la b or at or y dat a will b e pr o vi de d b y tre at m e nt gr o u p, wit h a b n or mal 
val ues  fl a g ge d, a n d i ncl u d e c e nter,  s u bject i d e ntifier, a ge, se x, r ace, wei g ht  a n d visit.  L a b orat or y 
refere nce r a n ges will als o be liste d. 
La b orat or y  val u es  ( he m at ol o g y, bi oc h e mistr y  a n d uri nal ysis)  will  be  liste d b y  s u bje ct a n d st u d y 
ti me p oi nt i n cl u di n g c ha n ges fr o m b aseli ne ( wit h t he e xce pti o n of uri nal ysis). Baseli ne will be 
defi ne d as descri be d i n Secti o n 4. 2 . 
All  val u es  o utsi de  t he cli nical ref ere nc e ra n ges will  b e  fla g ge d i n t he d ata  listi n gs. T he  a b n or mal 
val ues will b e fla g g e d wit h ‘ L’ f or val ues bel o w t h e l o wer li mit of t he cli nical refere n ce ra n g e 
a n d ‘ H’ f or val ues a b o ve t h e u p per li mit of t he cli nic al refer e nce ra n g e a n d i n cl u de d i n t he 
listi n gs. T he I n v esti gat or will assess w het her t he val ues o utsi de t he cli nical refere n ce ra n g e are 
cli ni call y si g nifi ca nt a n d t hese will be re p orte d as a b n or mal n ot cli nicall y si g nifica nt ( N C S) or 
a b n or mal cli nicall y si g nifica nt ( C S). Cli nic all y si g nifica nt la b orat or y val ues will be  re c or de d b y 
t he I n vesti g at or as A Es. 
Descri pti ve st atistics (f or n o n -cat e g oric al data i n cl u di n g he mat ol o g y a n d bi oc he mistr y) will be 
prese nte d  b y  c o h ort f or b ot h  i n di vi d ual val ues  ( N, m ea n,  S D,  me dia n,  mi ni m u m,  a n d m a xi m u m) 
a n d c ha n ges fr o m b aseli ne.  
B o x pl ots  o ver  ti m e (at ea c h sc he d ule d visit)  will  be  pr o vi de d  f or eac h l a b orat or y para meter.  
4. 1 1. 5  Vit al  Si g ns,  P h ysic al  Fi n di n gs  a n d  Ot her  O bser v ati o ns  Rel ate d  t o S afet y.  
 
4. 1 1. 5. 1  
Vital  Si g ns  
T he  act u al val ues  of  vital si g n  para m eters,  i n cl u di n g te m per at ure, h eart  r ate, wei g ht  a n d s yst olic 
a n d diast oli c B P, will be  prese nte d i n a  b y -s u bject listi n g. Vital si g n para m eter refer e nce ra n g es 
will als o be liste d.  
Bl o o d  press ure  will  be  s u m m ariz e d as  f oll o ws b y  treat me nt ar m: 
• Descri pti ve  st atistics, f or s yst olic a n d diast olic  B P  se paratel y 
o  Baseli ne  val ue  
o  Ma xi m u m  o n -treat me nt val ue  
o  C ha n ge  fr o m baseli ne  t o ma xi m u m  o n -treat me nt val ue  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3 2  of  3 5  
 
 
• Cate g ori cal  s u m mar y of  baseli ne  val ue,  m a xi m u m  o n -treat me nt v al ue  f or s yst olic a n d 
diast oli c B P se parat el y, wit h cate g ories defi n e d as f oll o ws:  
o  Diast olic  B P  
▪ <  8 0 m m H g  
▪ ≥ 8 0 –  8 9 m m H g  
▪ ≥ 9 0 m m H g  
o  S yst olic B P  
▪ <  1 2 0 m m H g  
▪ ≥ 1 2 0 –  1 2 9 m m H g  
▪ ≥ 1 3 0 –  1 3 9 m m H g  
▪ ≥ 1 4 0 m m H g  
• Cate g ori cal s u m mar y of baseli ne val ue, m a xi m u m o n -treat me nt v al ue f or s yst olic a n d 
diast oli c  B P  c o m bi ne d  usi n g  t he c ate g ories  defi n e  a b o ve (i.e., di ast oli c  < 8 0  m m  H g  a n d 
s yst olic < 1 2 0 m m H g, di ast oli c < 8 0 m m H g a n d s yst olic 1 2 0 –  1 2 9 m m H g)  
Heart  rate will  be  s u m m ariz e d as  f oll o ws b y  treat m e nt ar m: 
• Descri pti ve  statisti cs f or baseli ne  val ue,  mi ni m u m  o n -treat me nt v al ue,  ma xi m u m  o n 
treat me nt v al ue, c h a n ge fr o m b aseli n e t o m a xi m u m o n-treat me nt v al ue 
• Cate g ori cal  s u m mar y of  baseli ne  val ue,  mi ni m u m  o n -treat me nt v al ue,  ma xi m u m  o n - 
treat me nt v al ue, wit h cat e g ories defi ne d as f oll o ws:  
o  <  6 0 b p m  
o  ≥ 6 0 –  1 0 0 b p m  
o  >  1 0 0 b p m  
B o x pl ots  o ver  ti m e (at ea c h sc he d ule d visit)  will  be  pr o vi de d  f or ea c h  B P  a n d  heart  rate 
meas ure d.  
 
4. 1 1. 5. 2  
E C G,  E C H O/ M U G A,  a n d P h ysical  E xa mi nati o ns  
 
Per  pr ot oc ol,  E C Gs,  E C H O/ M U G A  res ults, a n d f ull p h ysical  e xa mi nati o ns  fi n di n gs are t o be 
c olle cte d at baseli ne o nl y. B y -s u bj ect listi n g will be pr o vi de d f or ea c h of t hese par a meters.  
 
4. 1 1. 6  S afet y  M o nit ori n g  
N o  data  m o nit ori n g  c o m mittee will  b e  set u p  f or m o nit ori n g t he safet y of st u d y  treat me nt. 
 
4. 1 2  Ot her  A n al yses  
 
4. 1 2. 1  P h ar m ac o ki netics  
T he  P K  data  c olle cte d  will  be  a nal y ze d  b y  sta n dar d p o p ulati o n  P K  met h o ds,  usi n g  a p pr o pri ate 
s oft ware. T he i nte nt of t his a nal ysis is t o c hara cterize t he para met ers of P K dis p ositi o n.  
A d diti o nal e x pl orati o n of t h e relati o ns hi p bet wee n d u velisi b e x p os ure a n d safet y or effica c y 
assess me nts  ma y  b e  c o m plet e d.  If t her e is o nl y  a li mite d a m o u nt of  plas m a  c o nc e ntrati o n  d ata  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3 3  of  3 5  
 
 
fr o m t his st u d y, t he data  ma y  be  p o ole d  wit h  t he res ults of  ot her  st u dies t o perf or m  t he p o p ulati o n 
P K a nal ysis. A se parate P K a nal ysis pl a n ma y be d e vel o pe d.  
4. 1 2. 2  Q u alit y  of  Life  ( Q o L) 
 
4. 1 2. 2. 1  
E C O G  Perf or ma n ce  Stat us  
S u m maries  of  E C O G  p erf or ma n ce  stat us will  be  pres e nte d  b y  visit.  S hift  ta bles f or c h a n ge i n 
E C O G perf or m a nce sc ore fr o m baseli ne b y w orst p ost -baseli ne sc or e will b e pr o d uce d.  
A  b y -s u bject listi n g of  E C O G  perf or ma nc e  stat us dat a  will  be  pr o vi de d.  
4. 1 2. 2. 2  
E Q -5 D -3 L  Sc ores  
 
T he E Q -5 D -3 L c o nt ai ns a descri pti ve s yste m wit h o ne res p o nse f or eac h of t h e 5 di m e nsi o ns 
( m o bilit y, self-care,  us ual  a cti viti es,  pai n/ disc o mf ort,  a n d a n xiet y/ de pr essi o n).  T he  first res p o nse 
is c o de d as 1 (i n di cati n g n o pr o ble ms), t he sec o n d res p o nse is c o de d as a 2 (i n di cati n g s o me 
pr o ble ms), a n d t h e t hir d r es p o nse is c o de d as a 3 (i n dicati n g e xtr e me pr o ble ms). A m bi g u o us 
res p o nses (e. g., m ore t ha n o ne r es p o nse i n a di me nsi o n, if a p pli ca bl e) are tr eat e d as missi n g 
val ues.  T h e  E Q -5 D  als o c o ntai ns  a Vis ual  A nal o g  Sc ale  ( V A S) f or healt h  st ate ra n gi n g fr o m 0  t o 
1 0 0, w here 0 re prese nts w orst i ma gi na bl e healt h stat e a n d 1 0 0 re prese nts t he best i ma gi n a ble 
healt h st ate. A m bi g u o us val ues (t h e li ne cr osses t he V A S t wice) s h o ul d be treate d as missi n g 
val ues.  
F or  ea c h di me nsi o n  of  t he descri pti ve  s yste m, t h e n u m ber  a n d  perce nta ge  of  s u bjects wit h  n o 
pr o ble ms, s o me pr o bl e ms, a n d e xtre me pr o ble ms will be re p ort e d at eac h visit.  
S u m mar y  statisti cs f or t h e V A S  of  healt h  state a n d t h e c ha n ges fr o m  baseli ne  will  b e  re p ort e d f or 
eac h visit. B y -s u bject listi n g of t hese d ata will be pr o vi de d.  
 
Als o  refer t o t he E Q -5 D -3 L  user  g ui de  [ 4] f or a d diti o nal c o nsi derati o ns. 
 
4. 1 2. 3  Ot her  E x pl or at or y  A n al yses  
T he  ot her  e x pl orat or y  e n d p oi nts,  i ncl u di n g bi o mar ker  e n d p oi nts,  will  be  s u m m ariz e d 
descri pti v el y. A se parate a nal ysis pla n m a y be de v el o pe d f or f or mal a nal yses.  
 
 
4. 1 3  Deter mi n ati o n  of  S a m ple  Size  
 
T he  sa m ple size f or eac h  ar m was  cal c ulate d  usi n g  a 2 -sta ge a p pr oac h. 
F or  e ac h ar m: i n Sta ge  1,  1 5  s u bjects will  be  r a n d o mi ze d. T he  e val uati o n  of  t h e first sta ge will 
ta ke pl ace after t h e 1 5 e nr olle d s u bje cts ha ve b ee n f oll o we d f or a mi ni m u m of 3 c ycles ( 1 8 
wee ks).  
If t here ar e fe wer t ha n 6 res p o n ders  ( P R or  C R)  a m o n g  t he first 1 5  s u bjects, c o nsi derati o n  ma y  be 
gi ve n t o t er mi n ate t he tre at m e nt ar m. T he d ecisi o n t o pr ocee d t o St a ge 2 will be base d o n t h e 
t otalit y of dat a o bser ve d, i n cl u di n g t y pes of res p o nses, safet y data, a n d disc o nti n uati o n rates. T h e 
treat me nt ar m m a y als o n ot pr oc ee d t o St a ge 2 if t he t otalit y of t h e dat a is vie we d as c o m pelli n g; 


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3 4  of  3 5  
 
 
s uc h sce nari os c o ul d i ncl u d e ( b ut are n ot li mit e d t o) acc u m ulati n g e n o u g h data i n Sta g e 1 t o 
c o ncl u de t he O R R e xc ee ds 3 0 %. If t he tr eat me nt ar m pr ocee ds t o St a ge 2, u p t o 3 6 a d diti o nal 
s u bjects will b e e nr olle d f or a t otal of 5 1. If f e wer t h a n 2 2 ( 4 3 %) res p o n ders ( P R or C R) are 
o bser ve d  i n 5 1  s u bjects, c o nsi derati o n ma y  b e  gi v e n  t o c o ncl u d e t h at t he treat me nt sc he d ule d oes 
n ot warra nt f urt h er st u d y i n t his p o p ulati o n. T he fi n al e val u ati o n of eac h sc he d ule will be base d 
o n t he t ot alit y of dat a o bser ve d, i ncl u di n g t y p es of res p o nses, safet y data, a n d disc o nti n u ati o n 
rates. T his desi g n yiel ds a t y pe I err or rate of 0. 0 2 5 ( 1-si de d) a n d p o wer of 9 0 % u n der t he 
ass u m pti o ns descri be d a b o ve.  
S u bjects will b e stratifie d b y n u m ber of pri or t h era pi es ( 1 or > 1), b ul k y disease stat us (l o n gest 
dia meter  of  baseli ne  l esi o n <  5  c m or  ≥ 5  c m) a n d ti me si nce l ast rec urre nc e ( ≥ 2 4  m o nt hs  or  <  2 4 
m o nt hs).  
N ote: “ E nr olle d ” mea ns s u bje cts’, or t heir le g all y ac ce pta ble re prese ntati ve’s, a gre e me nt t o 
partici pat e i n a cli nical st u d y f oll o wi n g c o m pleti o n of t he i nf or m e d c o nse nt pr oc ess. P ote ntial 
s u bjects w h o  are pr e -scree ne d f or t he p ur p ose  of  d eter mi ni n g  eli gi bilit y f or t he st u d y b ut  d o  n ot 
si g n a n i nf or me d c o nse nt f or m (I C F) are n ot c o nsi dere d e nr oll e d.  
 
 
4. 1 4  C h a n ges  i n t he C o n d uct  of  t he St u d y or  Pl a n ne d A n al ysis  
 
A d diti o nal  a nal yses  n ot  s pe cifi e d i n t his S A P  ma y  be  c o n d ucte d,  if ne cessar y.  I n s uc h cases,  a 
se parate a nal ysis pla n will be  creat e d t o d oc u me nt s uc h a nal yses. T he  S A P will be  u p date d as 
necessar y if t h e pr ot oc ol is a me n d e d.  
5  
R E F E R E N C E S  
 
[ 1] Si m o n, R. O pti mal t w o -sta ge d esi g ns f or p hase II cli nical trials. C o ntr oll e d Cli nical Trials 
1 9 8 9; 1 0( 1); 1 -1 0.[ 1] C hes o n B D, Pfist ner B, J u wei d M E, et al. R e vise d res p o nse criteri a f or 
mali g n a nt  l y m p h o m a. J o ur n al  of  cli nic al  o nc ol o gy  : offici al  j o ur n al of  t h e A meric a n  S ociet y  of 
Cli nic al O nc ol o gy. 2 0 0 7; 2 5( 5): 5 7 9 -5 8 6.  
 
[ 2] C hes o n  B D,  Fis her  RI,  Barri n gt o n  S F,  et al. R ec o m m e n dati o ns  f or i nitial e v al uati o n,  st a gi n g, 
a n d res p o nse assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o m a: t h e L u ga n o classifi cati o n. 
J o ur n al of cli nic al o nc ol o g y : offici al j o ur n al of t he A meric a n S oci ety of Cli nic al O nc ol o gy. 
2 0 1 4; 3 2( 2 7): 3 0 5 9 -3 0 6 8.  
 
[ 3] S A S ®  Versi o n  9. 3  of  t he S A S  S yste m  f or Pers o nal  C o m p uters.  C o p yri g ht  ©  2 0 1 1.  S A S 
I nstit ute I n c. S A S a n d all ot h er S A S I nstit ute I nc. pr o d uct or ser vic e na mes ar e re gist ere d 
tra de m ar ks or tra de m ar ks of S A S I nstit ute I nc., Car y, N C, U S A. 
[ 4] E Q -5 D -3 L  User  G ui de  ( Versi o n 6. 2 0 1 8)  
htt ps://e ur o q ol. or g/ w p -c o nte nt/ u pl oa ds/ 2 0 1 8/ 1 2/ E Q -5 D -3 L -User -G ui de _ versi o n -6. 0. p df.  
Accesse d J u ne 3, 2 0 1 9.  


P A R E X E L  I nt er nati o nal 
V S -0 1 4 5 -2 2 9  
Statistical  A nal ysis  Pla n  
T P -G D O -W W -0 1 6 -0 7.a  
Effecti ve Date:  3 0 J a n 1 9 
R elate d  t o: S O P -G D O -W W -0 1 9  
C O N FI D E N TI A L  
Pr oject  D oc u m e nt  Versi o n  N o . 3. 0  
Pr oject  D oc u m e nt  Eff ecti ve  D ate : Date  of  last si g nat ure 
Pa ge  3 5  of  3 5  
 
 
 
 
6  
A P P E N DI X  
 
A p pe n di x  1:  List  of  Preferre d  Ter ms  f or A d verse  E ve nts  of  S peci al  I nterest 
 
 
Gr o u pe d  Ter m  
Pr efe rr e d  Ter ms  
All  i nf e cti o ns (e xcl u di n g 
P ne u m o nia  a n d C O VI D - 
1 9 i nfecti o ns) 
All  preferre d  ter ms u n der  S O C  =  ‘I nfe cti o ns I nfe cti o ns a n d i nfestati o ns’ e xcl u di n g 
a n y preferre d ter m c o ntai ni n g t he w or d ‘ p ne u m o nia’ a n d e xcl u di n g a n y preferre d  
ter ms i ncl u de d i n t he C O VI D -1 9  i nfe cti o ns Gr o u pe d  Ter m.  
Diarr hea  
Diarr h oe a,  Diarr h oea  he m orr ha gic,  Defec ati o n  ur ge nc y  
C olitis  
C olitis,  C olitis  er osi ve,  E nter oc olitis,  E nter oc olitis  he m orr ha gic,  C olitis 
micr osc o pic, Ne cr otisi n g c olitis, C olitis ulc erati ve  
 
P ne u m o nia  
P ne u m o nia,  a n y P T  c o ntai ni n g  t he w or d/stri n g  " p ne u m o nia" e xc e pt f or 
" P ne u m o nia as pirati o n",  At y pical  p n ue m o nia,  At y pical  m yc o ba cterial  p n ue m o nia, 
Br o nc h o p ne u m o nia, Br o nc h o p ul m o nar y as per gill osis  
P ne u m o nitis  
P ne u m o nitis,  I nterstitial l u n g disease,  l u n g i nfiltrati o n, a c ute  i nterstitial 
p ne u m o nitis  
 
 
Tr a nsa mi nase  ele vati o n 
Ala ni ne a mi n otra nsferase i ncrease d, As partate a mi n otra nsferase i ncre ase d, 
Tr a nsa mi nases i ncre ase d, H y pertra nsa mi nasa e mia, He patic e nz y me i ncr ease d,  
Ac ute  he patic  fail ure, Dr u g -i n d uce d li ver i nj ur y, He patic  fail ure, He pat ocell ular 
i nj ur y, He pat ot o xicit y 
 
 
 
 
 
 
 
 
C uta ne o us  reacti o ns 
Der matitis, Der matitis aller gic, Der matitis b ull o us, Der matitis e xf oliati ve, 
Der matitis ps oriasif or m, Dr u g er u pti o n, Dr u g rea cti o n wit h e osi n o p hilia a n d 
s yste mic s y m pt o ms, Er yt he ma, Er yt he ma m ultif or me, Ge neralise d er yt he ma, 
E xf oliati ve ras h, Ras h, Ras h ge neralise d, Ras h er yt he mat o us, Ras h f ollic ular, 
Ras h ma c ular, Ras h ma c ul o -pa p ular, Ras h mac ul o vesic ular, Ras h pa p ular, Ras h 
pa p ul os q ua m o us, Ras h pr uritic, Ras h p ust ular, Ras h vesic ular, T o xic s ki n 
er u pti o n, Pal mar er yt he ma, Pal m o pla ntar kerat o der ma, Pal mar -pla ntar 
er yt hr o d ysest hesia  s y n dr o me, Peri vasc ular  der matitis,  S ki n  rea cti o n, s ki n t o xicit y, 
Ste ve ns -J o h ns o n s y n dr o me, T o xic  e pi der mal necr ol ysis  
Ne utr o pe nia  
Ne utr o pe nia,  Ne utr o p hil  c o u nt decrease d  
 
 
 
 
 
C O VI D -1 9  i nfe cti o ns 
As y m pt o matic  C O VI D -1 9,  C o n ge nital  C O VI D -1 9,  C or o na vir us  i nfe cti o n, 
C or o na vir us test p ositi ve, , C O VI D -1 9 p ne u m o nia, C O VI D -1 9 treat me nt, 
M ultis yste m i nfla m mat or y s y n dr o me i n c hil dre n,  
P ost -a c ute  C O VI D -1 9  s y n dr o me, S A R S -C o V -2  R N A  decre ase d,  S A R S -C o V -2 
R N A fl uct uati o n, S A R S -C o V -2 R N A i ncrease d, S A R S -C o V -2 se psis, S A R S - 
C o V -2 test false ne gati ve, S A R S -C o V -2 test p ositi ve, S A R S -C o V -2 vir ae mia,  
S us pecte d  C O VI D -1 9,  Va cci ne  deri ve d  S A R S -C o V -2  i nfecti o n 


D oc u me nt  I D: 7 3 2 0 1 5 8 8 8  - Na me  at P u blicati o n:  2 4 3 6 6 1 _ V S -0 1 4 5 -2 2 9 _ S A P _ 2 0 2 3 0 8 0 9 _ v 3. 0. d oc x 
T his d oc u me nt c o ntai ns a t otal of 3 6 pa ges i ncl u di n g a n y si g nat ure pa ge/s.  
 
 
P A R E X E L  I nt er n ati o n al El e ctr o ni c  Si g n at ur e  P a g e  
T his pa ge is t he ma nifestati o n of t he electr o nic si g nat ure(s) us e d i n c o m plia nce wit h P A R E X E L 
I nter nati o nal’s electr o nic  si g nat ure p olicies  a n d pr oce d ures  a n d i n c o m plia nce  wit h  a p plica ble  re g ulati o ns. 
 
 
 
 
 
User Na me:
 
Titl e:  
 
Date:  T h urs da y,  3 1  A u g ust  2 0 2 3,  0 2: 4 6  P M  G M T  Sta n dar d  Ti me 
Mea ni n g: D oc u m e nt c o nte nts a p pr o ve d.  
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =