Clinical trial NCT03801525
Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: CLL SLL
Sponsor: TG Therapeutics, Inc.
Start date: 2019-05-16; Completion date: 2022-12-20
Enrollment: 277 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
ULTRA-V: Study to Assess the Efficacy and Safety of Ublituximab in Combination with Umbralisib and Venetoclax (U2-V) Compared to Ublituximab and Umbralisib (U2) in Subjects with Chronic Lymphocytic Leukemia (CLL)

Detailed description:
This is an open-label, multicenter, Phase 2/3 study to evaluate the efficacy and safety of the combination of ublituximab + umbralisib + venetoclax (U2-V) compared to the combination of ublituximab + umbralisib (U2) in participants with either treatment naïve or previously treated CLL/ small lymphocytic lymphoma (SLL).

Arms: arm 1: Participants were administered ublituximab, 150 milligrams (mg), intravenous (IV) infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6; umbralisib, 800 mg, oral tablet, once daily (QD) through Cycles 1-24; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-24. MRD positive participants were administered umbralisib, 800 mg, oral tablet, QD, on Days 1-28 from Cycle 25 onwards (1 Cycle = 28 days), until disease progression, unacceptable toxicity, or withdrawal from the study. arm 2: Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, 9,12, and 15; umbralisib, 800 mg, oral tablet, QD through Cycles 1-15; venetoclax, oral tablet, QD, 20 mg on Days 1-7, 50 mg on Days 8-14, 100 mg on Days 15-21, 200 mg on Days 22-28 of Cycle 4, followed by 400 mg on Days 1-28 of Cycles 5-15 (1 Cycle = 28 days). arm 3: Participants were administered ublituximab, 150 mg, IV infusion on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1, followed by 900 mg on Day 1 of Cycles 2-6, then every three cycles along with umbralisib, 800 mg, oral tablet, QD (1 Cycle = 28 days) from Cycle 1 until disease progression, unacceptable toxicity, or withdrawal from the study.
Interventions: intervention 1: Ublituximab intervention 2: Umbralisib intervention 3: Venetoclax
Intervention descriptions: intervention 1: * recombinant chimeric anti-CD20 (cluster of differentiation 20) monoclonal antibody
* administered as an IV infusion intervention 2: * inhibitor of phosphoinositide 3-kinase (PI3K) delta and casein kinase 1 epsilon (CK1e)
* Tablet form intervention 3: * B-cell lymphoma 2 (BCL-2) inhibitor
* Tablet form

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: Phase 2/3 Randomized Study to Assess the Efficacy and Safety of 
Ublituximab in Combination with Umbralisib and Venetoclax (U2-V) Compared to 
Ublituximab and Umbralisib (U2) in Subjects with Chronic Lymphocytic Leukemia 
(CLL)  
NCT Number: NCT03801525
Document Date: Protocol version 4: 5-October-2021


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Local Protocol #:
Protocol U2-VEN-207 
TITLE: ULTRA-V: Phase 2/3 Randomized Study to Assess the Efficacy and Safety of 
Ublituximab in Combination with Umbralisib and Venetoclax (U2-V) Compared to 
Ublituximab and Umbralisib (U2) in Subjects with Chronic Lymphocytic Leukemia (CLL)  
Sponsor:
TG Therapeutics, Inc. 
2 Gansevoort Street, 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
IND Number: 
114,779
Study Drugs: 
Ublituximab, umbralisib, venetoclax 
Study Chair:   
 MD 
Tel: 
Medical Monitor:
 MD 
TG Therapeutics 
Tel:
Study Coordination: 
TG Therapeutics, Inc. 
2 Gansevoort Street, 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
Version: 1.0 
Date:  15 August 2018
Version: 1.1 
Date:  01 November 2018 
Version: 2.0 
Date:  07 October 2019 
Version: 3.0  
Date:  04 January 2021  
Version: 4.0
Date: 05 October 2021 
This document is a confidential communication of TG Therapeutics, Inc. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein shall be 
published or disclosed without prior written approval, except that this document may be disclosed to 
the appropriate Institutional Review Boards/Independent Ethics Committees under the condition that 
they keep it confidential.




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PROTOCOL ACCEPTANCE FORM 
Protocol Title: 
ULTRA-V: Phase 2/3 Randomized Study to Assess the 
Efficacy and Safety of Ublituximab in Combination with 
Umbralisib 
and 
Venetoclax 
(U2-V) 
Compared 
to 
Ublituximab and Umbralisib (U2) in Subjects with Chronic 
Lymphocytic Leukemia (CLL)
Protocol Number:
U2-VEN-207 
Date FINAL:
05 October 2021 
I have read the attached protocol and agree that it contains all the necessary details for performing 
U2-VEN-207. 
I will provide copies of the protocol and of the ublituximab and umbralisib Investigator’s Brochures, 
which were given to me by TG Therapeutics (Sponsor), to all members of the study team for whom I 
am responsible and who participate in the study. I will discuss this material with them to ensure that 
they are fully informed regarding venetoclax, ublituximab, and umbralisib, and the conduct of the 
study. 
Once the protocol has been approved by the Institutional Review Board (IRB), I will not modify this 
protocol without obtaining the prior approval of TG Therapeutics and of the IRB. I will submit the 
protocol modifications and/or any informed consent modifications to TG Therapeutics and the IRB, 
and approval will be obtained before any modifications are implemented. 
I understand the protocol and will work according to it, the principles of Good Clinical Practice 
(current ICH guidelines), and the Declaration of Helsinki (1964).  
Print Name 
Signature 
Date 


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TABLE OF CONTENTS 
Summary of Amendments .................................................................................................................. 8
STUDY SYNOPSIS ................................................................................................................................. 12
List of Abbreviations .......................................................................................................................... 22
1 Introduction ...................................................................................................................................... 26
1.1 Chronic Lymphocytic Leukemia .......................................................................................................................... 26
1.2 Ublituximab ................................................................................................................................................................. 26
1.2.1 Pre-Clinical Evaluations of Ublituximab ............................................................................................................................................. 27
1.2.2 Clinical Development of Ublituximab .................................................................................................................................................. 27
1.3 Umbralisib .................................................................................................................................................................... 30
1.3.1 Pre-Clinical Development of umbralisib ............................................................................................................................................. 30
1.3.2 Clinical Development of Umbralisib ..................................................................................................................................................... 32
1.4 Ublituximab and Umbralisib (U2) Combination .......................................................................................... 36
1.5 Venetoclax in CLL ...................................................................................................................................................... 36
1.6 Rationale/Hypothesis for U2 + Venetoclax Combinations ....................................................................... 37
2 Objectives and Endpoints ............................................................................................................. 38
2.1 Study Objectives ........................................................................................................................................................ 38
PHASE 2 STUDY OBJECTIVES ............................................................................................................................................................................. 38
PHASE 3 STUDY OBJECTIVES ............................................................................................................................................................................. 38
2.2 Efficacy Endpoints .................................................................................................................................................... 38
3 Eligibility Criteria ............................................................................................................................ 40
3.1 Inclusion Criteria ....................................................................................................................................................... 40
3.2 Exclusion Criteria ...................................................................................................................................................... 40
4 Study Design ...................................................................................................................................... 43
4.1 Overview of Study Design ...................................................................................................................................... 43
4.2 Efficacy and Safety Analyses ................................................................................................................................. 44
4.3 Registration and Randomization/Blinding .................................................................................................... 45
4.4 Study Sites .................................................................................................................................................................... 45
4.5 Discontinuation from Study .................................................................................................................................. 45
5 Study Assessment and Treatment Schedule (Phase 2) ...................................................... 46
6 Study Assessment and Treatment Schedule (Phase 3) ...................................................... 48
7 Laboratory Assessments ............................................................................................................... 51
7.1 Local Laboratory Assessments ............................................................................................................................ 51


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7.2 Central Laboratory Assessments ........................................................................................................................ 51
7.2.1 Sparse Sampling Pharmacokinetics (Subjects Enrolled to Phase 3 Only) ............................................................................ 52
 ........................................................................................ 53
7.2.3 Immunogenicity Assessment (Subjects Enrolled to Phase 3 Only) ......................................................................................... 53
8 Treatment Plan ................................................................................................................................. 55
8.1 Treatment Summary ................................................................................................................................................ 55
8.2 V1.0-2.0 – Subjects enrolled to Phase 2 U2-V Regimen ............................................................................. 55
8.3 (Protocol V3.0) Arm A Ublituximab + Umbralisib + Venetoclax (U2-V) Regimen ......................... 55
8.4 (Protocol V3.0) Arm B Ublituximab + Umbralisib (U2) Treatment Regimen .................................. 56
8.5 Agent Administration .............................................................................................................................................. 56
8.5.1 Guidelines for Administration of Ublituximab ................................................................................................................................. 57
8.5.2 Guidelines for Administration of Umbralisib ................................................................................................................................... 60
8.5.3 Guidelines for Administration of Venetoclax .................................................................................................................................... 62
8.5.4 Dose Hold/Modification: ublituximab, Umbralisib and Venetoclax ....................................................................................... 65
9 Study Medication Overview and Safety .................................................................................... 71
9.1 Ublituximab ................................................................................................................................................................. 71
9.2 Umbralisib .................................................................................................................................................................... 72
9.3 Ublituximab + Umbralisib Safety Information .............................................................................................. 72
9.4 Venetoclax .................................................................................................................................................................... 72
9.4.1 Adverse Reactions Reported in > 10% (Any Grade) of Subjects With CLL/SLL ................................................................ 73
9.4.2 Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in Subjects with CLL/SLL .............. 73
10 MEASUREMENT OF EFFECT ....................................................................................................... 75
10.1 Measurement of Effect and Method of Assessment.................................................................................. 75
10.2 Response Review .................................................................................................................................................... 75
10.3 Identification and Measurement of Tumor Lesions and Organomegaly ......................................... 75
10.3.1 Target Lesions ............................................................................................................................................................................................. 76
10.3.2 Spleen and Liver ......................................................................................................................................................................................... 76
10.3.3 Non-Target Lesions ................................................................................................................................................................................... 77
10.4 Definitions of Tumor Response and Progression ...................................................................................... 77
10.4.1 Complete Response ................................................................................................................................................................................... 77
10.4.2 Complete Response with incomplete marrow recoverY (CRi) ............................................................................................... 78
10.4.3 Partial Response......................................................................................................................................................................................... 78
10.4.4 Partial Response with PeristEnt Lymphocytosis (PR-L) ........................................................................................................... 78
10.4.5 Stable Disease .............................................................................................................................................................................................. 78
10.4.6 Definitive Disease Progression ............................................................................................................................................................ 79
10.4.7 Non-Evaluable ............................................................................................................................................................................................. 80
10.4.8 Lymphocytosis During Therapy .......................................................................................................................................................... 80


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11 Statistical Considerations .......................................................................................................... 81
11.1 Sample Size and Power ........................................................................................................................................ 81
11.2 General Analysis Convention ............................................................................................................................. 82
11.3 Analysis Population ............................................................................................................................................... 82
11.4 Subject Disposition ................................................................................................................................................ 83
11.5 Subject Demographics and Baseline Characteristics ............................................................................... 83
11.6 Medical History ........................................................................................................................................................ 83
11.7 Extent of Exposure ................................................................................................................................................. 83
11.8 Efficacy Analyses ..................................................................................................................................................... 83
11.9 Safety Analyses ........................................................................................................................................................ 84
11.10 Missing Value Handling Procedures ............................................................................................................ 84
11.11 Statistical Analyses .............................................................................................................................................. 84
11.11.1 Primary Efficacy Variables .................................................................................................................................................................. 84
11.11.2 Secondary Efficacy Outcomes ............................................................................................................................................................ 85
11.11.3 Interim Analyses ..................................................................................................................................................................................... 86
11.11.4 Multiplicity of Phase 3 Part ................................................................................................................................................................. 87
11.11.5 Stopping Rules .......................................................................................................................................................................................... 87
12 Adverse Event Reporting and Criteria ................................................................................... 88
12.1 Definition of Adverse Event ............................................................................................................................... 88
12.2 Criteria for Serious Adverse Events (SAE) ................................................................................................... 88
12.2.1 Adverse Event/Serious Adverse Event Grading ........................................................................................................................... 89
12.2.2 Adverse Events / Serious Adverse Event Causality Assessment ........................................................................................... 90
12.2.3 Adverse Event/Serious Adverse Event Recording ...................................................................................................................... 90
12.3 Diagnosis vs. Signs and Symptoms .................................................................................................................. 91
12.4 Persistent or Recurrent Adverse Events ....................................................................................................... 92
12.5 Deaths .......................................................................................................................................................................... 92
12.6 Hospitalization, Prolonged Hospitalization, or Surgery ......................................................................... 92
12.7 Pre-Existing Medical Conditions ...................................................................................................................... 92
12.8 Pregnancy .................................................................................................................................................................. 93
12.9 Study Drug Overdose ............................................................................................................................................ 93
13 Clinical Data Collection and Monitoring ............................................................................... 95
13.1 Data and Safety Monitoring Board .................................................................................................................. 95
13.2 Site Monitoring Plan .............................................................................................................................................. 95
13.3 Curricula Vitae and Financial Disclosures .................................................................................................... 95
13.4 Data Ownership and Publication...................................................................................................................... 95


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14 Ethical, Financial, and Regulatory Considerations ........................................................... 96
14.1 IRB Approval ............................................................................................................................................................ 96
14.2 Regulatory Approval ............................................................................................................................................. 96
14.3 Insurance and Indemnity .................................................................................................................................... 96
14.4 Informed Consent ................................................................................................................................................... 96
14.5 Confidentiality.......................................................................................................................................................... 97
14.6 Investigator and Staff Information .................................................................................................................. 98
14.7 Financial Information ........................................................................................................................................... 98
15 RECORD RETENTION AND DOCUMENTATION OF THE STUDY ...................................... 99
15.1 Documentation Required to Initiate Study .................................................................................................. 99
15.2 Study Documentation and Storage .................................................................................................................. 99
15.3 Amendments to the Protocol .......................................................................................................................... 100
15.4 Data Collection ...................................................................................................................................................... 101
15.5 Study Monitoring, Auditing, and Inspecting ............................................................................................. 101
15.6 Quality Assurance and Quality Control ...................................................................................................... 101
15.7 Disclosure and Publication Policy ................................................................................................................. 102
16 References .................................................................................................................................... 103
17 Appendix A - Contraception Guidelines ............................................................................. 108
18 Appendix B – NYHA Classifications ...................................................................................... 110
19 Appendix C – Hepatitis B Serologic Test Results ............................................................. 111
20 Appendix D – CYP3A Inducers, CYP3A Inhibitors, P-gp inhibitors and P-gp 
substrates ........................................................................................................................................... 112


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SUMMARY OF AMENDMENTS 
Version 1.1 (Dated 1 November 2018) of this protocol contains the following modifications: 
x
Typographical and administrative errors and inconsistencies were corrected throughout, 
including: 
o
The response assessment schedule by CT and/or MRI was clarified throughout to be 
“within 14 days prior to Cycles 4 & 13, and at least once every 12 cycles thereafter”; 
o
The footnotes in the study assessment table in Section 5 were corrected for 
misalignment. Serum pregnancy test was added within 3 days prior to Day 1 of Cycle 
1. 
x
Sections 1.5 and 1.6 were added to provide background information on venetoclax and 
rationale for the study; 
x
Section 6.2.3.3 was revised to allow dose delays of any study medication for durations longer 
than 28 days to recover from toxicity. All dose modifications should now be reported in the 
IWRS, with questions regarding dose modifications referred to TG Therapeutics; 
x
Section 6.2.1.3.1 was amended to provide dilution infusions for both the 25 mg/mL and 10 
mg/mL concentration vials of ublituximab; 
x
The sample size was adjusted from 60 patients to 90 patients and divided into 2 cohorts of 
approximately 60 non-BTK-refractory patients and approximately 30 BTK-refractory 
patients. 
Version 2.0 (Dated 07 October 2019) of this protocol contains the following modifications: 
•
Language was modified throughout to effect addition of 60 subject cohort of treatment naïve 
CLL; 
•
Synopsis and Section 3 Eligibility Criteria: 
o
Inclusion #1 updated to allow patients with treatment naïve CLL; 
o
Inclusion #2 updated to specify that adequate organ system function must be 
independent of growth-factor or transfusion support, and creatinine clearance 
requirement was lowered from >50 mL/min to >30 mL/min; 
o
Exclusion #1 was updated to lower the washout period for prior BTK inhibitors from 
21 days to 7 days; 
o
Exclusion #3 was reworded for clarity, and to suggest antiviral prophylaxis for HBV 
reactivation for subjects that are HBc antibody positive at Investigator discretion; 
o
Exclusion # 8 added to ensure patients with known barriers to obtaining access to 
commercially available venetoclax are not enrolled; 
•
Updated to clarify adverse events will be assessed and reported using the most up to date NCI 
Common Terminology Criteria for Adverse Events (CTCAE) V5.0; 
•
Reference to 10 mg/mL formulation of ublituximab removed throughout as this formulation 
is not available; 
•
Study Assessment Tables: 
o
Updated for clarity; 
o
End of Study visit added; 
o
The window for baseline bone marrow was extended to within 90 days of C1D1; 
o
The window for baseline FISH and TP53 was extended to within 60 days of C1D1; 
o
If IGHV status is found within the medical history, it does not need to be repeated; 


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o
Schedule of response assessment updated to align with study visits; 
o
The schedule for MRD testing clarified; 
•
Efficacy Endpoints updated for consistency in wording throughout the protocol. Time to 
response was added as an efficacy endpoint; 
•
Statistical Considerations updated in synopsis and body to remove reference to multi-arm 
comparisons and to clarify statistical testing; 
•
Section 5.1 Laboratory Assessment: 
o
Updated to clarify local labs required per the protocol. Updated to reflect CLL 
mutation panel to be done at local labs rather than at the central lab; 
•
Section 11 – Adverse Event Reporting Criteria updated to clarify criteria for event reporting 
and proper forms for reporting safety events. Typographical errors corrected throughout. 
Version 3.0 (Dated 04 January 2021) of this protocol contains the following modifications: 
x
Study title updated to reflect new study design; 
x
Study cover page updated with new medical monitor name and contact information; 
x
Introduction, overview of study drugs, and rationale for study drug combinations and study 
design updated; 
x
Phase 3 Study Objectives added; 
x
Eligibility criteria updated as follows: 
o
Inclusion #1 removed qualifier that initial absolute lymphocyte count (ALC) was to 
be ≥30,000/μL; updated to clarify exclusion for prior steroid use; 
o
Inclusion #6 updated to reflect requirement for contraception for 4 months after last 
dose of ublituximab, umbralisib or venetoclax;  
o
Exclusion #3 updated to clarify virology testing; 
o
Exclusion #8 updated to clarify that known barriers to commercially available 
venetoclax are exclusionary; 
o
Exclusion #14 updated to clarify unacceptable previous malignancies; 
x
Study Design updated to include a randomized Phase 3 component; 
x
Registration and Randomization updated to reflect a randomized Phase 3 design; 
x
Study Assessment and Treatment Schedule for subjects enrolled to V3.0, randomized Phase 
3 stage of the trial added; 
x
Local laboratory assessments updated to reflect CLL mutation panel is no longer required to 
be sent to the local lab and will be sent to the central laboratory; 
x
Central Laboratory assessments – updated to reflect central laboratories are required for 
subjects enrolled to the Phase 2 and Phase 3 stages; 
x
Treatment Summary updated to reflect the schedule for subjects enrolled to the Phase 3 stage 
of the trial for both the U2-V and U2 regimens; 
x
Agent administration - ublituximab section updated to include information on monitoring for 
hepatitis b reactivation and treatment for suspected hepatitis b reactivation; 
x
Ublituximab medication overview updated with all applicable information related to the 
addition of ublituximab 36mL vials (900 mg); 
x
Statistical considerations added for the Phase 3 randomized stage of the study; 
x
Typographical and grammatical errors corrected throughout. 
Version 4.0 (Dated 05 October 2021) of this protocol contains the following modifications:  
x
Editorial and consistency fixes throughout the document; 


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x
The Phase 3 portion of the study was amended to include SLL patients 
x
Section 1.5 was amended to include clarification that venetoclax is FDA approved for the 
treatment of adult patients with CLL or SLL; 
x
Section 2.2 was amended to remove definitive disease progression as an efficacy endpoint; 
x
Section 2.2 was amended to add overall survival as an efficacy endpoint;  
x
Section 3.1 was amended to include additional language clarifying contraception timelines;  
x
Section 3.2 was amended to include the most updated TG language regarding severe and/or 
uncontrolled medical conditions that could exclude the patient from the trial; 
x
Section 4.1 was amended to include language that Phase 2 was closed to enrollment and 
additional language added to reinforce need for use of central lab results when randomizing 
subjects; 
x
Section 4.1 was amended to include language regarding CT and/or MRI evaluation to 
determine disease progression;  
x
Section 4.5 was amended to include additional clarification on the type of situations that 
warrants a patient to be discontinued from the study and confirmation that PFS and/or OS 
would continue to be followed per the schedule of assessments; 
x
Section 5 and 6 were amended to include additional footnote verbiage regarding CMV 
screening and evaluation; 
x
Section 5 and 6 was updated to include additional clarification of study in the Phase 3 
schedule to include the addition of 30-Day and 90-Day Safety Follow-Up column for clarity;  
x
Section 6 was amended to include urine pregnancy, sparse PK, immunogenicity, and 
authorization for venetoclax in the study assessment table;   
x
Section 6 was amended to include an additional footnote regarding the dosing of umbralisib 
in Arm B;  
x
Section 7.1 was amended to include additional verbiage regarding urine pregnancy;  
x
Section 7.2 was amended to include updated verbiage regarding the MRD assessment for the 
Phase 3 portion trial;  
x
Section 7.2.1 was added to include verbiage and guidance for sparse PK;  
x
Section 7.2.3 was added to include verbiage and guidance related to the immunogenicity 
assessment; 
x
Section 8.3 Table 11 was amended to remove C16-24 from the dosing schema; 
x
Section 8.5.1 was amended to include the most updated verbiage regarding the 
administration of ublituximab;  
x
Section 8.5.1 was amended to include the most updated verbiage regarding the management 
of patients with hepatitis B;  
x
Section 8.5.1.3 was amended to include the most updated verbiage regarding the 
dispensation of ublituximab;  
x
Section 8.5.2 amended to include dosing for timing of dosing of umbralisib on Cycle 1 Days 1 
and 2.  When ublituximab will be administered, umbralisib should be administered prior to 
ublituximab pre-medication 
x
Section 8.5.2.2 was amended to include the most updated verbiage regarding the dose hold 
or modification of umbralisib; 
x
Section 8.5.3.3 was amended to include the most updated verbiage regarding the dose hold 
and modification of venetoclax; 
x
Section 8.5.4 was added to include a table displaying the study drug modifications for all IPs, 
and include verbiage regarding anaphylaxis, drug-related toxicity, and cytopenias/non-
hematologic toxicities;  
x
Section 9.1 was updated to include additional ublituximab storage information;  


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x
Section 10.1 was amended to include updated verbiage regarding Phase 3 disease 
progression and how the site should appropriately handle its possible occurrence; 
x
Section 11.1 was updated to include additional verbiage regarding the interim analysis and 
the sensitivity analyses;  
x
Section 11.11.1.1. was amended to include the most updated language regarding analyses of 
PFS for Phase 3;  
x
Section 11.11.2.4 was added to include the most updated verbiage for analyses of CR;  
x
Section 11.11.2.5 was added to include the most updated verbiage for analyses of ORR;  
x
Section 11.11.3 was added to discuss, in depth, the interim analysis;  
x
Section 11.11.4 was added to include the most updated verbiage for multiplicity of the Phase 
3 cohort;  
x
Section 11.11.5 was added to include the most updated verbiage on stopping rules;  
x
Section 12.2.3 was updated to include additional clarification regarding SAE/AE recording; 
x
Section 12.8 Language regarding pregnancy reporting added to this section;  
x
Section 13.1 Language regarding timing of the DSMB added to this section;   
x
Section 13.4 was amended to update language regarding data ownership and publication;  
x
Section 14 was amended to include most updated TG language; 
x
Section 15 was amended to include most updated TG language;  
x
Section 17 (Appendix A) was updated with additional guidance regarding contraception 
practices for fertile males and females.  
















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the previously treated cohort will be enrolled and evaluated independently of 
each other.
Patients will be stratified at randomization by the following factors:
x
Treatment naïve cohort: del17p by central lab (deleted or not deleted)
and IGHV status (mutated or not mutated)
x
Previously treated cohort: del17p by central lab (deleted or not deleted)
and BTK status (refractory to BTK: yes or no)
FIGURE 2: PHASE 3 STUDY DESIGN
During the study period, all subjects will be evaluated for response by CT and/or 
MRI. At each follow-up visit, subjects will be assessed for response/progression 
by physical examination and laboratory tests. The best clinical response as well 
as disease progression will be determined by an IRC. Subjects will remain on 
study treatment until the occurrence of definitive disease progression (subjects 
enrolled to the randomized Phase 3 stage must have PD confirmed by central 
radiology prior to discontinuing study drug), completion of treatment, 
unacceptable toxicity, or withdrawal from the study due to Investigator decision 
or other reasons. Subjects who discontinue from study treatment (either for 
unacceptable toxicity or Investigator choice) and have not progressed will 
continue to be followed for progression until confirmed by IRC. All subjects 
enrolled to the Phase 3 portion of the study will be followed for overall survival. 














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1 INTRODUCTION 
1.1 CHRONIC LYMPHOCYTIC LEUKEMIA 
In the United States, an estimated 21,040 new cases of chronic lymphocytic leukemia (CLL) and 
deaths due to CLL totaling 4,060 will be reported in 2020, according to National Cancer Institute 
(NCI) estimates (SEER Cancer Statistics Factsheets) (Howlander et al., 2020). During 2013-2017, the 
NCI estimated an age-adjusted incidence rate of 5.0 per 100,000 individuals. CLL mainly affects older 
adults with an onset typically around 70 years and is characterized by the accumulation of clonal 
mature B lymphocytes in the blood, bone marrow, and secondary lymphoid tissues (SEER Cancer 
Statistics Factsheets) (Howlander et al., 2020). CLL/small lymphocytic lymphoma (SLL) is a 
heterogeneous disease with several higher risk cytogenetic abnormalities which are generally more 
difficult to treat including 17p deletion, TP53 gene mutation, and 11q deletion which have been 
associated with marked lymphadenopathy (Hallek et al., 2018; Lin et al., 2002). Patients with TP53
gene mutations are associated with an adverse clinical outcome. 
With the advent of novel targeted therapies, the paradigm of treatment for CLL/SLL is rapidly 
evolving away from standard chemotherapy-based regimens, which while active, result in 
considerable toxicity to patients (Burger, 2020). Novel non-chemotherapy-based therapies have 
demonstrated greater clinical benefit than current standard of care regimens with the added 
advantage of significantly greater tolerability (Burger, 2020). Despite advancements in available 
therapies, CLL/SLL remains incurable with progressive disease and CLL/SLL-related complications 
accounting for 73% of deaths in CLL/SLL patients (Strati et al., 2017). Additionally, 5-year survival 
rates are lower than the general population in age and sex-matched comparisons (Howlander et al., 
2020), and 10-year survival rates even lower than 5-year rates (Weide et al., 2020); thus, highlighting 
the life-threatening nature of this malignancy. Furthermore, patients with higher risk cytogenetic 
abnormalities still present with a less than optimal response to approved therapies and a shorter 
duration of response and progression-free survival (PFS) (Roberts et al., 2019; Woyach et al., 2019). 
As such, there is a pressing need for new, innovative, combinations of targeted therapies to produce 
deep and durable responses for patients with CLL/SLL, especially those with cytogenetic 
abnormalities. 
1.2 UBLITUXIMAB 
Ublituximab is a recombinant IgG1 chimeric monoclonal antibody that targets the CD20 antigen 
expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, ublituximab 
mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating 
intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement 
cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity 
(ADCC) and antibody-dependent cellular phagocytosis (ADCP). 
FDA-approved anti-CD20 antibodies, such as rituximab and obinutuzumab, have proven clinical 
benefit in CLL/SLL. Ublituximab has been glycoengineered for reduced fucose content, which 
increases its affinity for FcγRIII compared to rituximab (De Romeuf et al., 2008). Ublituximab has 
demonstrated enhanced ADCC compared to rituximab and ofatumumab in human cancer cell lines 
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(Bellon et al., 2011). Ublituximab exhibits complement-dependent cytotoxicity (CDC) on par with 
rituximab and has also been demonstrated to induce programmed cell death upon binding to the 
CD20 antigen on B lymphocytes in pre-clinical studies (De Romeuf et al., 2008). Additionally, 
ublituximab has a unique protein sequence, and targets epitopes on CD20 not targeted by rituximab 
or ofatumumab, both currently approved anti-CD20 antibodies (Esteves et al., 2011). Clinically, 
ublituximab possesses activity in CLL patients previously treated with rituximab including those who 
are rituximab-refractory (Sawas et al., 2017). 
1.2.1 PRE-CLINICAL EVALUATIONS OF UBLITUXIMAB 
1.2.1.1 IN VITRO ACTIVITY 
In an in vitro assay using B-CLL/SLL cells from patient donors, ublituximab demonstrated an 
enhanced ability to kill CLL/SLL cells compared to rituximab. Ublituximab demonstrated improved 
Fcγ receptor IIIA (FcγRIIIA)/CD16 binding and FcγRIIIA dependent effector functions compared to 
rituximab. Additionally, ublituximab induced higher in vitro ADCC against CLL/SLL cells, and a higher 
FcγRIIIA mediated interleukin-2 (IL2) production by FcγRIIIA+ Jurkat cells (De Romeuf et al., 2008). 
Ublituximab demonstrated high ADCC against both patient-derived CLL/SLL cells and NHL cell lines. 
Ublituximab’s engagement to FcγRIIIA triggers a stronger NK cell cytotoxicity against CLL/SLL as 
compared to rituximab (in vitro) despite CD20 density, likely related to the glycosylation pattern (De 
Romeuf et al., 2008). 
1.2.1.2 IN VIVO ACTIVITY 
The anti-tumor effect of ublituximab was compared to that of rituximab with chemotherapy in 
follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft murine models (Esteves et al., 
2011). Single-agent ublituximab demonstrated dose-related anti-tumor activity with 100% tumor 
growth inhibition in the FL xenograft at a dose of 100 mg/kg, and a superior tumor growth delay (21 
days) compared to rituximab (Esteves et al., 2011). Ublituximab also demonstrated superior anti-
tumor activity compared to rituximab against MCL xenografts at all dose levels (Esteves et al., 2011). 
1.2.1.3 TOXICOLOGY 
In single-dose and repeat dose toxicology studies performed under GLP, ublituximab displayed a 
safety profile similar to what might be expected for anti-CD20 monoclonal antibodies. Single 
administration of up to 100 mg/kg ublituximab in cynomolgus monkeys was well tolerated, with no 
local irritation with intravenous administration. Genotoxicity studies (Ames test) showed that 
ublituximab was not mutagenic. Monkeys that received a single injection of 0.3 mg/kg of ublituximab 
developed an anti-ublituximab response, whereas anti-ublituximab antibodies were not detected in 
the animals which received 10 or 100 mg/kg. See the latest ublituximab Investigator’s Brochure for 
detailed results. 
1.2.2 CLINICAL DEVELOPMENT OF UBLITUXIMAB 
As of mid-2018, approximately over 1000 subjects (both treatment naïve and previously treated 
subjects with CLL/SLL) have been exposed to ublituximab across 9 Phase I or II clinical trials and 2 
Phase III clinical trials (UTX-IB-301 and UTX-TGR-304), either as a single-agent or in combination 
with a variety of anti-cancer agents, including ibrutinib, umbralisib, bendamustine, pembrolizumab, 
and/or lenalidomide. Two single-agent Phase I/Ib trials (CD20-0703 and TG-1101-101) have been 


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conducted evaluating ublituximab in both NHL and CLL/SLL subjects which includes a total of 41 
subjects with relapsed or refractory CLL/SLL. Following demonstration of safety and tolerability in 
these early single-agent studies, Phase I and II combination studies were undertaken with a variety 
of agents. Given the number of subjects exposed to ublituximab in early-phase trials, the safety profile 
of the agent is well characterized. 
Summaries of the single-agent clinical experience are provided below. 
Study CD20-0703 is a 2-part, first-in human dose escalation study, subjects with relapsed or 
refractory CLL/SLL. In Part I, subjects received a weekly infusion of single-agent ublituximab for 4 
doses in a 3+3 dose escalation design through 5 sequential dose levels. Part II of the study was a dose-
confirmation component which used an initial dose of 150 mg followed by 7 doses of 450 mg (total 
dose 3300 mg). The study has completed. In Part II, 12 subjects were enrolled at 9 centers in France 
and followed for 12 months. Demographic data for the 12 subjects enrolled in the study were as 
follows. The median age was 69.5 years [62–77]; median time from diagnosis to inclusion was 10.4 
years [4.0–23.6] and median prior therapies was 3 [range, 1–8] (Bruno Cazin et al., 2011). Seven 
subjects (58%) received at least one prior rituximab containing regimen (Bruno Cazin et al., 2011). 
The median lymphocyte BM infiltration was 85% [range, 40–94%] (Bruno Cazin et al., 2011). 
Most frequent drug-related AEs reported were infusion related reactions (IRR) (75% of the subjects, 
including 33% of subjects with Grade 3 IRRs) (Bruno Cazin et al., 2011). Other Grade 3/4 AEs 
observed in >10% subjects included: neutropenia (67%) and increases in ALT/AST (17%) (Bruno 
Cazin et al., 2011). All AEs were reversible spontaneously or with supportive care intervention. None 
of the reported AEs were considered as a dose limiting toxicity (DLT) according to the judgement of 
the study Safety Committee. Therefore, the maximum tolerated dose (MTD) was not reached in this 
study. Significant blood lymphocyte depletion was observed in all subjects: median lymphocyte count 
at baseline was 46.6 (x 109/L); after 1 month (M1) = 1.5 (↓94%); M4=1.4 (↓91%) and M6=2.0 (↓89%). 
No cases of serum anti-ublituximab antibodies were detected at any time point (Bruno Cazin et al., 
2011). 
Clinical response was based on the criteria established by the NCI-Working Group (NCI-WG) updated 
in 2008 (Hallek et al., 2008). All subjects but one received the planned 8 infusions without any dose 
reduction; one subject was prematurely withdrawn due to a concomitant secondary leukemia 
unrelated to ublituximab therapy. Response was evaluated at month 4 for the 11 evaluable subjects, 
with an initial response rate of 64% (7/11) with a confirmed response at month 6 in 5/11 subjects 
(45%) subjects (all PRs). Four of the 11 subjects achieved stable disease (SD). At the 1-year follow-
up, no responders had progressed, demonstrating all confirmed responses were durable despite no 
ublituximab maintenance therapy. The median PFS was not reached at the 12-month follow-up (B 
Cazin et al., 2013). 
Study TG-1101-101 is a Phase I trial of ublituximab (NCT01647971) subsequently undertaken in 
subjects with B-cell lymphoma who were relapsed or refractory to a prior rituximab containing 
regimen. This trial utilized a 3+3 design, assessing dose levels of 450 mg, 600 mg, 900 mg, and 1200 
mg. The trial is complete, and enrolled a total of 35 subjects, including 8 subjects with CLL. No DLTs 
were observed amongst the 12 subjects enrolled into the dose escalation part, and expansion cohorts 
were subsequently undertaken at 600 mg, 900 mg, and 1200 mg. Subjects with CLL were eligible to 
enroll into the expansion cohorts at 600 mg and 900 mg, receiving ublituximab on days 1, 8, and 15 
of Cycles 1 and 2, with monthly maintenance infusions starting in Cycle 3, followed by every 3 months 
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a mean ± SD, tmax: median (range), with respect to the start of infusion *Accurate determination not possible
Concentration was still measurable in at least one subject of the cohort up to Day 169. Values for Cmax
and AUCf increased from the first to the eighth infusion whereas t1/2 term decreased. 
1.3 UMBRALISIB  
Umbralisib (TGR-1202) is an orally available dual inhibitor of phosphoinositide 3-kinase delta 
(PI3KG) and casein kinase 1 epsilon (CK1H), with nanomolar inhibitory potency against both targets 
and exhibits enhanced selectivity for the delta isoform of PI3K over the alpha (D), beta (E), and 
gamma (J) isoforms. The PI3Ks are a family of enzymes involved in various cellular functions, 
including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. 
The delta (G) isoform of PI3K is highly expressed in cells of hematopoietic origin, and strongly 
upregulated, and often mutated in various hematologic malignancies. 
The FDA-approved PI3K delta inhibitors idelalisib (Furman et al., 2014) and duvelisib (Flinn et al., 
2018) have established the clinical potential of PI3K inhibition in CLL/SLL, however the use of these 
agents in treatment naïve CLL/SLL patients is not FDA-approved. Excess toxicity has been observed 
in the treatment naïve setting compared to the relapsed or refractory setting for these agents, and 
idelalisib specifically has a “Limitations of Use” statement in its USPI advising against first-line 
treatment of any patient (Gilead Sciences, 2018; Verastem, 2019). Preliminary clinical data suggests 
umbralisib exhibits a differentiated safety profile with lower rates of autoimmune-related toxicities 
(e.g., liver toxicity, severe diarrhea/colitis, and pneumonitis) (Davids et al., 2018). This difference 
may be attributable to a wider therapeutic window between the inhibition of PI3KG and the other 
PI3K isoforms and may also be augmented by the inhibition of CK1H, which has been demonstrated 
to have a supportive effect on regulatory T-cells (Maharaj et al., 2020). Furthermore, umbralisib has 
limited drug-drug interaction liabilities, which facilitates its combination with other novel agents. 
1.3.1 PRE-CLINICAL DEVELOPMENT OF UMBRALISIB 
The potency of umbralisib binding the human and mouse δ isoform of PI3K was evaluated in a 
homogeneous time resolved fluorescence (HTRF) based enzyme assay in the presence of ATP at its 
Km value (100 μM) (
, 2011d). Selectivity over the other 3 isoforms, namely, 
α, β, and γ was also determined (Figure 4) (
, 2011a, 2011b, 2011c). 
Data demonstrated the specificity of umbralisib towards PI3Kδ with >1000, 50 and 48-fold selectivity 
over α, β, and γ, respectively in an enzyme-based assay, indicating that the primary mode of action of 
this compound is via inhibition of the δ isoform. 




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1.3.1.2 TOXICOLOGY
To assess the safety and toxicity of umbralisib, a 28-day repeat dose study with a 14-day recovery 
period was conducted in CD-1 mice and beagle dogs, to evaluate the potential reversibility of findings 
and to support the use in humans. Umbralisib was administered orally in order to mimic the planned 
mode of clinical administration.
Once daily PO administration of umbralisib was tolerated in mice at free base dose levels of 50 and 
150 mg/kg/day. Increases in liver weights, microscopic findings in the liver and the increases in 
serum cholesterol, and female only ALT, AST, and GGT levels were observed at 750 mg/kg/day of 
free base (the highest dose tested) and were considered adverse. The no observed adverse effect 
level (NOAEL) was considered to be 150 mg/kg/day in mice.
Once daily PO administration by capsule of umbralisib was well tolerated in dogs at levels of 50 and 
150 mg/kg/day. The gastrointestinal tract, based on clinical signs, was the target organ system. 
Based on effects on body weight and the incidence and severity of emesis and diarrhea, the NOAEL 
was considered to be 150 mg/kg/day (114.5 mg/kg/day as free base) in this species.
Refer to the latest umbralisib Investigator’s Brochure for detailed information on toxicology studies 
conducted to date.
1.3.2 CLINICAL DEVELOPMENT OF UMBRALISIB 
As of September 2018, approximately 1000 subjects have been exposed to umbralisib across multiple 
Phase I or II clinical trials and one Phase III clinical trial (UTX-TGR-304) either as a single-agent or in 
combination with other agents. Single-agent umbralisib has demonstrated safety and efficacy in a 
Phase I clinical trial in subjects with a wide variety of relapsed or refractory hematologic 
malignancies. Several Phase II clinical trials with umbralisib used as monotherapy and in doublet 
combinations with ublituximab and/or venetoclax in a wide variety of hematological malignancies 
are ongoing. A Phase III four-arm trial (UNITY-CLL) evaluating umbralisib combined with 
ublituximab and umbralisib monotherapy has completed enrollment and met its primary endpoint. 
Given the number of subjects who have received umbralisib in clinical trials, both as a single-agent 
and in doublet combination regimens and triplet combination regimens, the safety profile of
umbralisib is well characterized.
1.3.2.1 SINGLE-AGENT IN SUBJECTS WITH RELAPSED OR REFRACTORY HEMATOLOGIC 
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Umbralisib was evaluated in a single-agent Phase I dose escalation study (Study TGR-1202-101; 
NCT01767766) in subjects with relapsed and refractory hematologic malignancies (Burris et al., 
2018). There were 90 subjects enrolled and eligible for safety evaluation, and 73 subjects evaluable 
for efficacy in the modified intention to treat population (ITT). The median age was 64 years (range 
51-72), 63% male, median number of prior therapies was 3, and 49% of subjects were refractory to 
their most recent prior therapy. Histological diagnoses included; CLL (n=24), FL (n=22), DLBCL 
(n=16), HL (n=11), MCL (n=6), MZL (n=5), WM (n=2), HCL and TCL (n=1 each). The majority of 
subjects (58%) had received 3 or more prior therapies. 
Patients were enrolled in a 3+3 dose escalation design starting at 50 mg QD with subsequent cohorts 
evaluating doses as high as 1800 mg QD. In an effort to further improve the oral bioavailability of 
umbralisib, the particle size of the drug product was reduced through a micronization process, 
resulting in greater absorption when tested in a bioequivalence crossover study in healthy subjects. 
This micronized formulation was introduced into dose escalation at 200 mg QD and dosed as high as 
1800 mg QD. The MTD was 1200 mg QD of the micronized formulation, with 800 mg of this 
formulation selected as the recommended Phase 2 dose (RP2D) based on changes in tumor burden 
correlated with dose-proportional plasma exposure. Intra-subject dose escalation rules allowed 
subjects enrolled into the study in early cohorts to increase their dose of umbralisib as subsequent 
higher cohorts cleared safety evaluation. The most common treatment-emergent adverse events 
(TEAEs) irrespective of causality were diarrhea (in 39 [43%] of 90 subjects), nausea (38 [42%]), and 
fatigue (28 [31%]). The most common Grade 3 or 4 AEs were neutropenia (in 12 [13%] subjects), 
anemia (8 [9%]) and thrombocytopenia (6 [7%]). Serious adverse events (SAEs) considered at least 
possibly related to umbralisib occurred in 7 subjects: pneumonia in 3 (3%) subjects, lung infection 
in one (1%), febrile neutropenia in one (1%), and colitis in 2 (2%), one of whom also had febrile 
neutropenia. Both cases of colitis occurred above the RP2D. No time-related trends in toxicity were 
noted. 
Dosing of umbralisib initially occurred in the fasting state, but was transitioned mid-study to fed state 
dosing, with subjects instructed to take umbralisib with food. All dosing of umbralisib is now 
conducted using the micronized formulation and in the fed state. 
Among 73 subjects in the modified ITT, which included subjects who received at least 800 mg/day of 
the original formulation or any dose of the micronized formulation and had at least one response 
assessment, 53 (73%) had reductions in disease burden, including 33 (45%) subjects with reductions 
of 50% or more, of which 3 (4%) were a CR and 30 (41%) were a PR. In subjects with relapsed or 
refractory CLL, 17 (85%) of 20 achieved an objective response, with 10 (50%) achieving an objective 
response per 2008 iwCLL criteria, 7 (35%) achieving a PR-L, and the remaining 3 (15%) achieving 
SD. Of 8 assessable subjects with CLL who had high risk cytogenetic features, 6 (75%) had a response, 
of whom 2 (25%) had a PR-L, and the remainder had SD. In subjects with FL, 9 (53%) of 17 subjects 
achieved an objective response, including 2 (12%) who achieved a CR; the remainder had PRs. In 
subjects with DLBCL, 4 (31%) of 13 achieved an objective response and 2 (15%) further subjects 
achieved SD. Responses for the other subject subgroups were HL: 1 CR, 4 SD, 4 PR; MZL: 1 PR, 4 SD; 
WM: 2 SD; and MCL: one PR, 4 SD, and 1 PD. In a post-hoc exploratory analysis, tumor reductions in 
most subjects with indolent lymphoma and CLL treated with umbralisib tended to improve over time. 
The mean DOR was 13.4 months (95% CI 7.7–19.1) in 16 subjects in the CLL cohort, 6.4 months (4.5–
17.3) in 4 subjects in the DLBCL cohort, and 9.3 months (3.6–15.1) in 9 subjects in the FL cohort. In 
a post-hoc exploratory analysis of PFS, median PFS was 24.0 months (95% CI 7.4 months–not 
reached) in 20 subjects with CLL, and 16 months (9.2 months–not reached) in 24 subjects with 






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1.4  UBLITUXIMAB AND UMBRALISIB (U2) COMBINATION  
A Phase I/Ib dose escalation study (Study UTX-TGR-103) was conducted in B-cell (CLL and NHL) 
malignancies to establish the MTD of the combination of ublituximab and umbralisib (U2) and 
characterize safety and efficacy (NCT02006485). The study Is completed. The MTD was not reached 
and the most common all grade, all causality AEs in > 20% of subjects were: diarrhea (57%), nausea 
(53%), fatigue (43%) and neutropenia (32%) (Davids et al., 2017). The ORR for the CLL/SLL cohort 
was 62% in the 21 evaluable subjects with a 10% CR rate (Lunning et al., 2019). U2 was well tolerated 
and the safety and efficacy profile supports further research with multi-drug regimens including 
novel targeted agents. 
The Phase 3 UNITY-CLL trial (NCT02612311) demonstrated that ublituximab and umbralisib (U2) 
prolonged PFS compared to the chemoimmunotherapy combination of obinutuzumab and 
chlorambucil in both treatment naïve and previously treated CLL populations (Gribben et al., 2020). 
The safety profile of the U2 combination was consistent with the profiles seen with umbralisib and 
ublituximab as monotherapies, and no new safety signals were identified. An interim analysis 
evaluated the individual contribution of umbralisib and ublituximab as single agents to the U2 
combination and confirmed U2 as superior compared to either agent as a monotherapy. These data 
establish U2 as superior to chemoimmunotherapy; thus, making U2 an appropriate control arm in 
both treatment naïve and previously treated CLL. 
1.5 VENETOCLAX IN CLL 
The BCL-2 family of genes encodes a family of closely related proteins that possess either pro-
apoptotic or anti-apoptotic activity and share up to 4 BCL-2 Homology (BH) domains. In CLL, 
microRNAs miR15a and miR16-1 that negatively regulate the transcription of BCL-2 are deleted or 
down regulated, resulting in increased expression of BCL-2 (Cimmino et al., 2005). Venetoclax is an 
orally administered BCL-2 inhibitor demonstrating in vitro activity against primary CLL cells and in 
lymphoid malignancy xenograft models (Souers et al., 2013). In a Phase I dose escalation study 
enrolling 116 relapsed/refractory CLL patients, tumor lysis syndrome (TLS) was initially observed 
but decreased after a dose escalation over 5 weeks was initiated. The terminal t1/2 of venetoclax was 
19 hours, allowing daily dosing. With the 5-week dose escalation and TLS precautions, only 1 of 60 


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patients had laboratory evidence of TLS and no patients had clinical sequelae. Otherwise, Grade 1/2 
diarrhea and nausea were observed in roughly 50% of patients as was neutropenia, reaching Grade 
3/4 in 41% (Roberts et al., 2016). Of the 116 patients, the response rate was 79%, with 20% CRs. Of 
the 23 patients who had a CR, 17 underwent MRD testing and 6 (35%) had negative results per 
standard criteria. The median PFS for the 60 patients in the dose escalation was 25 months and not 
yet reached at 17 months in the expansion cohort (estimated to be 66% at 15 months). 
Venetoclax is FDA-approved for treatment of adult patients with CLL or SLL(AbbVie, 2020). In 
treatment naïve CLL/SLL, the Phase 3 CLL-14 trial showed venetoclax plus obinutuzumab prolonged 
PFS compared to obinutuzumab-chlorambucil (Fischer et al., 2019). In the relapsed/refractory 
setting, the Phase 3 MURANO trial illustrated that the venetoclax plus rituximab combination 
improved PFS compared to bendamustine plus rituximab (Seymour et al., 2018). Furthermore, these 
trials highlighted the potential for time limited treatment using chemotherapy-free regimens with 12 
months of venetoclax in treatment naïve CLL/SLL and 24 months of venetoclax in 
relapsed/refractory CLL/SLL. Both trials demonstrated that venetoclax based regimens can produce 
high rates of uMRD which is associated with prolonged PFS independent of radiographic response 
(Kater et al., 2019). 
1.6 RATIONALE/HYPOTHESIS FOR U2 + VENETOCLAX COMBINATIONS 
While venetoclax therapy is highly active in patients with CLL/SLL,  relapses occur. Additionally, the 
majority of patients only achieve a PRs to currently available venetoclax combinations. Further, a 
practical limitation exists with the TLS risk mitigation strategy required for venetoclax 
administration, which requires intensive monitoring for patients at medium and high risk of TLS and 
makes administration challenging in the community setting. We hypothesize that the addition of 
venetoclax following U2 induction will provide deeper levels of remission than have been achieved 
with single-agent umbralisib, ublituximab, and venetoclax to date. Further, the sequential strategy 
has been designed to mitigate the risk of venetoclax related TLS by utilizing a debulking course of U2 
prior to initiation of venetoclax. Lastly, sequential monitoring for rate of undetectable MRD will be 
used to potentially inform future time limited therapies based on the achievement of early optimal 
response. 
Based on the above, we propose this Phase 2/3 trial to evaluate U2 with venetoclax (U2-V) and also 
to compare the U2 regimen in a randomized fashion to the triplet regimen of U2-V. 
The combination of U2-V has been evaluated in an ongoing Phase 1 study (NCT03379051) in patients 
with relapsed or refractory CLL, which supports the dosing regimen used in this study U2-VEN-207. 
Of 43 patients treated to date, Grade ≥3 AEs were infrequent with neutropenia (21%), leukopenia 
(12%), and IRRs (7%) occurring in over 5% of patients (Barr et al., 2020). Discontinuations due to 
AEs were also uncommon with 9% and 4% discontinuing umbralisib and venetoclax respectively. No 
DLTs were observed during the Phase 1 portion, and the RP2D was found to be umbralisib 800 mg 
QD, ublituximab 900 mg, and venetoclax at standard dosing. The Phase 1 study utilized a 3 Cycle 
debulking schedule for U2, similar to this Protocol U2-VEN-207. After 3 cycles of U2 debulking, there 
was an 81% relative reduction in high- and medium-risk TLS, and no patients developed clinical or 
laboratory TLS during venetoclax administration. Of 27 patients evaluable at Cycle 12, the triple 
combination of U2 plus venetoclax produced a 100% ORR, 41% CR, and high rates of uMRD in the 
peripheral blood (96%) and BM (77%). The findings of the Phase 1 study support continued 
investigation in the current trial. 


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2 OBJECTIVES AND ENDPOINTS 
2.1 STUDY OBJECTIVES 
PHASE 2 STUDY OBJECTIVES 
PRIMARY OBJECTIVES 
x
To determine the complete response (CR) rate of the combination of ublituximab + 
umbralisib + venetoclax (U2-V) 
x
To determine the overall response rate (ORR) of the combination of ublituximab + umbralisib 
+ venetoclax (U2-V) 
SECONDARY OBJECTIVES 
• 
To determine the rate of undetectable MRD 
• 
To determine time to response (TTR) and duration of response (DOR) 
• 
To characterize the safety of the combination regimen 
PHASE 3 STUDY OBJECTIVES 
PRIMARY OBJECTIVES 
x
To evaluate the efficacy of the combination of ublituximab + umbralisib + venetoclax (U2-V) 
compared to the combination of ublituximab + umbralisib (U2) in patients with either 
treatment naïve or previously treated CLL/SLL as measured by PFS 
SECONDARY OBJECTIVES 
x
To evaluate the CR rate and ORR of the combination of ublituximab + umbralisib + venetoclax 
(U2-V) compared to ublituximab + umbralisib (U2) as assessed by an independent review 
committee (IRC); 
x
To compare the rate of undetectable MRD; 
x
To compare OS; 
x
To characterize the safety of the combination regimens. 
2.2 EFFICACY ENDPOINTS 
Progression-free Survival (PFS) 
PFS is defined as the interval from enrollment to the earlier of the first documentation of definitive 
disease progression or death from any cause. 
Overall response rate (ORR) 
ORR is defined as the proportion of subjects who achieve a CR, CRi, PR or PR-L. 
Complete Response (CR) Rate 
CR rate is defined as the proportion of subjects who achieve a CR or CRi. 


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Rate of Undetectable Minimal Residual Disease (MRD) 
Undetectable MRD is defined as the proportion of subjects who are MRD negative, defined as a 
quantitative detection of less than one CLL/SLL cell in 10000 leukocytes by flow cytometry (MRD 
level, 10-4) in blood or BM. 
Time to Response (TTR) 
TTR is defined as the interval from enrollment to first documentation of CR, CRi, PR, or PR-L. 
Duration of Response (DOR) 
DOR is defined as the interval from the first documentation of CR, CRi, PR, or PR-L to the earlier of 
the first documentation of definitive disease progression or death from any cause. 
Overall Survival (OS) 
OS is defined as the interval from randomization (Phase 3 subjects only) to the first documentation 
of death from any cause. 


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3 ELIGIBILITY CRITERIA 
3.1 INCLUSION CRITERIA 
Subjects must meet all the following inclusion criteria to be eligible for participation in this study: 
1.
B-cell CLL/SLL that warrants treatment consistent with iwCLL 2018 criteria for initiation of 
therapy with diagnosis established according to iwCLL 2018 criteria and documented within 
medical records. At least one of the following criteria must be met: 
a.
Evidence of progressive marrow failure as manifested by the onset or worsening of 
anemia and/or thrombocytopenia; or 
b.
Massive (i.e., lower edge of spleen ≥ 6 cm below the left costal margin), progressive, or 
symptomatic splenomegaly; or 
c.
Massive (i.e., ≥ 10 cm in the longest diameter) or progressive or symptomatic 
lymphadenopathy; or 
d.
Progressive lymphocytosis in the absence of infection, with an increase in blood 
absolute lymphocyte count (ALC) >50% over a 2-month period or lymphocyte doubling 
time of <6 months; or 
e.
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs occurring in the absence of evidence of infection: 
i.
Unintentional weight loss of ≥10% within the previous 6 months; or 
ii.
Significant fatigue (≥ Grade 2); or 
iii.
Fevers >100.5°F or 38.0°C for ≥2 weeks; or 
iv.
Night sweats for >1 month. 
2.
Adequate organ system function, independent of growth-factor or transfusion support, defined 
as follows: 
a.
Absolute neutrophil count (ANC) > 750/mm3 (μL) / platelet count > 40,000/mm3 (μL); 
b.
Total bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's 
syndrome with bilirubin > 1.5 × ULN allowed per discussion with the Medical Monitor; 
c.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no 
liver involvement or ≤5 x the ULN if known liver involvement; 
d.
Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault 
formula). 
3.
ECOG performance status ≤ 2. 
4.
Male or female ≥ 18 years of age. 
5.
Ability to swallow and retain oral medication. 
6.
Female subjects who are not of child-bearing potential, and female subjects of child-bearing 
potential who have a negative serum pregnancy test within 3 days prior to Cycle 1, Day 1. 
Female subjects of child-bearing potential, and male partners must consent to use a medically 
acceptable method of contraception throughout the study period and for 4 months after the last 
dose of ublituximab and for at least 30 days after the last dose of umbralisib or venetoclax. Men 
of reproductive potential may not participate unless they agree to use medically acceptable 
contraception.  
7.
Willingness and ability to comply with trial and follow-up procedures and provide written 
informed consent. 
3.2 EXCLUSION CRITERIA 


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Subjects who meet any of the following exclusion criteria are not to be enrolled to this study: 
1.
Subjects receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational 
drug within 21 days of Cycle 1, Day 1 (within 7 days of Cycle 1, Day 1 for prior BTK inhibitor).  
a.
Corticosteroid use within 1 week prior to first dose of study drug are excluded, with the 
exception of steroid use for adrenal replacement, inhaled steroid for asthma, topical steroid 
use or other locally administered corticosteroids. Patients requiring systemic steroids for 
leukemia control or white blood cell (WBC)-count lowering are excluded.  
2.
Autologous hematologic stem cell transplant within 6 months of study entry. 
3.
Prior allogeneic hematologic stem cell transplant. 
4.
Evidence of chronic active hepatitis B (HBV) infection as evidenced by a detectable hepatitis B 
surface antigen (HBsAg); or chronic hepatitis C infection (HCV), cytomegalovirus (CMV), or 
known history of human immunodeficiency virus (HIV). Subjects with positive hepatitis B core 
antibody (HBc Ab) or hepatitis C virus antibody (HCV AB) or positive CMV by IgM or IgG are 
eligible only if PCR is negative for HBV DNA, HCV RNA or CMV.  
5.
Known histological transformation from CLL/SLL to an aggressive lymphoma (e.g., Richter’s 
Transformation, prolymphocytic leukemia, or DLBCL). 
6.
History of CNS involvement with CLL/SLL. 
7.
Prior exposure to any PI3K inhibitor (e.g. idelalisib, duvelisib, umbralisib (TGR-1202), etc.) or 
venetoclax (ABT-199, GDC-0199). 
8.
Known barriers to commercially available venetoclax. 
9.
Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal 
infections of skin or nails. 
10. Live virus vaccines within 4 weeks prior to or during study therapy. 
11. History of anaphylaxis (excluding IRR) in association with previous anti-CD20 monoclonal 
antibody administration. 
12. Any severe and/or uncontrolled medical conditions or other conditions that could adversely 
affect the safety of the subject or their participation in the study such as: 
a.
Ongoing alcoholic liver disease, nonalcoholic steatohepatitis, cirrhosis of the liver, primary 
biliary cirrhosis, portal hypertension
b.
Splenomegaly from causes other than CLL/SLL 
c.
Symptomatic, or history of documented congestive heart failure (New York Heart 
Association [NYHA] functional classification III-IV). Class 3 is defined as cardiac disease in 
which patients are comfortable at rest but marked limitation of physical activity due to 
fatigue, palpitations, dyspnea, or anginal pain; 
d.
Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of randomization; 
e.
Concomitant use of medication known to cause QT prolongation or torsades de pointes 
should be used with caution and at Investigator discretion; 
f.
Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, 
cardiac/vascular stenting within 6 months of randomization. 
13. Requirement for use of strong or moderate CYP3A inhibitors, strong or moderate CYP3A 
inducers, P-glycoprotein (P-gp) inhibitors, or narrow therapeutic index P-gp substrates (See 
Appendix D). 
14. Malignancy within 3 years of study enrollment except for adequately treated basal, squamous 
cell carcinoma or in situ carcinomas, superficial bladder cancer not treated with intravesical 


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chemotherapy or BCG within 6 months, or localized prostate cancer with a PSA <1.0 mg/dL on 2 
consecutive measurements at least 3 months apart with the most recent one being within 4 
weeks of study entry. 
15. Women who are pregnant or lactating. 


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4 STUDY DESIGN
4.1 OVERVIEW OF STUDY DESIGN
This is an open-label, multicenter, Phase 2/3 study designed to investigate the efficacy and safety of 
U2 combined with venetoclax in subjects with CLL/SLL. Patients with treatment naïve and previously 
treated CLL/SLL are eligible for enrollment. Based on preliminary results from ongoing ublituximab 
and umbralisib trials and changing landscape of approved CLL/SLL treatments, single-arm or 
randomized cohorts may be added for both safety and efficacy.
In the Phase 2 stage of the study (see Figure 8 below), 3 separate cohorts will be enrolled: a cohort 
of approximately 60 subjects with treatment naïve CLL; a cohort of approximately 60 subjects with 
previously treated CLL, this includes relapsed subjects who are not refractory to a prior BTK inhibitor;
and a cohort of approximately 30 subjects with BTK-refractory CLL will be enrolled in the study. BTK-
refractory is defined as disease progression while on, or within 6 months of the last dose of, a BTK 
inhibitor (e.g. ibrutinib, acalabrutinib, etc.). See Section 8 for details on umbralisib administration 
based on MRD status.  As of January 29, 2021, the Phase 2 portion of the study was closed to 
enrollment. 
FIGURE 8: PHASE 2 STUDY DESIGN
The Phase 3 stage of the trial (Figure 9) includes 2 independent randomized cohorts of CLL/SLL
patients; a treatment naïve cohort and a previously treated cohort. Following screening, qualified 
patients will be randomized 1:1 to 1 of the 2 arms:
•
Arm A: Ublituximab + Umbralisib + Venetoclax (U2-V)
•
Arm B: Ublituximab + Umbralisib (U2)


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Approximately 400 (200 per treatment arm) patients will be enrolled to the treatment naïve CLL/SLL
cohort and approximately 300 (150 per treatment arm) patients will be enrolled to the previously 
treated CLL/SLL cohort. The treatment naïve cohort and the previously treated cohorts will enroll 
independently of each other. 
Patients will be randomized and stratified by the following factors:
Treatment Naïve Cohort: 17p status by central lab (deleted or not deleted) and IGHV status (mutated 
or not mutated) 
Previously Treated Cohort: 17p status by central lab (deleted or not deleted) and BTK status 
(refractory 
to 
BTK; 
yes 
or 
no)
FIGURE 9: PHASE 3 STUDY DESIGN
During the study period, all subjects will be evaluated for response by CT and/or MRI. At each follow-
up visit, subjects will be assessed for response/progression by physical examination and laboratory 
tests. The best clinical response as well as disease progression will be determined by an IRC. Subjects 
will remain on study treatment until the occurrence of definitive disease progression (subjects 
enrolled to the randomized Phase 3 stage must have PD confirmed by central radiology prior to 
discontinuing study drug), completion of treatment, unacceptable toxicity, or withdrawal from the 
study due to Investigator decision or other reasons. Subjects who discontinue from study treatment 
(either for unacceptable toxicity or Investigator choice) and have not progressed will continue to be 
followed for progression until confirmed by IRC. All subjects enrolled to the Phase 3 portion of the 
study will be followed for overall survival.
4.2 EFFICACY AND SAFETY ANALYSES
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Ref
erence_5x7.pdf).


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Efficacy will be determined according to the iwCLL guidelines for the treatment of CLL/SLL (Hallek 
et al., 2018). 
4.3 REGISTRATION AND RANDOMIZATION/BLINDING 
Subjects who have signed an informed consent will be registered and receive a unique subject 
identifier. Subjects must be registered in the IRT system prior to dispensing any drug to the 
participant. Subjects enrolled to the Phase 3 randomized stage of the study will be randomized in the 
IRT system. Treatment arm will be assigned by the IRT system. Once randomized, subjects should 
start study treatment within 7 days of randomization. Further details about the subject registration 
and randomization process are available in the IRT Manual. 
4.4 STUDY SITES 
This study may be conducted in approximately 125 centers. Enrollment is expected to take 
approximately 24 months. 
4.5 DISCONTINUATION FROM STUDY 
Discontinuation from study treatment (discontinuation of all study drugs) and discontinuation from 
the study might be linked or might be separate events, depending on the triggering action, decision 
or outcome. Subjects will be discontinued from study treatment for any of the following reasons: 
x
Disease progression 
x
Intolerable toxicity (all study drugs discontinued)  
x
Subject requests to withdraw consent for treatment 
x
Pregnancy 
x
Initiation of therapeutic intervention not permitted by the protocol 
x
Investigator discretion 
x
Discontinuation of the study by the Sponsor 
Subjects will continue to be followed for PFS and/or OS per the schedule of assessments. 
Subjects who discontinue from study treatment will continue to be followed for AEs and other 
protocol required procedures as per the study assessment table. 
All subjects who have CTCAE Grade 3 or 4 laboratory abnormalities at the time of withdrawal should 
be followed until the laboratory values have returned to Grade 1 or 2, unless in the opinion of the 
Investigator, it is not likely that these values are to improve because of the underlying disease. In this 
case, the Investigator must record his or her reasoning for making this decision in the subject’s 
medical records and as a comment on the eCRF.














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The following assessments will be shipped to and analyzed at a central laboratory. Please see the 
Study Laboratory Manual for processing, handling, and shipping instructions. 
Subjects Enrolled to Phase 2:  
x
MRD assessment
o
Cycle 6: Peripheral blood at Cycle 6 for all subjects without clinical signs 
of progression; repeat every 6 cycles
o
Cycle 12 & 24: Peripheral blood; subjects in a PR or better and are MRD 
negative by PB, should have MRD by BM 
o
CR before Cycle 12 that are MRD negative by PB: MRD in BM. If MRD BM 
positive, repeat MRD by BM at next response assessment and continue to 
draw MRD by PB  
x
T/B/NK Cell Subsets: only subjects enrolled to Protocol V1.0-2.0/Phase 2 
Portion, No longer required in subjects enrolled to Phase 3 
o
To be drawn pre-dose C1D1, during Cycle 4, Cycle 12, and approximately 
every 6 cycles thereafter until Cycle 24 
Protocol Version 3.0+, Subjects Enrolled to Phase 3: 
x
MRD assessment  
o
MRD in peripheral blood at baseline and Cycle 6, Cycle 12, Cycle 15 and 
Cycle 24 (MRD drawn only if subject is in PR or better). One MRD by bone 
marrow aspirate should be completed for all patients who are MRD 
negative by peripheral blood. Thereafter, all subjects without signs of 
clinical progression, repeat MRD every 6 cycles (peripheral blood). See 
laboratory manual for collection, processing, and shipment instructions. 
x
CLL mutation panel (FISH and NGS)– Peripheral blood to be drawn at screening 
for FISH and NGS. Central lab FISH results required at the time of randomization 
for stratification. 
x
Sparse PK Sampling
x
Immunogenicity Sampling
7.2.1 SPARSE SAMPLING PHARMACOKINETICS (SUBJECTS ENROLLED TO PHASE 3 ONLY) 
All subjects enrolled to Arm A (U2 + Venetoclax) must participate in the sparse sampling population 
pharmacokinetic (PK) assessment. The sampling time-points below will be utilized for the population 
pharmacokinetic assessment. A Cycle 4, Day 1, pre-dose (baseline) sample will be obtained from all 
subjects, however, subjects will be randomized (when randomized into the study by the IWRS) to 
only 1 post-baseline sample among the timepoints listed below. On days PK samples are being 
obtained, umbralisib and venetoclax must be administered orally immediately at the start of the 
ublituximab infusion.  The PK sample must be drawn prior to drug administration.  
Sparse PK blood samples for all subjects will be taken as follows (Pre-dose on Cycle 4, Day 1, 
then one randomly assigned post-baseline sample.  The possible post-baseline PK randomly 
assigned by the IRT system is one of the following: Day 1 of Cycles 5, 6, 9, 12 or 15. 
P


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A total of 2 serum samples should be collected from each subject for sparse population PK analyses 
(Pre-dose on Cycle 4, Day 1, and one randomly assigned post-baseline sample) with the possibility of 
one additional sample timepoint assigned later during treatment to ensure all sample timepoints for 
the study have been collected. 
Nonlinear mixed effects modeling will be used for the population pharmacokinetic analysis. 
Covariates to be evaluated to assess the effect on pharmacokinetic parameters include age, weight, 
gender, ethnicity, hemoglobin (Hb) concentration, platelet count, white blood cell (WBC) count, liver 
function (ALT and AST), creatinine concentration and the co-administration of ublituximab. 
7.2.3 IMMUNOGENICITY ASSESSMENT (SUBJECTS ENROLLED TO PHASE 3 ONLY) 
One hundred subjects enrolled to Arm A and 100 subjects enrolled to Arm B in both treatment naïve 
and previously treated cohorts (total 400 patients) must participate in the ublituximab 
immunogenicity assessment.  The sampling schedule for these subjects is detailed in Table 8 below:  
TABLE 8: IMMUNOGENICITY ASSESSMENT  








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8.5.1 GUIDELINES FOR ADMINISTRATION OF UBLITUXIMAB 
x
Method of Administration: Ublituximab will be administered as an intravenous infusion 
through a dedicated line. 
x
Potential Drug Interactions: No drug interactions have been reported to date. 
x
Pre-medications:  
o
Pre-medications should include an antihistamine (diphenhydramine 50 mg or 
equivalent), and a corticosteroid (dexamethasone 10 – 20mg or equivalent) 

The guidance above for pre-medication represents a minimum. Additional 
pre-medications such as montelukast, rupatadine, famotidine, etc. may be 
added per institutional guidelines and treating investigator, and should be 
considered for initial ublituximab doses. 

If pre-medications are administered IV: start ublituximab 30 minutes after 
conclusion of last pre-med infusion 

If pre-medications are administered orally: start ublituximab 45 – 60 minutes 
after ingestion of pre-meds 
o
Use of oral acetaminophen 650 mg (or equivalent) should be restricted to subjects 
who experience fever or pyrexia after Week 1 dose, or as clinically warranted. 
o
Prophylaxis with an antiviral agent effective against hepatitis B is required in subjects 
with a prior history of hepatitis B and for those with a positive anti-HBc with negative 
HBsAg at screening. If the subject has a negative reaction to the prophylactic antiviral 
agent, consider using a different prophylactic medicine. 
x
Hypersensitivity and IRR Precautions: Medication and resuscitation equipment must be 
available per institutional guidelines prior to ublituximab administration for the emergency 
management of potential anaphylactic reactions. 
x
Subject Care Implications: 
o
Ublituximab should not be administered as an IV push or bolus 
o
Diluted ublituximab should be checked before administration for cloudiness, color, or 
deposits. Ublituximab should not be administered if does not conform to the 
specifications. Immediately inform the Monitor/Sponsor with any product quality 
concerns or questions 
o
It is recommended that ublituximab be administered immediately after dilution 
o
No other treatment may be co-administered with ublituximab (other than for 
immediate intervention for an AE)
o
Since infusion related hypotension may occur, consider holding antihypertensive 
medications 12 – 24 hours prior to and throughout infusion of ublituximab 
o
For subjects at risk for TLS in the opinion of the treating Investigator, prophylaxis with 
allopurinol or per recommended institutional standards should be considered 
o
Hepatitis B reactivation may occur in subjects with a positive HBsAg, negative HBsAg 
with positive anti-HBc and those who appear to have resolved hepatitis B infection. 
Promptly consult clinicians, with expertise in managing subjects with a prior history of 


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hepatitis B, regarding monitoring and consideration of options for hepatitis B antiviral 
therapy for prophylaxis/treatment  
o
Monitor subjects with a prior history of hepatitis B closely as clinically indicated based 
on liver tests and any observed signs/symptoms such as jaundice, abdominal pain, 
dyspepsia, decreased appetite, dark-colored urine often accompanied by lighter than 
normal colored stools, nausea, vomiting or fatigue. 

For patients with a prior history of hepatitis B who experience an increase in 
liver enzymes while on study, hold ublituximab immediately and assess for 
active hepatitis B infection. If negative for hepatitis B, ublituximab may be 
resumed, see Table 22 Study Drug Modifications. If reactivation of hepatitis B 
is confirmed, institute hepatitis B antiviral treatment and promptly consult 
clinicians with expertise in managing subjects with a prior history of hepatitis 
B. Once hepatitis B infection has resolved, ublituximab may be resumed at 
Investigator discretion after discussion with medical monitor. 
8.5.1.1 INFUSION RELATED REACTIONS AND INFUSION RATE GUIDANCE - UBLITUXIMAB 
IRRs including severe reactions have been reported with ublituximab administration in subjects with 
CLL/SLL. Guidelines are provided below for subjects who experience such reactions. Symptomatic 
infusion reactions, despite premedication, may be treated at the discretion of the treating physician, 
including but not limited to: oral acetaminophen 650 mg (or equivalent), corticosteroids, 
antihistamines, oxygen, and bronchodilators. 
The following are recommended infusion rate reduction/hold guidelines for subjects who experience 
severe IRRs in which treatment should be interrupted. Final decision for infusion rate reduction/hold 
or discontinuation resides with the treating Investigator. 
1st or 2nd Infusion Interruption (Same Day): 
x
Hold infusion and closely monitor subject, institute symptomatic medical management until 
resolution of IRR symptoms 
x
Following the judgement of the Investigator, and provided the subject is stable, the infusion 
may be resumed at no more than half the previous rate 
x
If the subject does not experience any further IRR symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate at the treatment cycle dose 
3rd Infusion Interruption (Same Day): 
x
Discontinue infusion for that day – monitor subject for resolution of all symptoms. Subject 
should have all vital signs completed as well as any other standard of care procedures 
completed as warranted by the Investigator prior to release of subject from study site. 
x
Any remaining diluted investigational product should be discarded. 
If the infusion discontinued is the Cycle 1, Day 1 infusion, administer the scheduled Cycle 1, Day 2 
dose according to the protocol dosing schedule. 
If at any time during ublituximab treatment, an IRR is observed, the treating Investigator may reduce 
the infusion flow rate at their discretion. 
8.5.1.2 FLOW RATE RECOMMENDATIONS FOR UBLITUXIMAB ADMINISTRATION 
TABLE 12. CYCLE 1, DAY 1 AND DAY 2 INFUSION OVER 4 HOURS  






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antiviral prophylaxis is per Investigator discretion and institutional SOC, with the following 
as recommendations: 
o
Antiviral Prophylaxis: Valacyclovir (Valtrex£) 500 mg daily or Acyclovir 400 mg BID 
or equivalent 
o
PJP Prophylaxis: Dapsone 100 mg daily or equivalent 
If antiviral or antifungal prophylaxis is not tolerated, we recommend alternating to a different 
prophylactic agentor modifying the schedule for the prophylactic agent, or discontinuing prophylaxis 
at Investigator discretion. Final choice of PJP and antiviral prophylaxis therapy is per Investigator 
discretion. Umbralisib will be dispensed at the sites by the research coordinator or designee under 
the direction of the PI or by a pharmacist at the site. Subjects must be provided drug in its original 
container. Subjects should be instructed to return any unused tablets when they return the bottle to 
the site. Study drug compliance should be reviewed with the subject at the beginning of each new 
treatment cycle and as needed. Missed doses will be documented in the subjects’ medical record. 
Umbralisib will be self-administered (by the subject). On Cycle 1 Days 1 and 2, when ublituximab will 
be administered, umbralisib should be administered prior to ublituximab pre-medication.  Tablets 
should be taken at approximately the same time each day with food. Subjects should be instructed to 
swallow the tablets whole. Do not chew or crush umbralisib. 
If a dose of umbralisib is missed, it should be taken as soon as possible on the same day. If it is missed 
for a period greater than 12 hours, it should not be replaced. If vomiting occurs, no attempt should 
be made to replace the vomited dose. 
8.5.2.1 DISPENSING OF UMBRALISIB 
Before dispensing, the site pharmacist or his/her representative must check that the umbralisib is in 
accordance with the product specifications and the validity is within the retest date. 
The exact dose and the date of administration of umbralisib must be recorded within the eCRF, 
subject’s medical records, and/or in the drug accountability records. For the purpose of drug 
accountability and compliance, an umbralisib subject diary will be provided. Any error in drug 
administration should be recorded (e.g., missed dose) in the eCRF. 
The pharmacist or his/her representative should record the date dispensed and subject’s number, as 
well as complete the accountability record in the electronic drug accountability system with 
information concerning the dispensation of umbralisib. 
8.5.2.2 DOSE HOLD/MODIFICATION: UMBRALISIB 
Supportive care should be considered for any subject who experiences Grade ≥ 2 cytopenias, or Grade 
≥ 1 non-hematologic toxicities. If a subject experiences a treatment-related AE requiring dose 
modification during the course of therapy, then study drug administration should be held, as 
necessary, until the AE resolves or stabilizes to an acceptable degree. In addition, the subject should 
be notified of the change in dose and the appropriate clinic staff should instruct the subject about the 
revised number of study medication tablets to be used per dose according to the new dose level. Any 
questions regarding dose modification should be referred to TG Therapeutics. 
The  adjunctive supportive care recommendations listed in the dosing hold and modification tables 
are meant to serve as guidelines and are not meant to replace Investigator discretion. Final toxicity 






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c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in 
real time. 
d For subjects at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each 
subsequent ramp-up dose. 
8.5.3.2 PROHIBITED MEDICATIONS AND FOODS 
Please see the venetoclax package insert for the most up to date information regarding drug 
interactions 
and 
contraindications, 
which 
can 
be 
found 
at 
https://www.accessdata.fda.gov/drugsatfda docs/label/2018/208573s009lbl.pdf. 
Strong CYP3A Inhibitors 
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during ramp-up phase 
is contraindicated.  
For subjects who have completed the ramp-up phase and are on a steady daily dose of venetoclax, 
reduce the venetoclax dose by at least 75% when used concomitantly with strong CYP3A inhibitors. 
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after 
discontinuation of the inhibitor. 
Moderate CYP3A Inhibitors and P-gp Inhibitors 
Avoid concomitant use of moderate CYP3A inhibitors or P-gp inhibitors with venetoclax. Consider 
alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the 
venetoclax by at least 50%. Monitor subjects more closely for signs of venetoclax toxicities 
(Venetoclax prescribing information, 2017). 
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 
to 3 days after discontinuation of the inhibitor. 
Avoid grapefruit products, Seville oranges, and starfruit during treatment with venetoclax, as they 
contain inhibitors of CYP3A. 
CYP3A Inducers 
Avoid concomitant use of venetoclax with strong CYP3A inducers or moderate CYP3A inducers. 
Consider alternative treatments with less CYP3A induction. 
8.5.3.3 DOSE HOLD/MODIFICATION: VENETOCLAX 
Supportive care should be considered for any subject who experiences Grade ≥ 2 cytopenias, or Grade 
≥ 1 non-hematologic toxicities. If a subject experiences a treatment-related AE requiring dose 
modification during the course of therapy, then study drug administration should be held, as 
necessary, until the AE resolves or stabilizes to an acceptable degree. In addition, the subject should 
be notified of the change in dose and the appropriate clinic staff should instruct the subject about the 
revised number of study medication tablets to be used per dose according to the new dose level. Any 
questions regarding dose modification should be referred to TG Therapeutics. Please see Table 22 
for further guidance.  












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Investigator 
discretion)**.  
Monitor labs at least 
weekly until Grade 1.  
Once resolved to 
Grade ≤1, taper 
prednisone. Resume 
umbralisib at next 
lower dose level 
when Grade ≤1.  
*Assess for disorders of lipids and glucose, thyroid disorders, alcohol use, viral infections, etc. 
**Supportive Care – Aggressive management of lipid, glucose, other metabolic disorders, viral infections, etc. 
Important: Before initiating steroids, check for viral hepatitis or CMV infection. 
If Grade 4 anaphylaxis is observed at any point during ublituximab treatment, permanently 
discontinue ublituximab treatment and intervene as per Investigator discretion. 
If a subject requires a dose reduction of umbralisib due to study drug-related toxicity, the dose may 
not be re-escalated. If further evaluation of the toxicity reveals the event was not related to 
umbralisib, this must be recorded in the medical record and dose re-escalation to the next higher 
dose level may be considered at the discretion of the Investigator. 
Supportive care should be considered for any subject who experiences Grade ≥ 2 cytopenias, or Grade 
≥ 1 non-hematologic toxicities. If a subject experiences a treatment-related AE requiring dose 
modification during the course of therapy, then study drug administration should be held, as 
necessary, until the AE resolves or stabilizes to an acceptable degree. 


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9 STUDY MEDICATION OVERVIEW AND SAFETY 
9.1 UBLITUXIMAB 
Chemical Name: 
ublituximab 
 
Other Names:   
TG-1101 
Classification:   
Recombinant chimeric anti-CD20 monoclonal antibody (mAb)
Mode of Action: 
Targets CD20 antigen on B cells 
 
Description: 
Ublituximab is a genetically engineered chimeric mAb directed against the 
CD20 antigen found on the surface of B lymphocytes. It is composed of a 
murine variable region fused onto human constant regions. 
How Supplied: 
Concentration of 25 mg/mL in 6 mL (150 mg) single use vials or 36mL 
(900mg) single use vials 
Storage: 
Ublituximab vials must be stored in a secured limited-access refrigerated area 
at a temperature ranging from +2°C to + 8°C (36 - 46°F). Once a vial of 
ublituximab has been diluted, it should be used immediately. If not used 
immediately, diluted solutions must be stored refrigerated. The storage 
duration of ublituximab diluted in polyvinyl chloride (PVC) or non-PVC 
polyolefin (PO) material is up to 24 hours when refrigerated at 2 – 8°C (36 – 
46°F). After allowing the diluted bag to come to room temperature, use 
immediately. Ublituximab must not be frozen. Temperature should be 
monitored, documenting minimum and maximum daily.  
Retest dates are provided via the electronic drug accountability system.  
Route of  
Administration: 
Intravenous 
Packaging: 
Ublituximab is packed in kits. Each kit contains: 
x
6 vials containing 150 mg solution 
or  
x
One vial containing 900 mg solution 
Availability: 
 
Ublituximab is available from TG Therapeutics. 
The Investigator’s Brochure (IB) is the primary source for safety information. The ublituximab IB 
includes a summary of AE data and discussion on potential risks and AEs of special interest that have 
been observed or may be predicted to occur with these study drugs. Refer to the most recent IB, 
which is updated periodically, for current information available on ublituximab. 
Refer to the IB and pharmacy manual for the most up to date information. 


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9.2 UMBRALISIB 
Chemical Name: 
umbralisib 
Other Names:   
TGR-1202 
Classification:   
Phosphatidylinositol-3-Kinase (PI3K) delta inhibitor 
Formulation: 
 
See Investigator Brochure
Mode of Action: 
Inhibits activity of the Class I Delta isoform of PI3K and Casein Kinase 1 
Epsilon 
How Supplied:  
200 mg tablets 
Storage: 
Store at 20°C – 25°C. Excursions permitted from 15°C to 30°C. 
Stability: 
Retest dates will be provided periodically via the electronic drug 
accountability system. 
Route of  
Administration: 
Oral 
Packaging: 
Umbralisib is provided in bottles each containing 30 tablets 
Availability: 
 
Umbralisib is available from TG Therapeutics 
The IB is the primary source for safety information. The umbralisib IB includes a summary of AE data 
and discussion on potential risks and AEs of special interest that have been observed or may be 
predicted to occur with these study drugs. Refer to the most recent IB, which is updated periodically, 
for current information available on umbralisib. Refer to the IB and pharmacy manual for the most 
up to date information. 
9.3 UBLITUXIMAB + UMBRALISIB SAFETY INFORMATION 
The IB is the primary source for safety information. The ublituximab and umbralisib IBs include a 
summary of AE data and discussion on potential risks that have been observed or may be predicted 
to occur with these study drugs. Refer to the most recent IBs, which are updated periodically, for 
current information on ublituximab and umbralisib. 
9.4 VENETOCLAX 
Chemical Name: 
venetoclax 
Classification:   
BCL-2 inhibitor 
Formulation: 
 
See Prescribing Information 
How Supplied:  
10, 50, and 100 mg tablets 


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Storage:
Store at or below 86°F (30°C) 
Route of  
Administration: 
Oral 
Packaging: 
Venetoclax is stored either in a wallet containing blister packs or a bottle 
Availability: 
 
Venetoclax is commercially available from Abbvie Inc. and Genentech USA, Inc.  
9.4.1 ADVERSE REACTIONS REPORTED IN > 10% (ANY GRADE) OF SUBJECTS WITH 
CLL/SLL 
Please 
refer 
to 
the 
US 
prescribing 
information 
(https://www.accessdata.fda.gov/drugsatfda docs/label/2018/208573s009lbl.pdf) 
and 
www.venetoclax.com for the most up to date information including warnings and precautions, 
adverse reactions, and boxed warnings. 
x
Blood and lymphatic systems disorders: Neutropenia, anemia, thrombocytopenia, 
lymphopenia, febrile neutropenia 
x
Gastrointestinal disorders: Diarrhea, nausea, abdominal pain, vomiting, constipation 
x
General disorders and administration site conditions: Fatigue, pyrexia, edema 
x
Infections and infestations: Upper respiratory tract infection, pneumonia, lower 
respiratory tract infection 
x
Musculoskeletal and connective tissue disorders: Musculoskeletal pain, arthralgia 
x
Nervous system disorders: Headache, dizziness 
x
Respiratory, thoracic, and mediastinal disorders: Cough, dyspnea 
x
Skin and subcutaneous tissue disorders: Rash 
9.4.2 ADVERSE REACTIONS OF TLS AND RELEVANT LABORATORY ABNORMALITIES 
REPORTED IN SUBJECTS WITH CLL/SLL 
TABLE 23. ADVERSE EVENTS OBSERVED IN SUBJECTS WITH CLL/SLL 
Parameter 
All Grades (%) 
N=66 
Grade ≥3 (%) 
N=66 
Laboratory TLSa 
6 
6 
Hyperkalemiab 
20 
2 
Hyperphosphatemiab 
15 
3 
Hypocalcemiad 
9 
3 
Hyperuricemiae 
6 
2 
aLaboratory abnormalities that met ≥2 of the following criteria within 24 hours of each other: 
potassium >6 mmol/L, uric acid >476 μmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 
mmol/L; or were reported as TLS events. 
bHyperkalemia/blood potassium increased.
cHyperphosphatemia/blood phosphorus increased. 
dHypocalcemia/blood calcium decreased. 
eHyperuricemia/blood uric acid increased. 


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Please 
refer 
to 
the 
US 
prescribing 
information 
(https://www.accessdata.fda.gov/drugsatfda docs/label/2018/208573s009lbl.pdf) 
and 
www.venetoclax.com for the most up to date information including warnings and precautions, 
adverse reactions, and boxed warnings. 


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10 MEASUREMENT OF EFFECT 
10.1 MEASUREMENT OF EFFECT AND METHOD OF ASSESSMENT 
The determination of response and progression will be based on iwCLL criteria (Hallek et al., 2018). 
Radiographic and clinical tumor assessments will be subject to independent confirmation by the IRC 
in subjects enrolled to the Phase 3 stage of the study. 
Subjects will be assessed for response/progression by physical examination and laboratory tests. In 
addition, at any time during follow-up when clinical or laboratory findings suggest that the response 
may have improved from SD to PR, or from PR to CR, imaging should be performed to confirm the 
response. Conversely, imaging is required to document suspected PD by physical examination or 
suspected based on symptoms. 
CT scan with contrast is the preferred method for radiographic tumor assessment. MRI scanning may 
be used at the Investigator’s discretion in subjects for whom this may be a preferred alternative to 
CT scanning; however, if MRI is performed, a non-contrast CT of the chest should be performed. 
Contrast-enhanced scanning is preferred, but iodine-containing or gadolinium contrast material may 
be omitted in subjects for whom use of a contrast agent would be medically contraindicated. Chest x-
ray, ultrasound, endoscopy, laparoscopy, PET, radionuclide scans, or tumor markers will not be 
considered for response assessment. 
For radiographic evaluations, the same method of assessment and the same technique (e.g., scan type, 
subject position, dose of contrast, injection/scan interval) should be used to characterize each 
identified and reported lesion at baseline and during study treatment and follow-up. However, if a 
subject is imaged without contrast at baseline, subsequent assessments should be performed with 
contrast, unless medically contraindicated. 
Subjects will remain on study treatment until the occurrence of definitive disease progression, 
unacceptable toxicity, or withdrawal from the study due to Investigator decision or other reasons. 
For Phase 3 subjects, if PD is suspected, scans and relevant clinical data should be sent to central 
radiology for expedited PD review. This PD confirmation should be obtained prior to subject being 
removed for PD (except in rare cases where it is in the patients best interest to be discontinued 
immediately). Subjects who discontinue from study treatment (either for toxicity or physician 
choice) and have not progressed will continue to be followed for progression as per the protocol. 
10.2 RESPONSE REVIEW 
An IRC will provide a review of radiographic data and pertinent clinical data in order to provide 
expert interpretation of changes in tumor status. 
Please see imaging manual for detailed instructions for tumor assessment and submission of scans 
for independent review. 
10.3 IDENTIFICATION 
AND 
MEASUREMENT 
OF 
TUMOR 
LESIONS 
AND 
ORGANOMEGALY 


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10.3.1 TARGET LESIONS 
At baseline, up to 6 lymph nodes should be selected as target lesions that will be used to quantify the 
status of the disease during study treatment. Ideally, the target lesions should be located in disparate 
regions of the body. 
Target lesions will be measured and recorded at baseline and as per the study assessment schedule. 
The cross-sectional dimensions (the largest cross-sectional diameter, i.e., the LD × LPD) will be 
recorded (in cm) for each target lesion. The product of the perpendicular diameters (PPD) (in cm2) 
for each target lesion and the sum of the products (SPD) (in cm2) for all target lesions will be 
calculated and recorded. The baseline SPD will be used as references by which objective tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL/SLL progression will be characterized. All LD and LPD 
diameters will be reported in centimeters and all PPDs and SPDs will be reported in centimeters 
squared. 
A nodal mass may be selected as a measurable nodal target lesion if it is ≥ 1.5 cm in long axis diameter 
and > 1.0 cm in short axis diameter. At follow-up time points, the LDs for individual lesions and the 
SPD of all nodal target lesions will be considered. 
A new node that measures ≥1.5 cm in the longest diameter (LD) will be considered progressive 
disease. 
In cases in which a large lymph node mass has split into multiple components, all sub-components 
regardless of size will be used in calculating the SPD. Progression of the lesion will be based on the 
SPD of sub-components. Lesion sub-components will have the true PPDs calculated. Similarly, lesion 
sub-components that are visible but neither abnormal nor measurable will have the default PPD of 
1.0 cm2 (1.0 cm × 1.0 cm) used in calculating the SPD. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer be 
separated by this boundary, the newly merged lesion will be measured bi-dimensionally. 
10.3.2 SPLEEN AND LIVER 
Both the spleen and liver will be assessed by CT/MRI scan and by physical examination at baseline 
and as per the study assessment schedule. The baseline and nadir values for the longest vertical 
dimension (LVD) of each organ will be used as reference to characterize the objective tumor response 
of the measurable dimensions of the CLL/SLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters. 
By imaging, the spleen will be considered enlarged if it is >13 cm in LVD, with the LVD being obtained 
by multiplying the number of sections on which the spleen is visualized by the thickness of the 
sections (e.g., if the spleen is seen in 14 contiguous cross-sectional images with 0.5 cm thickness, the 
LVD is recorded as 7 cm). 
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of the 
spleen at baseline or nadir, not changes relative to the total splenic LVD. 


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A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the spleen in its LVD 
or decrease to ≤ 13 cm by imaging is required for declaration of a splenomegaly response. Conversely, 
an increase in splenic enlargement by ≥ 50% from nadir (minimum increase of 2 cm) is required for 
declaration of splenic progression. By imaging, the liver will be considered enlarged if it is >18 cm in 
LVD. 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the liver in its LVD 
or decrease to ≤ 18 cm is required for declaration of a hepatomegaly response. Conversely, an 
increase in liver enlargement by ≥ 50% from nadir (minimum increase of 2 cm) is required for 
declaration of hepatic progression. 
Splenic and/or hepatic progression, if the only criteria for PD, must be documented by CT/MRI scan. 
10.3.3 NON-TARGET LESIONS 
Any other measurable and abnormal nodal lesions not selected for quantitation as target lesions may 
be considered non-target lesions. In addition, non-measurable evidence of CLL/SLL such as nodal 
lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal disease, 
ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal masses that are 
not confirmed and followed by imaging techniques, cystic lesions, previously irradiated lesions, and 
lesions with artifacts may be considered as non-target disease. 
The presence or absence of non-target disease should be recorded at baseline and as per the study 
assessment schedule. If present at baseline, up to 6 non-target lesions should be recorded. The non-
target disease at baseline will be used as a general reference to further characterize regression or 
progression of CLL/SLL during assessments of the objective tumor response during treatment. 
Measurements are not required, and these lesions should be followed as “present” or “absent”. 
10.4 DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION 
Responses will be categorized as CR, CRi, nPR, PR, SD, or PD. In addition, a response category of not 
evaluable (NE) is provided for situations in which there is inadequate information to otherwise 
categorize response status, and partial response with lymphocytosis (PR-L) for subjects who have an 
elevated absolute lymphocyte count but otherwise meet all criteria for a PR. 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference for 
disease progression the smallest measurements recorded since treatment started). 
10.4.1 COMPLETE RESPONSE 
To satisfy criteria for a CR, all of the following criteria must be met: 
x
No evidence of new disease 
x
ALC in peripheral blood of <4 x 109/L 
x
Regression of all nodal masses to normal size <1.5 cm in the LD 
x
Normal spleen and liver size 
x
No constitutional symptoms 


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x
Cytological or pathological evaluation of the BM smear or biopsy must be at least 
normocellular for age, without evidence for typical CLL/SLL lymphocytes by morphological 
criteria. This evaluation is not based on a flow cytometry–based MRD assessment 
x
Peripheral blood counts meeting all  the following criteria: 
o
ANC ≥1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF); 
o
Platelet count ≥100 x 109/L without need for exogenous growth factors; 
o
Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (e.g., erythropoietin); 
10.4.2 COMPLETE RESPONSE WITH INCOMPLETE MARROW RECOVERY (CRi) 
Subjects who fulfill all the criteria for a CR (including BM criteria) but who have a persistent anemia, 
thrombocytopenia, or neutropenia or a hypocellular BM that is related to prior or ongoing drug 
toxicity (and not to CLL/SLL) will be considered as a CR with incomplete marrow recovery (CRi). 
10.4.3 PARTIAL RESPONSE 
To satisfy criteria for a PR, all of the following criteria must be met: 
x
No evidence of new disease; 
x
A change in disease status meeting ≥2 of the following criteria, with the exception that if only 
1 parameter was abnormal before therapy, only 1 needs to improve:  
o
In a subject with baseline lymphocytosis (ALC ≥4 x 109/L), a decrease in peripheral 
blood ALC by ≥50% from baseline; or a decrease to <4 x 109/L; 
o
A decrease by ≥50% from the baseline in the SPD of the target nodal lesions and no 
new enlarged lymph nodes (diameter > 1.5cm); 
o
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 10.3.2; 
o
In a subject with enlargement of the liver at baseline, a hepatomegaly response as 
defined in Section 10.3.2; 
o
A decrease by ≥50% from baseline in the CLL/SLL marrow infiltrate or in B-lymphoid 
nodules. 
x
No target, splenic, liver, or non-target disease with worsening that meets the criteria for 
definitive PD 
x
Peripheral blood counts meeting 1 of the following criteria: 
o
Platelet count >100 x 109/L or ≥50% increase over baseline without need for 
exogenous growth factors; 
o
Hemoglobin >110 g/L (11.0 g/dL) or ≥50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (e.g., erythropoietin). 
10.4.4 PARTIAL RESPONSE WITH PERISTENT LYMPHOCYTOSIS (PR-L) 
Subjects who fulfill all the criteria for a PR but have not had a decrease in peripheral blood ALC by 
≥50% from baseline or a decrease to <4 x 109/L will be considered as a PR with persistent 
lymphocytosis (PR-L). 
10.4.5 STABLE DISEASE 
To satisfy criteria for SD, the following criteria must be met: 


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x
No evidence of new disease; 
x
There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD.
10.4.6 DEFINITIVE DISEASE PROGRESSION 
The occurrence of any of the following events indicates definitive PD when compared with nadir 
values: 
x
Evidence of any new disease: 
o
A new node that measures ≥1.5 cm in the LD; 
o
An increase by ≥50% in greatest determined diameter of any previous site (≥1.5 cm); 
o
New or recurrent splenomegaly, with LVD > 13 cm; 
o
New or recurrent hepatomegaly, with LVD > 18 cm; Unequivocal reappearance of an 
extra-nodal lesion that had resolved; 
o
A new unequivocal extra-nodal lesion of any size; 
o
*New non-target disease (e.g., effusions, ascites, or other organ abnormalities related to 
CLL/SLL). 
*Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence alone of PD 
unless histologically confirmed. Thus, a declaration of PD should not be made if this is the only 
manifestation of apparently new disease. 
x
Evidence of worsening of target lesions, spleen or liver, or non-target disease: 
o
Increase from the nadir by ≥50% from the nadir in the SPD of target lesions; 
o
Increase from the nadir by ≥50% in the LD of an individual node or extra-nodal mass that 
now has an LD of ≥1.5 cm; 
o
Splenic progression, defined as an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and LVD >13 cm); 
o
Hepatic progression, defined as an increase in hepatic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and LVD >18 cm); 
o
Unequivocal increase in the size of non-target disease (e.g., effusions, ascites, or other 
organ abnormalities related to CLL/SLL); 
o
Transformation to a more aggressive histology (e.g., Richter’s syndrome) as established 
by lymph node or other tissue biopsy (with the date of the biopsy being considered the 
date of CLL/SLL progression if the subject has no earlier objective documentation of 
CLL/SLL progression). 
x
Occurrence of cytopenias (decrease in platelet count or hemoglobin) directly attributable to 
CLL/SLL and unrelated to autoimmune cytopenias confirmed by BM biopsy showing an 
infiltrate of clonal CLL/SLL cells 
o
The current platelet count is <100 x 109/L and there has been a decrease by ≥50% from 
the highest on study platelet count at least 3 months after treatment; 
o
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by ≥20 
g/L (2 g/dL) from the highest on study hemoglobin at least 3 months after treatment. 
If there is uncertainty regarding whether there is true progression, the subject should continue study 
treatment and remain under close observation pending confirmation of progression. In particular, 
worsening of constitutional symptoms in the absence of objective evidence of worsening CLL/SLL 


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will not be considered definitive disease progression; in such subjects, both CLL/SLL-related and 
non-CLL/SLL-related causes for the constitutional symptoms should be considered. 
Worsening of disease during temporary interruption of study treatment (e.g., for intercurrent illness) 
is not necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other 
relevant evaluations should be considered in order to document whether definitive disease 
progression has occurred. Subjects who meet the criteria for PD at any assessment may, in 
consultation with the Study Chair, remain on study for confirmation of PD at the following disease 
assessment. If subsequent evaluations suggest that the subject has experienced persistent definitive 
CLL/SLL progression, then the date of progression should be the timepoint at which progression was 
first objectively documented. 
10.4.7 NON-EVALUABLE 
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 
x
There are no images or inadequate or missing images; 
x
Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy). 
A time point will be considered to have a response of NE if any target lesion is missing. PD may be 
assigned at any time point regardless of the extent of missing target or non-target lesions. Missing 
non-target lesions will not impact the ability to assess for response or disease progression. 
10.4.8 LYMPHOCYTOSIS DURING THERAPY 
Upon initiation of umbralisib, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from 
baseline and above ALC of 5,000/mcL) may occur. The onset of isolated lymphocytosis usually occurs 
during the first few weeks of umbralisib therapy and usually resolves within 3 to 4 months. Subjects 
with lymphocytosis in the absence of other signs of progression should be continued on study drug 
until the occurrence of definitive disease progression (i.e., disease progression that is manifest by 
worsening CLL/SLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy. 


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11 STATISTICAL CONSIDERATIONS 
Details of the analyses will be provided in the Statistical Analysis Plan. 
11.1 SAMPLE SIZE AND POWER 


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11.2 GENERAL ANALYSIS CONVENTION 
Unless otherwise stated, all analyses will be performed using SAS Version 9.2 or higher. 
Summary tabulations will display the number of observations, mean, standard deviation, median, 
minimum, maximum, and appropriate percentiles for continuous variables, and the number and 
percentage by category for categorical data. Summaries will present data by cohort and overall, if 
appropriate. The data listings will include all available efficacy and safety data. 
11.3 ANALYSIS POPULATION 
The safety population will consist of all subjects who received at least one dose of study drug 
(ublituximab, umbralisib, or venetoclax). For the Phase 2 component, the ITT population will consist 
of all subjects who received at least one dose of each study drug (ublituximab, umbralisib, and 
venetoclax). 


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For Phase 3, the ITT population will consist of all randomized subjects, regardless of administration 
of study treatment. Analyses of this population will assign subjects the treatment they were 
scheduled to receive, regardless of any errors of dosing or dose modifications. Subjects who received 
treatment in the group that is different from what they have been randomized to, will be noted in the 
clinical study report. The ITT population is the primary analysis population for efficacy analyses. 
The per protocol population will include all ITT subjects without major protocol violations. Major 
protocol violations will be documented. Analyses based on per protocol population may be 
performed. 
11.4 SUBJECT DISPOSITION 
Subject disposition summaries will include the number and percentage of enrolled/randomized 
subjects in the safety, ITT, and per protocol populations. The summaries will also include the reasons 
for permanent discontinuation of study treatment and study. 
11.5 SUBJECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline demographic and clinical characteristics will be summarized as percentages for categorical 
variables and as mean, standard deviation, median, minimum and maximum for continuous 
measures. The analyses of baseline characteristics will be performed for the ITT population. 
11.6 MEDICAL HISTORY 
Medical history will be captured at the screening visit. Medical history will be coded using MedDRA 
and will be summarized by MedDRA system organ class and preferred term for the safety population. 
11.7 EXTENT OF EXPOSURE 
The dose (mg) of study drugs administered, the total number of doses of study drugs, and the 
duration of treatment (number of study cycles) will be summarized with descriptive statistics. The 
number and percentage of subjects whose dose is modified at any time will be summarized by each 
type of modification by cycle and overall. 
11.8 EFFICACY ANALYSES 
Each subject will be assigned to one of the following categories: 1) CR (including CRi), 2) PR, 3) PR-
L, 4) SD, 5) PD, 6) early death from malignant disease, 7) early death from toxicity, 8) early death 
because of other cause, or 9) unknown (not assessable, insufficient data). 
Many of the efficacy measures will be based on disease assessments. The best clinical response as 
well as disease progression may be assessed by an IRC. Definitive disease progression will be based 
on standard criteria (Hallek et al., 2018) occurring for any reason (e.g., increasing lymphadenopathy, 
organomegaly or bone marrow involvement; decreasing platelet count, hemoglobin, or neutrophil 
count; or worsening of disease-related symptoms) other than treatment-related lymphocytosis. 


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11.9 SAFETY ANALYSES 
Safety analyses will be performed using the safety population. Safety analyses will be primarily based 
on the incidence, severity, and type of AEs, as well as on clinically meaningful laboratory results, 
physical examination, and vital signs as available. Safety variables will be tabulated and presented by 
the dose of ublituximab, umbralisib, and/or venetoclax actually received. Exposure to study 
treatment and reasons for discontinuation of study treatment will also be tabulated. 
Detailed information collected for each AE will be included in a listing: AE term, start/stop dates of 
the AE, seriousness, severity, relationship to study drug(s), action taken, and outcome. In addition, 
the number and percentage of subjects experiencing at least one treatment-emergent AE will be 
tabulated by body system, preferred term, and CTCAE grade. Treatment-emergent AEs, drug-related 
AEs, AESIs, SAEs, AEs with a fatal outcome, and AEs leading to discontinuation/dose modification 
will be further summarized. Summary statistics for actual values and for changes from baseline will 
be tabulated for clinical laboratory results by scheduled visit. Subjects with laboratory values outside 
of the normal reference range at any post-baseline assessment will be summarized and graded per 
NCI CTCAE Version 5.0 as applicable. Subject incidence of abnormal laboratory results will be 
summarized by treatment group and maximum grade for each abnormal laboratory finding. 
11.10 MISSING VALUE HANDLING PROCEDURES 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing. The algorithms for imputation of partial dates vary depending upon the parameter and are 
presented in the Statistical Analysis Plan. 
11.11 STATISTICAL ANALYSES 
11.11.1 PRIMARY EFFICACY VARIABLES 
11.11.1.1 PROGRESSION-FREE SURVIVAL (PHASE 3) 
PFS is defined as the number of days between randomization and the date of progression (as 
confirmed by the IRC) or death due to any cause, whichever occurs first.  Subjects who had no event 
(progression or death) will be censored at the day of their last adequate disease assessment. If no 
baseline or post-baseline assessment is available, the subject will be censored at the date of 
randomization. If death or PD occurs after 2 or more consecutive missing disease assessments, 
censoring will occur at the date of the last adequate disease assessment prior to the missed 
assessments. The use of a new anticancer therapy prior to the occurrence of PD will result in 
censoring at the date of last adequate disease assessment prior to initiation of new therapy. 
Hypothesis testing for comparison between the treatment arms will be performed using a stratified 
(by randomization stratification factors) log-rank test via SAS Lifetest procedures. For each 
treatment arm, the median duration of PFS and the proportion of subjects alive and progression-free 
at 6, 12, 24, and 36 months will be estimated using the Kaplan-Meier method. For each estimate, a 
95% confidence interval will be reported. The hazard ratio with 95% confidence interval will be 
estimated by stratified (by randomization stratification factors) Cox proportional hazards model. 


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Sensitivity analyses will be conducted, including using investigator assessment of PFS, using different 
censoring rules (ignoring new anti-cancer therapy, ignoring 2 or more consecutive missing 
assessments). In addition, the potential impact of COVID-19 on patients for the efficacy results may 
be included in the sensitivity analysis (censoring all subjects at the last adequate assessment if 
subject discontinued study or death due to COVID-19). Other sensitivity analyses may be conducted 
as needed. 
11.11.1.2 COMPLETE RESPONSE RATE (PHASE 2) 
CR rate is defined as the percent of subjects who achieve a CR or CRi. Estimated CR rate with exact 
95% confidence interval based on Clopper-Pearson method will be presented for the Phase 2 
component.  
11.11.1.3 OVERALL RESPONSE RATE (PHASE 2) 
ORR will be determined according to the criteria of the iwCLL (Hallek et al., 2018). 
ORR is defined as percent of subjects who achieve CR, CRi, PR or PR-L. Estimated ORR with exact 95% 
confidence interval based on Clopper-Pearson method will be presented for the Phase 2 component.  
11.11.2 SECONDARY EFFICACY OUTCOMES 
11.11.2.1 MINIMAL RESIDUAL DISEASE NEGATIVITY 
The MRD negativity rate is defined as the proportion of subjects who achieve MRD negative status 
post-baseline. Subjects who do not have an MRD assessment at any post-baseline visits will be 
considered non-responders and will be included in the denominator when calculating MRD 
negativity rate. Estimated MRD negativity rate with exact 95% confidence interval based on Clopper-
Pearson method will be presented for the Phase 2 component, while the Phase 3 will utilize a 
Cochran-Mantel-Haenzel (CMH) test stratified by the randomization factors. 
11.11.2.2 DURATION OF RESPONSE 
DOR defined as the interval from the first documentation of CR, CRi, PR or PR-L to the earlier of the 
first documentation of definitive disease progression or death from any cause. This variable will be 
analyzed using Kaplan-Meier method for responders only. The estimated median DOR with 95% 
confidence interval will be presented. 
11.11.2.3 TIME TO RESPONSE (TTR) 
TTR is defined as the interval from enrollment to first documentation of CR, CRi, PR, or PR-L. TTR 
will be analyzed via Kaplan-Meier method. 
11.11.2.4 COMPLETE RESPONSE RATE 
For the Phase 3 portion of the study, CR rate will be analyzed using a Cochran-Mantel-Haenzel (CMH) 
test stratified by the randomization factors. Additional logistic analyses model may be used to assess 
the impact of demographic and baseline parameters. 
11.11.2.5 OVERALL RESPONSE RATE 


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For the Phase 3 portion of the study, ORR rate will be analyzed using a CMH test stratified by the 
randomization factors. Additional logistic analyses model may be used to assess the impact of 
demographic and baseline parameters. 
11.11.2.6 OVERALL SURVIVAL 
Overall Survival (OS) is defined as the interval from randomization to death from any cause.  As 
subjects are expected to survive for a long time relative to the duration of the study, OS analysis may 
not be reliable due to heavily censored data.  OS data will be censored at the last documented date 
that the subject is confirmed alive for subjects who withdraw consent or are lost to follow-up prior 
to the end of the study, and for subjects whose vital status in the study cannot be determined.  The 
Kaplan-Meier estimator for OS will be presented for all subjects in the ITT population. An interim 
analysis of OS will occur at the time of the PFS analysis, and a final OS analysis will occur 1 year after 
the PFS analysis. 
11.11.3 INTERIM ANALYSES 
One interim analysis is planned for each of the Treatment Naïve and Previously Treated cohorts 
during the conduct of the study to assess efficacy and safety of U2-V compared with U2 and to allow 
for release of the results earlier than the planned final analysis in case of significant difference in 
treatment effect in favor of U2-V. 
For the Treatment Naïve cohort, the interim analysis will be performed when approximately 115 PFS 
events have occurred in both treatment arms combined (67% of the 172 events required for the final 
primary efficacy analysis). The stopping boundary is based on a Lan-DeMets O’Brien Fleming type 
spending function. Based on 115 events, the duration of PFS will be tested at the interim analysis, 
approximately corresponding to a 1-sided p-value of 0.00618 (HR of 0.65). If the number of events is 
not exactly 115 by the time of the analysis, then the boundary will be updated to reflect the number 
of events.  
For the Previously Treated cohort, the interim analyses will be performed when approximately 82 
PFS events have occurred in both treatment arms combined (67% of the 122 events required for the 
final primary efficacy analysis). The stopping boundary is based on a Lan-DeMets O’Brien Fleming 
type spending function. Based on 82 events, the duration of PFS will be tested at the interim analysis, 
approximately corresponding to a 1-sided p-value of 0.00618 (HR of 0.60). If the number of events is 
not exactly 82 by the time of the analysis, then the boundary will be updated to reflect the number of 
events.  
The DSMB will evaluate efficacy and safety data at the interim analyses and recommend if the study 
result for each individual cohort should be released early.  The same stratification factors as specified 
in the primary efficacy endpoint analysis will be used. For each of the treatment naïve and previously 
treated cohorts individually, if the p-value of the stratified 1-sided log-rank test is ≤ 0.00618 for the 
IRC-assessed PFS analysis and the observed HR is favorable for the U2-V combination treatment, the 
cohort will have shown statistically significantly longer duration of PFS in the U2-V arm and will have 
met its primary efficacy endpoint. The results are expected to be presented to the health authorities 
for potential registrational purposes. 
The final primary efficacy analyses for each cohort will be performed when approximately 172 PFS 
events and 122 PFS events have been observed in the treatment naive and previously treated cohorts, 


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respectively, where PFS will be tested at the significance level of approximately 0.0462 (two-sided), 
corresponding to detecting an HR of ≤ 0.74 or less for the treatment naïve cohort and an HR of ≤ 0.70 
or less for the previously treated cohort. If necessary, the statistical test level will be adjusted to 
incorporate the alpha spent at the interim analysis so that the overall type I error rate will be 
maintained at the 2-sided 0.05 level. 
11.11.4 MULTIPLICITY OF PHASE 3 PART 
In the efficacy analyses, the following gatekeeping procedures will be implemented to preserve the 
overall type I error rate across the primary and secondary endpoints of the Phase 3 part of the study 
at a 2-sided significance level of 0.05.  
The type I error control is applied separately to the two cohorts of the study (the treatment naïve 
cohort and the previously treated cohort) as they are intended to be conducted and analyzed 
independently and have independent powering. 
The primary endpoint PFS analysis will serve as the gatekeeper for the secondary endpoint analyses, 
i.e., the primary efficacy hypothesis must be rejected before the efficacy hypotheses for the secondary 
efficacy endpoints can be evaluated.  
The secondary endpoints will be sequentially tested at the 2-sided 0.05 significance level in the 
following order: 
x
Complete Response (CR) Rate 
x
Rate of Undetectable Minimal Residual Disease (uMRD) 
x
Overall Response Rate (ORR) 
x
Overall Survival (OS) 
If a null hypothesis is not rejected, formal sequential testing will be stopped and only nominal 
significance will be cited for the remaining secondary endpoints.  Note, CR Rate, uMRD, and ORR will 
only be tested once either at the interim or final analysis depending on the outcome of the PFS 
analysis. 
11.11.5 STOPPING RULES 
For the Phase 3 portion of the study the following stopping rules will be followed:  
x
>2 treatment-related Grade 5 events of the same preferred term; 
x
>5% of enrolled patients discontinuing all therapies due to a treatment-related hematologic 
toxicity of the same preferred term; OR  
x
>5% of enrolled patients discontinuing all therapies due to a treatment-related  
non-hematologic toxicity of the same preferred term. 


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12 ADVERSE EVENT REPORTING AND CRITERIA 
12.1 DEFINITION OF ADVERSE EVENT 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product. An AE does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporarily associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline condition. 
An AE can occur at any time, including during screening, run-in or washout periods, even if no study 
treatment has been administered. It is the responsibility of the Investigator, based on their 
knowledge and experience, to determine which untoward medical occurrences should be considered 
AEs. 
12.2 CRITERIA FOR SERIOUS ADVERSE EVENTS (SAE) 
The definitions of SAEs are described below. The Investigator is responsible for ensuring that all staff 
involved in the study are familiar with the content of this section. 
An SAE or reaction is defined as any untoward medical occurrence that meets at least one of the 
following criteria:  
x
Results in death: 
In the case of deaths, the event(s) leading to the death should be recorded and 
reported as SAE(s) with the outcome “Fatal”. The death itself will not be reported as 
an SAE, unless the cause of the death is unknown (e.g., in case of unexplained or 
sudden death); 
x
Is life-threatening: 
The term "life-threatening" refers to an event in which the subject is at immediate 
risk of death at the time of the event; it does not refer to an event which hypothetically 
might cause death if it was more severe; 
x
Requires inpatient hospitalization or prolongation of existing hospitalization; 
x
Results in persistent or significant disability/incapacity; 
A disability is defined as any substantial disruption of a subject’s ability to conduct 
normal life functions; 
x
Is a congenital anomaly/birth defect; and/or 
x
Is medically important. 
Medical and scientific judgement must be exercised in deciding whether an AE is 
considered “medically important”. Medically important events may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed 
in this definition. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
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Progression of disease (including fatal outcomes), if documented by use of appropriate method (for 
example, as per IWCLL Hallek et al., 2018), should not be reported as a SAE. 
Situations Not Considered SAEs: 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be treated 
as an SAE and immediately reported i.e., could meet the definition of important medical event): 
x
Emergency Department or Emergency Room; 
x
Hospitalization for drug administration, diagnostic procedure, or social circumstances; 
x
Outpatient or same day surgery units; 
x
Observation or short-stay unit; 
x
Rehabilitation facility; 
x
Hospice or skilled nursing facility; 
x
Nursing homes, Custodial care or Respite care facility. 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as an SAE to the Sponsor, but if 
hospitalization is prolonged due to an event this would be reportable to Sponsor or designee. 
Serious Versus Severe AEs: 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not synonymous. 
Severity is a measure of intensity; however, an AE of severe intensity need not necessarily be 
considered serious. For example, nausea which persists for several hours may be considered severe 
nausea but may not be considered an SAE. On the other hand, a stroke which results in only a 
limited degree of disability may be considered only a mild stroke but would be considered an SAE. 
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
eCRF. 
12.2.1 ADVERSE EVENT/SERIOUS ADVERSE EVENT GRADING 
The NCI CTCAE v5.0 is to be used for the grading of severity of AEs. 
For AEs not covered by the NCI CTCAE grading system, the following definitions should be used: 
x
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; 
x
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age 
appropriate instrumental ADL*; 
x
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**; 
x
Grade 4: Life-threatening consequences; urgent intervention indicated; 
x
Grade 5: Death related to AE. 


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Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
12.2.2 ADVERSE EVENTS / SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT 
The Investigator must also assess the causal relationship of any AE to the study drug(s) (whether no 
study drug, monotherapy or combination therapy was administered), based on available 
information, using the following guidelines: 
x
Not Related: Clear cut temporal and/or mechanistic relation to a cause other than the study 
drug(s) 
x
Doubtful: There is no reasonable possibility that the event is related to the study drug(s) but 
a definite cause cannot be ascertained 
x
Possible: There is still a reasonable possibility that the cause of the event was the study 
drug(s) but there exists a more likely cause of the event such as complications of progressive 
disease 
x
Probable: The most likely cause of the event is the study drug(s) but other causes cannot be 
completely excluded 
x
Definite: Clear cut temporal and/or mechanistic relation to the study drug(s). All other 
causes have been eliminated. Events classified as definite will often be confirmed by 
documenting resolution on discontinuation of the study drug and recurrence upon 
resumption 
12.2.3 ADVERSE EVENT/SERIOUS ADVERSE EVENT RECORDING 
All non-serious AEs regardless of relationship to the study drugs are to be recorded on the eCRF 
from Cycle 1/Day 1 until 30  days after discontinuation or completion of protocol-specific 
treatment. . Immune-related AE (irAEs) are to be recorded on the eCRF from Cycle 1/Day 1 until 90 
days after study discontinuation or completion of protocol-specific treatment. All AEs must include 
the Investigator’s assessment of the event’s seriousness, severity, and causality to study drug. 
All serious AEs (i.e. SAEs) regardless of relationship to the study drug(s) are to be recorded on the 
eCRF and the SAE Report Form from signing of informed consent until 30  days after 
discontinuation or completion of protocol-specific treatment. Immune-related SAEs (irSAEs) are to 
be recorded on the eCRF and SAE Report Form from signing of informed consent until 90 days after 
study discontinuation or completion of protocol-specific treatment. All SAEs must include the 
Investigator’s assessment of the event’s seriousness, severity, and causality to study drug. 
If an AE is deemed by the Investigator as serious, as per the SAE criteria, it should be reported as 
soon as possible and no later than 24 hours of awareness to the Sponsor or designee using the 
SAE Report Form and recorded within the same timeframe on the eCRF. Follow-up information for 
SAEs and information on non-serious AEs that become serious should also be reported as soon as 
possible but no later than 24 hours to the Sponsor or designee using the SAE Report Form and 
recorded on the eCRF. SAEs should be followed until resolution (including results of an autopsy 
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and transmission of the SAE Report Form should be confirmed by the site personnel submitting the 
form. 
Disease progression or death due to disease progression should be reported by the Investigator as a 
SAE only if it is assessed that the study drugs caused or contributed to the disease progression (i.e., 
by a means other than lack of effect). Unrelated events of CLL/SLL progression should be captured 
on the appropriate eCRF and not on the AE eCRF. 
Other untoward events occurring in the framework of the study are also to be recorded as AEs (i.e., 
AEs that occur prior to assignment of study drug that are related to a protocol-mandated 
intervention, including invasive procedures such as biopsies, medication washout, or no treatment 
run-in).  
All AEs (non-serious and serious) resulting in discontinuation should be followed until resolution 
or stabilization of the event for up to 30 days (for any AEs/SAEs) or 90 days (for irAEs/irSAEs) as 
part of the study follow-up period. All new AEs (non-serious and serious) occurring during the 
follow-up period must be reported and followed until resolution unless, in the Investigator’s 
judgement, these are not likely to improve due to the underlying disease.  
After the 30-day (for any AEs/SAEs) or 90-day (for irAEs/irSAEs) follow-up period, only AEs and 
SAEs, which include death, assessed by the Investigator as drug-related are to be reported in the 
eCRF or SAE Report Form, as applicable. 
After this period, investigators should report any deaths, serious adverse events, or other adverse 
events of concern that are believed to be related to prior treatment with study drug.  
Investigators must report SAEs and follow-up information to their responsible IRBs/Independent 
Ethics Committee (IEC) according to the policies of the responsible IRB/IEC. 
Investigators should use correct medical terminology/concepts and avoid colloquialisms and 
abbreviations when recording AEs or SAEs on the eCRF and/or SAE Report Form. 
12.2.3.1 ABNORMAL LABORATORY VALUES, PHYSIOLOGICAL RESULTS, AND VITAL SIGNS 
Abnormal laboratory values, physiological test results (e.g., QTc prolongation in electrocardiogram 
[ECG]), or vital signs should not be reported as an AE unless any criterion for an SAE is fulfilled, if it 
results in the subject to discontinue study drug, if it is associated with an overdose, or in the 
Investigator’s judgement the abnormality should be reported as an AE. 
If an abnormal finding is associated with a clinical sign and/or symptom, the sign or symptom 
should be reported as an AE, and the associated laboratory value or vital sign should be considered 
additional information that must be collected in the relevant eCRF. If the laboratory abnormality is 
a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report Form or 
AE eCRF.
12.3 DIAGNOSIS VS. SIGNS AND SYMPTOMS 


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All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the opinion 
of the Principal 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 
named 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 eCRF). If a diagnosis is subsequently established, it should be reported as 
follow-up information is available. If a diagnosis is determined subsequent to the reporting of the 
constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
12.4 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between subject evaluation time 
points. Such events should only be recorded once on the SAE Report Form and/or the eCRF. If a 
persistent AE becomes more severe (changes from a Grade 1 or 2 AE to a Grade 3 or 4 AE) or lessens 
in severity (changes from a Grade 3 or 4 AE to a Grade 1 or 2 AE), it should be recorded on a separate 
SAE Report Form and/or eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation time points, and 
subsequently recurs. All recurrent AEs should be recorded on an SAE Report Form and/or eCRF for 
each recurrence. 
12.5 DEATHS 
Deaths that occur during the protocol-specified AE reporting period and are attributed by the 
Investigator solely to progression of the subject’s disease progression for up to 30 days post the last 
dose of study drug will be recorded on the appropriate study eCRF and not reported on the AE page 
of the eCRF and will be exempted from SAE reporting. 
All other on-study deaths (i.e. not solely attributed to CLL/SLL progression), will be reported to the 
Sponsor or designee on an SAE Report Form and recorded on the AE page of the eCRF. 
When recording the death as an SAE, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the AE page of the eCRF. If the cause of 
death is unknown and cannot be ascertained at the time of reporting, record “Death NOS” on the eCRF 
AE page. 
12.6 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY 
Any AE that results in hospital admission or prolongs hospitalization should be documented and 
reported as an SAE. There are some hospitalization scenarios that do not require reporting as an SAE 
when there is no occurrence of an AE. See Section 12.2.1 Serious Adverse Event Criteria. 
12.7 PRE-EXISTING MEDICAL CONDITIONS 


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A pre-existing relevant medical condition is one that is present at the start of the study. Such 
conditions should be recorded on the study’s appropriate medical history eCRF. A pre-existing 
medical condition should be recorded as an AE or SAE only if the frequency, severity, or character of 
the condition worsens during the study. When recording such events on the appropriate SAE Report 
Form and/or eCRF, it is important to convey the concept that the pre-existing condition has changed 
by including applicable descriptors. 
12.8 PREGNANCY 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
During the study, all female subjects of child-bearing potential (the definition of females of child-
bearing potential are listed in Appendix A - Contraception Guidelines ) must contact the treating 
Investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period should be reported to the treating Investigator).  
If an Investigator suspects that a subject may be pregnant prior to administration of study drug(s), 
the study drug(s) must be withheld until the result of the pregnancy test is confirmed. If a pregnancy 
is confirmed, the subject must not receive any study drug(s) and must be discontinued from the study. 
If an Investigator suspects that a subject may be pregnant after the subject has been receiving study 
drug(s), the study drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed. If a pregnancy is confirmed, the study drug(s) must be immediately and permanently 
stopped, the subject must be discontinued from the study, and the Investigator must notify the Study 
Chair or Medical Monitor within 24 hours of awareness. 
Pregnancy should be recorded on a Pregnancy Report Form and reported by the Investigator to the 
Sponsor or designee in the same timeframe (within 24 hours of awareness) as reporting an SAE.  
The Pregnancy should be followed up to 6 months after the end of the pregnancy, which can include 
birth, spontaneous abortion, or voluntary termination, to collect the outcome with details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications, as applicable. Follow-up to a pregnancy should be recorded on a Pregnancy 
Report Form and should include an assessment of the causal relationship to the study drug and 
reported by the Investigator to the Sponsor or designee. Pregnancy outcomes must be reported for 
the female partners of any males who took study drug on the Pregnancy Report Form. Consent to 
report information regarding these pregnancy outcomes should be obtained from the mother.  
Any SAE experienced during pregnancy must be reported on the SAE Report Form. Congenital 
anomalies/birth defects always meet SAE criteria, and should therefore be reported as an SAE using 
the previously described process for SAE reporting. 
12.9 STUDY DRUG OVERDOSE 
Symptomatic and asymptomatic overdose must be reported in the appropriate eCRF. Any accidental 
or intentional overdose with any of the study drug(s) that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the Sponsor or designee immediately (within 24 hours of 
awareness) using the SAE Report Form, and following the same process described for SAEs. If a study 


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drug overdose occurs, subjects should stop study drug and be clinically monitored as appropriate, 
managing symptoms/side effects that may occur. 


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13 CLINICAL DATA COLLECTION AND MONITORING 
13.1 DATA AND SAFETY MONITORING BOARD 
For the Phase 3 randomized stage of this study, an independent Data Safety Monitoring Board 
(DSMB) will be established to advise the Sponsor on safety and provide benefit/risk oversight of the 
study. This independent DSMB will meet approximately every 6-9 months to review the AEs, SAEs, 
and safety trends (if any) depending on enrollment. The DSMB will recommend changes in the 
protocol conduct or corrective actions as necessary. They may advise the Sponsor to terminate the 
study early or modify the protocol to address safety signals or benefit/risk concerns that they may 
identify. Relevant output from the DSMB meetings will be archived in the TGTX trial master file or 
designated controlled location. 
13.2 SITE MONITORING PLAN 
A study initiation site visit, a teleconference and/or a planned Investigator meeting will be performed 
to review Investigator responsibilities and protocol requirements. During the study, the Sponsor or 
Sponsor delegate will make visits to the sites as defined in the monitoring plan in order to review 
protocol compliance, examine eCRFs, laboratory data, safety data, and individual subject medical 
records, and ensure that the study is being conducted according to the protocol and pertinent 
regulatory requirements.  
Site monitoring shall be conducted to ensure the human subject protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality and 
meet the Sponsor, GCP/ICH and, when appropriate, regulatory guidelines. The Site Monitoring Plan 
shall define aspects of the monitoring process. 
13.3 CURRICULA VITAE AND FINANCIAL DISCLOSURES 
All Principal Investigators will be required to submit to the Sponsor or its designee a current signed 
curriculum vitae (CV), , and a completed FDA form 1572 (or equivalent) and financial disclosure 
statement. In addition, all sub-investigators will be required to submit to the Sponsor or its designee 
a current signed CV, and a completed financial disclosure statement. 
13.4 DATA OWNERSHIP AND PUBLICATION 
The results of and all data generated during the conduct of this study belong to the Sponsor, are 
considered Sponsor’s proprietary and confidential information, and are subject to the confidentiality 
provisions in the Clinical Trial Agreement (CTA) governing the participation of the Investigator in 
the study. Sponsor retains the sole and exclusive right to the first publication of the results of this 
study. Such publication is intended to be a multi-center publication, collected from all investigators 
and institutions participating in the study rather than publication based on individual site data. Any 
manuscripts, abstracts, or other presentation materials generated by Investigator must be reviewed 
and approved by the Sponsor prior to submission as set forth in the CTA and must meet all other 
applicable conditions set forth in the CTA. 


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14 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This study will be conducted according to the standards of Good Clinical Practice, ICH E6 Guidelines, 
CFR Title 21 and part 312, Declaration of Helsinki, applicable government regulations, institutional 
research policies and procedures and any other local applicable regulatory requirement(s).  
14.1 IRB APPROVAL 
The study protocol, ICF, IB, available safety information, subject-facing documents (e.g., study diary), 
advertisements), information about payments (i.e., PI payments) and compensation available to the 
subjects and documentation evidencing the PI’s qualifications must be submitted to the IRB per their 
guidelines for ethical review and approval prior to the study start. 
The PI/Sponsor and/or designee will follow all necessary regulations to ensure initial and ongoing, 
IRB study review. The PI/Sponsor (as appropriate) must submit and, where necessary, obtain 
approval from the IRB for all subsequent protocol amendments and changes to the informed consent 
document.  
Premature termination of this study may occur at the discretion of the Sponsor due to a safety 
concern, or a regulatory authority or ethics committee decision. If a study is prematurely terminated 
or discontinued, the Sponsor will promptly notify the investigator. After notification, the investigator 
must contact all participating subjects. 
. If applicable, the PI will notify the IRB at the end of the study, or if the study terminates early, the 
PI must notify the IRB of the termination. A reason for the early termination must be provided (as 
defined in Directive 2001/20/EC). 
14.2 REGULATORY APPROVAL 
As required by local regulations, the Sponsor will ensure approval of the appropriate regulatory 
bodies is obtained, prior to study initiation. If required, the Sponsor will also ensure that the 
implementation of substantial amendment to the protocol and other relevant study documents 
happen only after approval by the relevant regulatory authorities. 
Safety updates for ublituximab and/or umbralisib will be prepared by the Sponsor or its 
representative as required, for submission to the relevant regulatory authority. 
14.3 INSURANCE AND INDEMNITY 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and the Sponsor. 
14.4 INFORMED CONSENT 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study that are 


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relevant to the subject's decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of the 
study. Each consent form must include all of the relevant elements currently required by the 
responsible regulatory authority, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the study. Once the essential information has been provided to the prospective 
candidate, and the Investigator is sure that the individual candidate understands the implications of 
participating in this study, the candidate will be asked to give consent to participate in the study by 
signing an informed consent form. A notation that written informed consent has been obtained will 
be made in the subject’s medical record. A copy of the informed consent form, to include the subject’s 
signature, will be provided by the Investigator to the subject. Written informed consent for 
participation in the study must be obtained before performing any study-specific screening tests or 
evaluations. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
subjects, the subject’s consent to continue participation in the study must be obtained. 
14.5 CONFIDENTIALITY 
Subject Confidentiality 
Confidentiality of subject’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. To protect the 
personal data of subjects, Sponsor will assign a unique study number to each subject, which will be 
used on the eCRF or other documents submitted to the Sponsor. This information, together with the 
subject’s date of birth, will be used in the database for subject identification. Participant names or 
other information that would make the participant identifiable will not be entered in the eCRF or 
database or transferred in other documents submitted to Sponsor.  No material bearing a subject’s 
name will be kept on file by the Sponsor.  
Subjects will be informed of their rights within the ICF.  HIPAA regulations require that, in order to 
participate in the study, the subject should be informed of following: 
What protected health information (PHI) will be collected from subjects in this study; 
x
Who will have access to that information and why; 
x
Who will use or disclose that information; 
x
That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal or 
state privacy laws; 
x
The information collected about the research study will be kept separate from the subject’s 
medical records, but the subject will be able to obtain the research records after the 
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x
Whether the authorization contains an expiration date; and 
x
The rights of a research subject to revoke his or her authorization. 
In the event that a subject revokes authorization to collect or use his or her PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e., that the subject is alive) at the end of 
their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that the 
Investigator and institution permit authorized representatives of the Sponsor, the regulatory 
authorities and the IRB direct access to review the subject’s original medical records at the site for 
verification of study-related procedures and data. The subject must be informed about the potential 
for this type of monitoring and auditing access. 
14.6 INVESTIGATOR AND STAFF INFORMATION 
Personal data of the investigators and sub-investigators may be included in the Sponsor database 
and shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the Investigator or sub-Investigator, the Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
14.7 FINANCIAL INFORMATION 
The finances for this study will be subject to a separate written agreement between the Sponsor and 
applicable parties. Any Investigator financial disclosures as applicable to 21CFR Part 54 shall be 
appropriately provided. 


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15 RECORD RETENTION AND DOCUMENTATION OF THE STUDY 
15.1 DOCUMENTATION REQUIRED TO INITIATE STUDY 
 The Sponsor/Sponsor designee will ensure that documentation is required to be in place before the 
study may start, in accordance with FDA regulations and/or local regulatory authorities, ICH E6, and 
Sponsor SOPs will be available before any study sites are initiated..  
Documents at a minimum required to begin the study include, but are not limited to, the following: 
x
A signature authorized protocol and contract; 
x
A copy of the official IRB approval of the study and the IRB members list or assurance 
verification; 
x
Current Curricula Vitae for the principal Investigator and any associate Investigator(s) who 
will be involved in the study; 
x
Indication of appropriate accreditation for any laboratories to be used in the study and a copy 
of the normal ranges for tests to be performed by that laboratory; 
x
 Form FDA 1572 (Statement of Investigator), or equivalent appropriately completed and 
signed; 
x
A copy of the IRB-approved consent form  
x
Financial disclosure forms for all investigators listed on Form FDA 1572; 
x
GCP Certificate for study training; 
x
Verification of Principal Investigator acceptability from local and/or national debarment 
list(s). 
15.2 STUDY DOCUMENTATION AND STORAGE 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated study 
duties and should ensure that all persons assisting in the conduct of the study are informed of their 
obligations. All persons authorized to make entries and/or corrections on the eCRFs are to be 
included on this document. All entries in the subject’s eCRF are to be supported by source 
documentation . 
Source documents are the original documents, data, records and certified copies of original records 
of clinical findings, observations and activities from which the subject’s eCRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, 
medico-technical department and pharmacy records, diaries, microfiches, EKG traces, copies or 
transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence.  
The PI and study staff are responsible for maintaining a comprehensive and centralized filing system 
(Site Study File/SSF or ISF) of all study-related (essential) documentation, suitable for inspection at 
any time by representatives from the Sponsor and/or applicable regulatory authorities. The ISF/SSF 


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must consist of those documents that individually or collectively permit evaluation of the conduct of 
the study and the quality of the data produced. The ISF/SSF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP and 8 CFR Part 312.57, including key 
documents such as the IB and any amendments, protocol and any amendments, signed ICFs, IRB 
approval documents, Financial Disclosure forms, subject identification lists, enrollment logs, 
delegation of authority log, staff qualification documents, laboratory normal ranges, and records 
relating to the study drug s.. In addition, all original source documents supporting entries in the eCRF 
must be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest records 
as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application 
has been approved by FDA; or, in the event that the marketing application has not been approved by 
FDA, for no less than 2 years after the last shipment / delivery of the drug for investigational use is 
discontinued and FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation / records of IRB activities as per 21CFR Part 56.115 
for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not been 
approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating subjects (sufficient information to link records e.g., medical records), all original, signed 
informed consent forms, and copies of all eCRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents. The documents listed 
above must be retained by the Investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development or after the last 
marketing approval). The Sponsor or its representative will notify the Investigator(s)/institutions(s) 
when the study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, either the Sponsor 
or its representative should be prospectively notified. The study records must be transferred to an 
acceptable designee, such as another Investigator, another institution, or to Sponsor. The 
Investigator must obtain the Sponsor written permission before disposing of any records, even if 
retention requirements have been met. All study files will be maintained by the Sponsor or its 
representative throughout the study and will be transferred to the Sponsor at the conclusion of the 
study. 
15.3 AMENDMENTS TO THE PROTOCOL 
If an amendment to the protocol is required, the amendment will be originated by the Sponsor and 
approved by the Sponsor and the Study Chair. The written amendment must be submitted to the 
IRB/Ethics at the investigator’s facility for the approval per IRB/Ethics requirements. 


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The amendment will be submitted formally to the FDA or other regulatory authorities by the Sponsor 
as applicable. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
subjects, their consent to continue participation in the study should be obtained. 
15.4 DATA COLLECTION 
The study eCRF is the primary data collection instrument for the study. An electronic case report 
form will be utilized for the collection of all data and all data will be entered using the English 
language and should be kept current to enable the monitor to review the subjects’ status throughout 
the course of the study. 
In order to maintain confidentiality, only study number, subject number,  and partial date of birth 
will identify the subject in the eCRF. The Investigator will maintain a personal subject identification 
list (subject numbers with corresponding subject identifiers) to enable records to be identified and 
verified as authentic. Subject data/information will be kept confidential, and will be managed 
according to applicable local, state, and federal regulations. 
15.5 STUDY MONITORING, AUDITING, AND INSPECTING 
The Investigator will permit study-related monitoring, quality audits, and inspections by government 
regulatory authorities, the Sponsor or its representative(s) of all study-related documents (e.g., 
source documents, regulatory documents, data collection instruments, case report forms). The 
Investigator will ensure the capability for inspections of applicable study-related facilities. The 
Investigator will ensure that the study monitor or any other compliance or QA reviewer is given 
access to all study-related documents and study-related facilities. 
At the Sponsor’s discretion, Source Document Verification (SDV) may be performed on all data items 
or a percentage thereof. 
15.6 QUALITY ASSURANCE AND QUALITY CONTROL 
Independent auditing may be conducted during the conduct of the study to assess compliance with 
GCP and applicable regulatory requirements. Data or documentation audited shall be assessed for 
compliance to the protocol, accuracy in relation to source documents and compliance to GCP and 
applicable regulations. 
Each study site shall be required to have processes that enable compliant study conduct, and 
investigator oversight of data generation & collection, recording of data/documentation and 
reporting according to the protocol, GCP and any applicable local, national or international 
regulations. 
Accurate and reliable data collection will be ensured by verification and cross check of the eCRFs 
against the investigator’s records by the study monitor (source document verification) Collected data 


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will be entered into a computer database and subject to electronic and manual quality assurance 
procedures. 
15.7 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  By conducting this study, the 
Investigator affirms to the Sponsor that he or she will maintain, in strict confidence, information furnished 
by the Sponsor including the results of and data generated from this study, except as exempted for regulatory 
purposes.  
A clinical study report will be prepared upon completion of the study. The format of the clinical study 
report will comply with ICH E3 guidelines for structure and content of a clinical study report. The 
Sponsor will comply with any applicable local laws/regulations regarding the posting of study 
results.
The financial disclosure information will be provided to the Sponsor prior to study participation from 
all PIs and Sub-Investigators who are involved in the study and named on the FDA 1572 form. 
All data generated during the conduct of this study is owned by the Sponsor and may not be used by 
the Investigator or affiliates without the expressed written consent of the Sponsor. 
All manuscripts, abstracts, or other presentation materials generated by site investigators must be 
reviewed and approved by the Sponsor prior to submission as set forth in the clinical trial agreement 
(CTA) governing the Investigator or his/her institution’s participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to Sponsor at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA. 


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J., Robak, T., De La Serna, J., Jaeger, U., Cartron, G., Montillo, M., Humerickhouse, R., Punnoose, E. 


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17 APPENDIX A - CONTRACEPTION GUIDELINES  
Female Not of Child-bearing Potential are Defined as Follows: 
Women are considered post-menopausal and not of child-bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum 
FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral 
oophorectomy (with or without hysterectomy) at least 6 weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow-up hormone 
level assessment is she considered not of child-bearing potential. 
Contraception Guidelines for Females of Child-Bearing Potential: 
Females of child-bearing potential, defined as all females physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 4 months after the last 
treatment dose of ublituximab and for at least 30 days after last treatment dose of umbralisib or 
venetoclax. The highly effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male 
partner should be the sole partner for that subject. 
4. Oral contraception, injected or implanted hormonal methods. 
5. Use of a combination of any 2 of the following (a+b): 
a.
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b.
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
The following are unacceptable forms of contraception for females of child-bearing potential:  
x
Female condom  
x
Natural family planning (rhythm method) or breastfeeding  
x
Fertility awareness  
x
Withdrawal  
x
Cervical shield 


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Females of child-bearing potential must have a negative serum pregnancy test ≤ 72 hours prior to 
initiating treatment. 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring must use a condom 
during treatment, and for 4 months after the last treatment dose of ublituximab and for at least 30 
days  after last treatment dose of umbralisib or venetoclax, and should not father a child in this 
period. 


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18 APPENDIX B – NYHA CLASSIFICATIONS 
New York Heart Association (NYHA) Classifications  
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective 
evidence 
of 
minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at 
rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective 
evidence 
of 
moderately 
severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may 
be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Objective 
evidence 
of 
severe 
cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 
1994:253-256. 
 
 


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19 APPENDIX C – HEPATITIS B SEROLOGIC TEST RESULTS 


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20 APPENDIX D – CYP3A INDUCERS, CYP3A INHIBITORS, P-GP 
INHIBITORS AND P-GP SUBSTRATES 
Examples of clinical inhibitors for P450-mediated metabolisms 
Strong Inhibitors 
Moderate 
Inhibitors 
Weak Inhibitors 
CYP3A 
boceprevir, 
cobicistat, 
conivaptan, danoprevir and 
ritonavir, elvitegravir and 
ritonavir, grapefruit juice, 
indinavir 
and 
ritonavir, 
itraconazole, ketoconazole, 
lopinavir 
and 
ritonavir, 
paritaprevir and ritonavir 
and 
(ombitasvir 
and/or 
dasabuvir), 
posaconazole, 
ritonavir, saquinavir and 
ritonavir, 
telaprevir, 
tipranavir 
and 
ritonavir, 
troleandomycin, 
voriconazole 
aprepitant, 
cimetidine, 
ciprofloxacin, 
clotrimazole, 
crizotinib, 
cyclosporine, 
dronedarone, 
erythromycin, 
fluconazole, 
fluvoxamine, 
imatinib, 
tofisopam, 
verapamil 
chlorzoxazone, 
cilostazol, 
fosaprepitant, 
istradefylline, 
ivacaftor, lomitapide, 
ranitidine, ranolazine, 
tacrolimus, ticagrelor 
Examples of clinical inducers for P450-mediated metabolisms 
Strong Inducers 
Moderate 
Inducers 
Weak Inducers 
CYP3A 
carbamazepine, 
enzalutamide, 
mitotane, 
phenytoin, 
rifampin, 
St. 
John’s wort 
bosentan, 
efavirenz, 
etravirine, 
modafinil 
armodafinil, 
rufinamide 
Examples of clinical substrates for transporters 
Transporter 
Substrate 
P-gp 
dabigatran, digoxin, fexofenadine 
Examples of clinical inhibitors for transporters 
Transporter 
Substrate 
P-gp 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, 
ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
verapamil